JPS62138448A - Production of 3-oxaisocarbacycline compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound having natural-type steric configuration, high chemical stability and strong pharmacological activity in high stereoselectivity, by hydrating a 1,2,3-trinor- <4>-isocarbacycline compound having natural-type steric configuration and reacting the hydrated product with a haloacetic acid. CONSTITUTION:The compound of formula I [R<21> and R<31> are tri-hydrocarbon- silyl or group forming acetal bond together with O of OH; R$4 is H or methyl; R<5> is alkyl, alkenyl, phenyl, etc.; steric configuration at 15-site is configuration of formula II when R<4> is H and (R) and/or (S) configuration when R<4> is methyl] is subjected to hydration reaction, preferably hydration reaction consisting of hydroboration reaction and subsequent oxidization reaction to obtain a 1,2,3- trinor-4-hydroxyisocarbacycline compound of formula II having natural-type steric configuration. The compound is made is made to react with the compound of formula III (X is Cl, Br or I; R<11> is H, alkyl, phenyl, etc.) in the presence of a base to obtain the objective compound of formula IV in high stereoselectivity.

Description

[Detailed description of the invention]

Technical Field> The present invention relates to a method for producing 3-oxanecarbacyclines having a natural configuration and a method for producing 3-oxanecarbacyclines VC having a natural configuration. More specifically, 1,2,3-t U true Δ- having the natural configuration
112+3-)' which has a natural configuration obtained by subjecting incarbacyclines to a water addition reaction.
) /R-4-Hydroxyisocarbacycline@I/
C-hapacetic acids are reacted in the presence of salt crystals, and then, as necessary, depolymerization and/or hydrolysis reaction and/or esterification reaction and/or salt formation reaction are performed to convert the natural configuration to 1. 15 Methods for constructing 3-oxanecarbacyclines and the resulting 3-oxisocarbacyclines #AK
It is related to <Prior art> Natural prostacyclin is a ms factor that regulates functions in the living body, and attempts are being made to provide it directly as a medicine [P.J. Lewis, J.O. Grady (P.J. ,J,Lewfs+J
, 0. Grady) et al. @Clinical Pharmacology (CNn1cal Pharma-eology)
of Proatacyelin) ”RavenPress + N, y, l 19
81). However, natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, so it is easily deactivated under neutral or acidic conditions, and is therefore not a desirable compound for pharmaceutical use due to its chemical instability. . For this reason, chemically stable synthetic prostacyclin derivatives that have physiological activities similar to natural prostacyclin have been intensively investigated at home and abroad. Among them, derivatives in which the 6,9-position oxygen atoms of prostacyclin are substituted with methylene groups, ie, 9(0)-methanoprostaglandin I! (carbacyclines) [G.R. Vane et al., @ boostacyclines (P
rostacyclin) ” + Lapen Press (
Raven Press) + N, Y, 1979.
PP3l-41] and 9(0)-6(9α) meta/-Δ-prostaglandin, (incarbacyclines) (%KOKAI Publication No. 59-210044, etc.), the chemical stability of which was determined by optical spectroscopy. It is known as a booster cycline that satisfies people's needs and is expected to be used as a drug. By the way, 9(O)-methanoprostaglandin I,
9(0)-methano-3-oxaprostaglandin 1, in which the methylene group at the 3-position of (carbacyclines) is substituted with an oxygen atom, (3-oxacarbacyclines) are derivatives that improve the in vivo lifespan of carbacyclines. It has been reported as
7-145833, etc.). 9(0)-methano-purustabrangin II C carbacyclines 2-2
Compounds in which one bond is reduced to form a 1311iB combination] 9(0)- in which the methylene group at the 3-position is replaced with an oxygen atom
Methanol-3-oxaprostaglandin L#t has also been reported (Patent Publication No. 92255/1983), but this is thought to be 314I11 for the expression of prostacyclin activity.Δ or Δ6(9a) double Has no bond. 9(0)-methano-Δ6(9a)-prostaglandin I, 3-oxisocarbacyclines in which the methylene group at the 3-position of (incarbacycline) is substituted with an rR atom also has a % opening of 11@60- Although it is described in Publication No. 181041, it is ranked 8th, 9th, and 11th in Korichaka.
A synthetic method for obtaining only optically active isomers in which positions 1, 12, and 15 all have the natural configuration, and 8, 9, and 1
1st place. Optical 3-oxine carbacyclines in which both the 12th and 15th positions have a natural configuration are not explicitly described, nor is 3-oxinecarbacyclines having a methyl group at the 15th position. 3-thiainecarbacycline/a in which the methylene group at the 3-position of incarbacyclines is substituted with a sulfur atom is described in %Kokai No. 60-181041. <Object of the Invention> Among the above-mentioned 3-oxanecarbacyclines, the 8th and 9th positions are particularly useful. Optically active isomers with natural configurations at positions 11, 12, and 15 were synthesized stereoselectively. The present invention was achieved by discovering that 3-oxisocarbacyclines having such a natural configuration are chemically stable and have strong pharmacological activity. <Configuration of the Invention> That is, in the present invention, 1+2+3-trinor-Δ4-incarbacyclines having a natural configuration represented by the following formula CI] are subjected to a water addition reaction to form a natural product represented by the following formula (11). 1,2,3-tri/-4-hydroxyisocarbacyclines having the following configuration were obtained.
・・・・・・・・・Haloacetic acids represented by [■1] are reacted in the presence of a base, and according to necessity 11, defamation and/or hydrolysis reaction and/or esterification reaction and/or salt formation are performed. A method for producing 3-oxanecarbacycline having a natural configuration represented by the following formula is provided. In the above formula (Il and the above formula (11), 1 prefecture and R'' are the same or different, and are tri(C, -(lq) hydrocarbon silyl group, or form a 7-cetal bond with the oxygen atom of the hydroxyl group) )!j (c, ~q) Examples of hydrocarbon silyl groups include trimethylsilyl and triethylsilyl.

[such as -butyldimethylsilyl group] Li(C, ~C,
) alkylsilyl, di(C, to C1)furkylphenylsilyl such as dimethylphenylsilyl group. t --j Diphenyl (such as tyldiphenylsilyl group)
Preferred examples include C, -C,) alkylsilyl, triphenylsilyl, and tribenzylsilyl groups. Particularly preferred are t-butyldimethylsilyltrimethylsilyl and triethylsilyl groups. Groups that form a 7-secyl bond with the oxygen atom of a hydroxyl group include 6 such as methoxymethyl, 1-ethoxyethyl,
2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl. Mention may be made of the (3,1,0)hex-4-yl group in 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-o. Among these, 2-tetrahydropyranyl, 2
-tetrahydrofuranyl group is particularly preferred. The above formula [Engine], the above formula (II) and the above formula ([%')
In R4 represents a hydrogen atom or a methyl group. In the above formula [I], the above formula [■] and the above formula (IV), IC is a straight chain or branched chain C, which may contain an oxygen atom, ~C1° alkyl crystal; a straight chain or branched chain C
, -C,, alkenyl group; straight chain or branched chain ct''
+Qo alkynyl crystal; optionally substituted Q~C1
6sicI: +furkyl group; optionally substituted phenyl group; optionally substituted phenoxy group; or t!
A phenyl group which may be substituted with @ chain or branched chain C1-C amed with phenoxy group or C8-CIO cycloalkyl group. Represents an alkyl group. Straight chain or branched chain C8~ which may contain an oxygen atom
The CIO alkyl group is 2-methoxyethyl+2-ethoxyethyl, propyl, butyl. Pentyl, hexyl, heptyl, octyl, decyl, 1
-Methylpentyl, l-methylhexyl, 1.1-dimethylpentyl, 2-methylpentyl, 2-methylhexyl, 5-methylhexyl, 2.5-dimethylhexyl, etc., preferably butyl, pbutyl , hexyl, ■- or ■]- or (R8)-1-methylpentyl, @- or (1- or (R3)-
Examples include 2-methylhexyl group. ~C5° alkenyl group is 2-butenyl group. Examples include 2-pentenyl group, 3-pentenyl group, 2-hexenyl group, 4-hexenyl group, 2-methyl-4-hexenyl group, 2,6-cymethyl-5-hebutenyl group, and the like. The Cs-CIO alkynyl group is 2-butynyl. 2-pentynyl, 3-bentynyl, 2-hexynyl
3-hexynyl/I/I 4-hexynyl, 2-octynyl, 5-decynyl, 1-methyl-3-pentynyl,
Examples include l-methyl-3-hexynyl and 2-methyl-4-hexynyl groups. Examples of the Cs-''-C8o cycloalkyl group, which may be substituted, include cyclopropyl crystal, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group,
Cyclooctyl group, (C1-C,)alkylcyclopentyl M, (C,-c4)alkylcyclohexyl group, dimethylcyclopentyl group, dimethylcyclohexyl group, chlorocyclopentyl group, bromocyclohexyl group, iodocyclopentyl group, fluorocyclohexyl crystal, etc. are mentioned, preferably a cyclopentyl group or a cyclohexyl group. Examples of substituents for the optionally substituted ~C3 cycloalkyl group, the optionally substituted phenyl group, and the optionally substituted phenoxy group include halogen atom, hydroxy group, ct~C, acyloxy IQ, /%G
7 C optionally substituted with a gun atom, -C, furkyl group, no log/CI~C4 optionally substituted with an atom
Flukoxy^, nitrile crystal, carboxyl group or (C,
~q) Alkoxycarbonyl group and the like are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of acyloxy groups include acetoxy, propionyloxy, n-butyryloxy, 1so-butyryloxy+n-valeryloxy,
Examples include 1so-valeryloxy, KabuG-(ruoxy, enantyloxy or benzoyloxy). Examples of C1-q alkyl crystals which may be substituted with halogen include methyl, ethyl, n-propyl +S
Preferred examples include OS bupyl, n-butyl, chloromethyl, dichloromethyl, trifluoromethyl and the like. ) C optionally substituted with
6-C, as a flukoxy group. For example, methoxy, ethoxy, n-propoxy. Igo-pσboxy, n-butoxy, chlormethoxy,
Preferred examples include cyclomethoxy and trifluoromethoxy. As a (C, ~C,) alkoxycarbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, phthoxycarbonyl, hexyloxycarbonyl, and the like. Substituted phenyl group or substituted phenoxy group. It can have 1 to 3, preferably 1 substituent as described above. Optionally substituted phenyl group, phenoxy crystal, C5
A-Cto cycloalkyl group-substituted phenyl group or phenoxy crystal that may be substituted in the Zhizhen or Bun & Miao C+~C, fulkyl crystal, the above-mentioned ones can be suitably mentioned as they are. . As the C5-C3゜cycloalkyl group, the above-mentioned ones can be suitably used as they are, and the straight chain or branched @C+~C, furkyl group includes methyl, ethyl, propyl + 1so-propyl, butyl + 1110-butyl, Examples include 5ec-butyl, t-butyl, and pentyl crystals. The substituent may be bonded at any position thereof. In the above formula [u1], R” is a woody atom + C1 to cI
0 Alkyl group - substituted or unsubstituted phenyl group. Substituted or unsubstituted C8-C5° cycloalkyl group. Represents a substituted or unsubstituted phenyl (C1-C,)furkyl group. Examples of the alkyl crystals of 01 to Cl11 include methyl, ethyl, n-gouvyl, and 1so-propyl. n-butyl, formula -butyl, tert-butyl + n-pentyl, n-hexyl, n-hegtyl + n-octyl,
Examples include linear or branched ones such as n-nonyl and n-decyl. Examples of substituents for substituted or unsubstituted phenyl groups include halogen atoms and hydroxy groups. C, C, acyl group, Q-Q alkyl group optionally substituted with a halogen atom, C3-C, flukoxy group optionally substituted with a halogen atom. A nitrile group, a carboxyl & or (C, -(4) flukoxyl group), etc. are preferred.As a halogen atom, fluorine, chlorine or bromine, etc. are particularly preferred.Fluorine or chlorine is particularly preferred.As a C1-q acyloxy group, 1, for example, acetoxy , propionyloxy, n-butyryloxy+ 111
0-butyryloxy, n-valeryloxy + tSO-
Mention may be made of valeryloxy, caproyloxy, enantyloxy or benzoyloxy. Examples of the C3-C, furkyl group which may be substituted with halogen include methyl ethyl + n-propyl, 1so-
Preferred examples include bouvyl, n-butyl, pp-methyl-dichloro-p-methyl, and trifluoromethyl. 01-C may be substituted with Hapgun
4 As an alkoxy group, 1 such as methoxy, ethoxy+
n-propoxyrjso-propoxy, n-butoxy. Preferred examples include pρmethoxy, chloromethoxy, and trifluoromethoxy groups. ,
Examples of the (C, to C,)alkoxysulfonyl 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 C5-CI0 dichlorofurkyl groups include saturated or unsaturated C5-C, preferably C5-Q groups 1, for example cyclofurkyl, substituted with the same substituents as mentioned above or unsubstituted. Provil, cycloglutinyl, cyclohexyl. cyclohexenyl, cycloheptyl, cyclooctyl,
Can you name cyclodecyl, etc.? Examples of the substituted or unsubstituted phenyl (C, -C,) alkyl group include benzyl, α-phenethyl, and β-7enethyl, in which the phenyl group is substituted with the same ml18 group as mentioned above, or unsubstituted. Let it go. In the above formula [river], X represents a chlorine atom, a bromine atom or an io:A atom, preferably a bromine atom. In the above formula (IV), R1 is a hydrogen atom IC, ~C+
o alkyl1. Substituted or unsubstituted phenyl group. Substituted or unsubstituted C1-CIO cycloalkyl represents a substituted or unsubstituted phenyl (C, to C,) alkyl crystal, or 1 equivalent of a cation. C3-C11,
Furkyl group, substituted or unsubstituted 7-enyl group, substituted or unsubstituted (4""' CIO dichlorofurkyl group,
Specific examples of substituted or unsubstituted phenyl (C, ~C,) alkyl crystals are the same as R'' in the above formula (Ill). Examples of 1-equivalent cations include EbaN1-J+, tetramethyl7ammonium- Seven methyl ammonium, dimethyl seven ammonium, trimethyl ammonium, benzyl ammonium. Anomonic cations such as phenethyl ammonium, morpholinic cation/, monoethanol ammonium, piperidinium cation; alkali metal cations such as Na + K; 1 /2C is +. Examples include divalent or trivalent metal cations such as 11/2Mg", 1/2Zn", and 1/3A/'+. A cation of C, ~Qs alkyl & or 1 equivalent is preferred. In the above formula (IV) Ic, ■σ and ■e are the same or different, and are a hydrogen atom, ) U (C, -C,) hydrocarbon silyl group, or Water 1! Represents a group that forms an ateptal bond or an ester bond with the oxygen atom of 1.) !I (C, -C?) Hydrocarbon silyl &. Forms a 7-cell bond with the oxygen atom of the hydroxyl group The preferable groups are the same as those listed for the above formula [+n]+7)It''. Examples of groups that form ester bonds with the acid atoms of the water tg group include formyl, acetyl, and propionyl groups. Examples include (C, -q)alkanoyl crystals such as butameyl crystals and pentanoyl groups; substituted or unsubstituted benzoyl groups such as benzoyl groups and tolyl groups. Among these R1 and R3, a hydrogen atom, an L-guthyrunmethylsilyl group, a tetrahydropyranyl group, and a 7-cetyl group are particularly preferable, and a hydrogen atom is more preferable. In the above formula (Z), when R' is a hydrogen atom, the configuration at position 15 represents the natural configuration vIL represented by the following formula (1-1), and when 1c4 is a methyl group, (
15R)-configuration + (15S)-configuration and mixtures thereof in any proportion. Similarly, when the configuration at the 15th position in the above formula [13 and R4 is a hydrogen atom, the natural configuration represented by the following formula (II-1) is represented.
When R4 is a methyl group, (15R)-configuration, (15S)-
configurations and mixtures thereof in arbitrary proportions. Similarly, in the above formula (IV), the configuration at position 15 is 1l
When j4 is a water IA atom, it represents the natural configuration represented by the following formula (% formula %), and when R4 is a methyl group, it represents the (15R)-configuration, (15S)-configuration, and any proportion thereof. The stereochemistry at positions 8, 9, 11 + 12 of the compound represented by the above formula CI), (In and [!V]) represents a mixture of natural prostacyclin, so KWK is a useful stereoisomer. In the present invention, stereoisomers due to different configurations at each position are not included, but they can also be easily synthesized by the same method. 11 having the natural configuration represented by the above formula CI]
213-)! By subjecting J true Δ-incarbacyclines to a water addition reaction, 1,2,3-trinor-4-hydroxyincarbacyclines having the natural configuration represented by the above formula (II) are obtained. It will be done. The water addition reaction is the usual 2! Any reaction that adds a water molecule to a bond can be used (1+* Experimental Chemistry Course. Volume 14, Synthesis and Reactions of Organic Compounds CI) 497-507
Page, edited by the Chemical Society of Japan, Maruzen et al.) is particularly preferred, and a water addition reaction using a hydroboration reaction followed by an oxidation reaction is particularly preferred. The hydroboration reaction and subsequent oxidation reaction can be carried out in a conventional manner [Organic Reacti
ons) + Vol, 13Chapter l
+John Willie and Sons'
iley&5ona) + Inc+ New Yo
rk+ 1963, etc.). Hydroboration reagents include dicyamylporan, 9-polaviscic a (
Dialkylporanes such as 3,3,1) nonane (9-BBN), dicyclohexylporane, diimpinocamphenylporan, catecholphorane, dihalophora/etc. are suitable. % dialkylporane is preferably used. As the oxidizing agent used in the oxidation reaction following the hydroporation, hydrogen peroxide, trimethylamine oxide, air oxidation, etc. are preferably used. The amount of hydroboration E drug used in the hydroboration reaction is 1.
2.3-trinor-4,5-dehydroin 0.5 to 30 equivalents, preferably 1 to 5 equivalents relative to carbacyclines
It is equivalent. The reaction temperature at this time is -78°C to 50°C, preferably -0°C to temperature. The reaction time is 10 minutes to 20 hours, preferably 30 minutes to 3 hours. The reaction is usually carried out using tetrahydrofuran, diethyl ether,
Ether solvents such as diglyme and triglyme are preferred, and tetrahydrofuran is particularly preferred. The alkylporane produced by the hydroboration reaction is usually not isolated, but is oxidized by adding an oxidizing agent directly to the reaction system, and is led to the alcohol represented by the above formula (11). When using hydrogen peroxide as an oxidizing agent, a base such as sodium hydroxide is used at the same time. Hydrogen peroxide solution can be used at any concentration, but one with a concentration of around 3096 is generally used. The amount of hydrogen peroxide used for convenience is 0.5 to 50 equivalents, preferably 3 to 10 equivalents, relative to 1,2,3-trinor-4,5-dehydroin lupacyclines. Sodium hydroxide can be used as a solid or as an aqueous solution, but generally an aqueous solution of 1 to IO normal strength is used. The amount used is 0.5 to 50 equivalents, preferably 3 to 10 equivalents. The reaction temperature at this time is θ°C to 100°C, preferably 40'C to 70°C. The reaction time is 5 minutes to 5 hours, preferably 20 minutes to 1 hour. When trimethylamine oxide is used as an oxidizing agent, usually L2,
3-)') Use 0.5 to 50 equivalents, preferably 3 to 10 equivalents, relative to the true delta incarbacyclines. The haloacetic acids represented by the above formula (I) were added to the thus obtained 1,2,3-t!J true Δ-incarbacyclines having the natural configuration represented by the above formula (Il). By reacting in the presence of a base and optionally subjecting to deretention and/or hydrolysis reaction and/or esterification reaction and/or salt formation reaction, the natural configuration represented by the above formula CIV) is achieved. - Oxisocarbacyclines can be obtained. !, 2.3-) dinor-4- represented by the above formula (II)
Hydroxyisocarbacyclines and the above formula (ill)
The anti-L6 reaction with hekuchi vinegar #R expressed by is carried out by the usual alcohol fullkylation reaction method (New Experimental Chemistry Course Vol. 14-IP567-P572. Edited by the Chemical Society of Japan,
(See Maruzen). A base is usually used in this reaction, and examples of the base include sodium hydride, potassium hydride, sodium 7mide, butyllithium, sodium hydroxide,
Potassium hydroxide, sodium t-butoxide, potassium t-butoxide, etc. are preferably used, but other substances that act as a base can also be used. The amount of the base used is (15 to 50 equivalents, preferably 1 equivalent to 1 equivalent to) O equivalent relative to 1,2,3-trinor-4-hydroxyincarbacyclines.
The amount of 1 in the octa-acetic acids represented by (lit) is 0.5 to 50 equivalents, preferably 1 to 10 equivalents, relative to 112.3-trinor-4-hydroxyincarbacyclines. The reaction temperature at this time is 0°C to 200°C, preferably 20°C.
The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 3 hours. The reaction is usually carried out in a solvent, and the reaction solvents used include nonaqueous 1% solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; ethereal solvents such as tetrahydrofuran, diethyl ether, and dimethoxyethane. : Benzene-based solvents such as benzene, toluene, and xylene are ideal. In order to make the reaction proceed smoothly, among the above-mentioned solvents, water-soluble hydroxides such as sodium hydroxide and potassium hydroxide in a two-layer bath medium of water and a solvent that do not mix with water and form two layers are used. However, the reaction can also be carried out in the presence of a phase transfer catalyst. As the phase transfer catalyst used here, for example, those listed in the following book can be used (Compendium Otsu Phase - Transfer Reactions and Related Synthesis Catalysts)
m of Phase-Transfer Reac
tions andRelated 5yntheti
c Ms + thoda; Water E Keller (W
alterE, Keller) 'if,
FIukaAG, CH-9470Buchs +
5w1tzarland; 1979]. Among them, ia hydrogen tetra-butylammonium, tetra-n-butylammonium iodine, isodyltriethylammonium chloride, etc. are preferably used. The reaction mixture obtained by the above reaction can be isolated using general separation means such as silica gel column chromatography, silica gel thin layer chromatography, high-performance liquid crystal column chromatography, and recrystallization after a normal extraction operation. I can do this. The product thus obtained can be further subjected to a deprotection reaction and/or a hydrolysis reaction and/or an esterification reaction and/or a salt formation reaction, if necessary. Removal of the protecting group of the hydroxyl group (removal of purulence) is carried out using 1, for example, acetic acid + p-toluenesulfonic acid, pyridinium p-)rue / It is preferable to use sulfonate, cation exchange resin, etc. as a catalyst, and use water, methanol, ethanol, or tetrahydro-7rane, ethyl ether, dioxane, 7-setone, acetonitrile, etc. as a reaction solvent in the coexistence of water, methanol, ethanol, etc. will be implemented. The reaction temperature is generally -78°C to +50°C for about 10 minutes to 3 days. Horonki is a bird (C,
-C,) In the case of hydrocarbon groups, trapping is carried out in the reaction solvents described above at similar temperatures using an acid catalyst such as acetic acid, p-)pyridinium p-)luenesulfonate, or tetrabutyl Using fluorine-based test materials such as fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride-pyridine, tetrahydrofuran, ethyl ether, dioxane, and acetone. The reaction is more preferably carried out using 7cetonitrile or the like as a reaction solvent at the same temperature and for the same time period as above. The hydrolysis reaction of the 1st-position ester is carried out using a conventional method such as a water bath solution or a water-alcohol mixed solution of caustic powder, caustic potash, calcium hydroxide, or an alcohol containing sodium methoxide, potassium methoxide, or sodium ethoxide. This can be carried out by hydrolysis using a mixed solution of water. Alternatively, for example, using an enzyme such as lipase, the temperature can be increased from -10℃ to +10℃ in water or a solvent containing water.
It is carried out at a temperature range of 60° C. for 10 minutes to 24 hours. Post-treatment and purification after the hydrolysis PS reaction is carried out by conventional methods such as removing dilute salt and neutralizing the bales with an acid such as oxalic acid. The carboxyl group-containing compound produced by the above-mentioned hydrolysis reaction is then further subjected to a salt-forming reaction, if necessary, to yield the corresponding carboxylate. The salt formation reaction itself is known, and carboxylic acid is an equivalent amount of a basic compound such as sodium hydroxide, potassium hydroxide, or sodium carbonate, or ammonia, trimethylamine,
This is carried out by neutralizing monoethanolamine, morpholine, etc. using a conventional method. Carboxylate salts can also be obtained directly by hydrolysis reaction of the above esters. Esterification of a hydroxyl group is easily achieved by the usual method of reacting an acid anhydride or acid halide in the presence of a base, i.e., by reacting acetic anhydride, 7-cetylchloride, benzoylchloride, etc. with a base such as pyridine-triethylamine. (New Experimental Chemistry, Vol. 14-■, P100)
2-P4O10, edited by the Chemical Society of Japan, Maruzen @ # Teru). Isolation and purification of the compound is represented by the above formula [■] as described above. 1,2.3-) Sonoru-4-Hydroxyisocarbacyclines may be reacted with heliacetic acids represented by the above formula (ill), but deprotection reaction and/or hydrolysis reaction and/or ester After carrying out the chemical reaction and/or the salt forming reaction, conventional silica gel column chromatography, silica gel thin layer chromatography, 7aJ high speed liquid lipography. This may be carried out by using general separation means such as recrystallization. 11213- ) which has the natural configuration represented by the above formula CI) which is the raw material of the heather invention! 7-1 Incarbacyclines are represented by the following formula (V). Methylenation is easily produced by methylenating an aldehyde of an enal having a natural configuration. Wittig reaction used (Shinmi Ken Kagaku Koza, Vol. 14, No. 1, pp. 224-243. Edited by the Chemical Society of Japan, Maruzen@Oteru) Reagent reaction prepared from titanium tetrachloride-dibu p-momethane-zinc (z ru q
7 Bardo (L, Lombardo) + Tetrahedron Letters
s) + vol. 23, p. 14293,] 982; Takai et al., Tetrahedron Letters (Tet
rahedron Letters) + 1978
2417], etc.). The enals having the natural configuration represented by the above formula CVI can be obtained by a method known per se (T. Masa et al., Tetrahedron Letters) +
Volume 25, page 5087. 1984], it can be produced from allylcyclopentanones having a natural configuration represented by the following formula (Vl) through several steps. The natural allylcyclopentanone represented by the above formula (Vl) with mv:h is. The method separately proposed by the present inventors, that is, the (4R)-4-human p xishic ρ bentenones (when R21 is t-butyldimethylsilyl crystal, [α]D-+67° (Co, a, MeO
H) ) K Allyl chlorocarbonate reaction is performed on the enolate produced by conjugate addition of a lithium compound represented by the following formula [■] and an organocopper reagent that is whisked from a copper compound such as iodide hook p pentyne copper or thiophenyl steel. 7
Decarburize the lylic carbonate ester by reacting with a palladium compound such as tetrakistriphenylphosphine palladium! !
I! Obtained by 7-lylation (I! #Kaisho 5
(See Publication No. 9-44336, etc.). The present invention further provides 3-oxanecarbacyclines having the natural configuration represented by the above formula (IV). W in the above formula ([V). The configurations of u'' + pt'', R' + it' and the 15th position are as described above. Preferred specific examples of the 3-oxane carbacyclines having the natural configuration provided by the present invention include the compounds shown below. 6(9α) 111 9 (0)-methano-Δ -3-oxaprostaglandin I. +21 20-) -F-/l--9(0) -) l
/ -Δ6(9a' -3-oxaprostaglandin 11 +31J6-methyl-9(0)-methano-Δ6(9a)
-3-Oxaprostaglandin. (4) (31 (16R) integral 151 +31 (168) integral 161 16.16-cymethyl-9(0)-methanol△
6(9")-3-oxaprostaglandin!1 (7117-methyl-9(0)-methano-muro(9")
-3-Oxaprostaglandin 11 f81 17120 9) + Le9(0) -Meta/-Muro(9''-3-Oxaprostaglandin I. (9+) (17R) integral part of +81 (17S) ) Integral α11 15-) Chill-9 (0) -) Evening/-1,
6(9a' -3-oxaprostaglandin 11 α3 αυ's (15R) 03 all's (158) <14 17+18 f HiF q 9(0)
) Yu/b"9a'-3-oxaprostaglandin. α920-implubiritene-1fumethyl-9(0)
-Methano-Δ6(9a) 3-Oxasubμ staglandin Il αG 18.18,19.19-Tetratrue+:+
-16-methyl-9(0)-methano-Δ6(9a)
3-Oxaprostaglandin 11 αη 18.18, 19.19-tetrahydro-16,
20-dimethyl-9(0)-methano-muro(9a)
3-Oxaprostaglandin. (1 & Q4) , Gel/) (16S ) body QIQ
41. 4-16 (R) body-16,17,18,19,20-pentanol-15-
Cyclobenru9(0)-methano-Δ6(9a)
3-Oxaprostaglandin 11 (21) 16.1? , IL19,20-pentanol-15-cyclohexyl-9(0)-mechnorΔ6 (
9a) -3-Oxaprostaglandin. (22) 17.18, 19.20-Tetra True 1
6-(p-fluorophenoxy)-9(0)-methano-Δ6(9a) 3-oxaprostaglandin 11
(23) 17.18.19.20-Tetra True 1
6-Cyclobenru9(0)-Mek/-△6(9a)
3-Oxaprostaglandin I. (24) Methyl ester of flll~(23) (25)
Ethyl ester of (11-(23) (26) +1+
t-methyl ester of ~(23) (27) ill~(
23) Sodium salt (28) tlr-(23) Potassium salt (29) +1+~(28) 11.15-bis-(t-butyldimethylsilyl)ether (30) (o~(28) 11 .15-bistetrahydropyranyl ether (31) fil to (28) 11.15-diacetate (32) (1) to (28) 11115-dipenzoate, etc., but are limited to these. It is well known that among prostaglandin compounds, compounds with natural configuration exhibit higher catalytic activity than mixtures with isomers with non-natural configuration. For example, in the case of prostaglandin compounds, isomers with a configuration different from the natural configuration not only have almost no physiological effect, but also may cancel out the effects of the isomer with the natural configuration, greatly attenuating the effect. is known. (K, C, N1col
aou) et al., Prost sp.
aglandins) + vol. 16, p. 789. 1978]. Therefore, the QJi method of the present invention, which allows isomers having the natural configuration 1 to be extracted in pure form, and the 3-oxanecarbacyclines having the natural configuration of the present invention, are known as follows. (3-oxanecarnocyclins σ, which are mixtures with isomers such as enantiomers that differ from the natural configuration)! It is very useful compared to Method A and 3-oxanecarbacyclines which are mixtures of natural stereochemistry and isomers such as the i45 enantiomer. 3-oxanecarbacyclines having the natural configuration represented by the above formula C[], especially 3-oxanecarbacyclines having the natural configuration in which Re and Rs are hydrogen atoms. -Oxanecarbacyclines have prostaglandin-like activities such as anti-platelet aggregation and vasodilatory effects. They are platelet aggregation inhibitors in LQli mammals, including humans. They are useful for the treatment or prevention of thrombus formation. They are also useful as therapeutic agents for hypertension because they have a blood pressure lowering effect.
Anti-endotoxic shock, anti-pulmonary arterial hypertension, anti-stroke, anti-transient ischemic attack (tra)
scientific attack)
+Anti-platelet aggregation effect Can be administered for cancer, anti-deep vein thrombosis or anti-peripheral vasculopathy. Also,
The active compounds of the invention can also be administered to inhibit malignant fibrillation or metastasis of malignant tumors. The compounds of the present invention are. It could also be used as an antithrombotic system during organ transplantation, vascular surgery or extracorporeal circulation. Furthermore, these compounds have cell-protective effects and are effective in the treatment and prevention of liver disorders, kidney disorders, brain disorders, diabetic ulcers, etc. Hereinafter, the present invention will be explained in more detail with reference to Examples. Reference example (il (il+methyltriphenylphosphonium bromide 900119 (2,5
mmo/ ) and potassium t-butoxide 338 m
g (3.06 mmo/) was added to the flask, the flask was purged with nitrogen, cooled with water, and 16 lj of dry tetrahydrofuran was added. After stirring the yellow colored suspension at room temperature for 40 minutes, 1+2
+3.4+5-pentanol-5-formyl-9(0)-
Methanol-Δ6(9a)-boostaglandin I, 11.
A solution of 960 mg (1.9 mmo/) of 15-bis-t-butyldimethylsilyl ether (compound (1)) in tetrahydrofuran (8a) was added, and the mixture was stirred at room temperature for 40 minutes. Add n-hexane (40 Jlj) and saturated ammonium chloride F6 solution (25317), and vacuum with Celite.
After 1 minute, the solution was washed with q-). After re-extracting water 1- with n-hexane, the combined Ichiki layer was mixed with dilute hydrochloric acid, saturated sodium bicarbonate solution,
After washing with saturated brine for 1 m, it was dried over magnesium sulfate and the solvent was distilled off. The desired crude product was purified by silica gel column chromatography, resulting in 2X ethyl acetate-
1.2 of 886# (yield 92%) was added to the n-hexane elution part.
．． 3-trinor-9(0)-methano-Δ4'6(9a)
-Prostaglandin I, 11.15-bis-t-butyldimethylsilyl ether [Compound (11)] was obtained. NMR (67 items): 0-71-0 (21H) + 2.7-3.3 (IH9b
r). 3.72 (IH9q + J=8k) 13.8-4
．． 1 (IH+br). 4.75.2 (2H+m), 5-35.6 (3R1m
). 6.50 (IHldd; J=18tlz, 10 mouths 2
)IR(λ””+cl!-”) :ax 1260.1110.970,900,835,775
Mass (EI, m/e): 504 (M”
), 4471tJ to obtain the following compound. (17S)-1,2,3-trinor-17,20-dimethyl-9(0)-mecnorme4+6 (9a)
-Prostaglandin 1,11.15-bis-t-butyldimethylsilyl ether NMR (δCD hook): MS 0.7-1.0 (24H), 2.7-3.3 (IH
,br). 3, 54.3 (2H + m) + 4.75.2 (2H
+rn). 5.3-s, 7(3H+m)+6.51(IH, dd
; J=1811z+10Hz)IR(2ne”+cr
n”): ax 1110.967.835,775 Mass (El, m/e): 532 (M”), 475
(17R)-1,2,3-)sonoru 1f, 20-di)
9-k -9(0) -/l/-mu""9a'
-7'c:z Slgrandin I, II, 15-bis-1-butyldimethylsilyl ether NMR (δC1) CJ, 21'MS 0.7-1.0 (24H), 2-7-3 .3(1)i
,br). 3.5-4.3 (2H+m), 4.7-5.2 (2H
, m). 5.3-5.7 (3H, m), 6.50 (IH, dd
; J=1811z,]IJIIz)neat-1 1R(λ,a): 1llX 1258111101965,)137,775Mas
s (EI, m/e): 532 (M+), 475i
, 2.3-+ sonoru 16-methyl-9(0)-methanome 4.6(9a)-prostaglandin L 11
+15-bis-t-butyldimethylsilyl ether CD
C1a): NMR (δTMSO,71,0(24H)+2.73.3(IH+b
r). 3.5-4.3 (2H, m), 4.7-5.2 (2H
, m). 5, J-5,6 (3H9m) + 6.51 +
IH, tici ; J==l 8Hy, ] 0Hz)
I R (1"at, (:ll+-') : ax 1252.968.835.772 Mass (EI, m/e) : 518 (M+)
, 4611.2, 3116, 17.18, 19.20
-Tatanol-15-cyclopentyl-9(0)-methanome4.6(9a)-Prostaglandin I, 111
15-bis-t-7' til dimethyl ether bL-NMR (δCDCJs): MS 0.7-J, 0 (18H), 2.7 3.3 (IH+
br) +3.5-4.0 (2H, m), 4.7-5
．． 3 (2H, m). 5.3-U, 7 (3H, m), 6.50 (IH, dd;
J=18&, lO[z)IR(2neat, 3-1
): ax 1258.1112,968,835,775Mass
(EI +m/e): 502 (M”), 4451.2.
311fj, 17118. IL2 (+-octanoru1
5-Cyclohexyl-9(O)-methano-Δ4.6+9
“)-Prostaglandin 1. 11.15-bis-t
-Methyldimethylsilyl ether NMR (δCDCIIm): MS 0.7-1.0(18H)+ 2.73.3(1)i,
br)-3,5-4,0(2H,m), 4.7-5.
3 (2H, mL + 5.3-b, 7 (31, m) s 6
．． 51 (IH+dd; J=18Hz, ]0tlz)I
R(2neat, c-+a'): aX 1256.1112,967.835,775Maag
(El, m/e): 516 (M+), 4591.
2.3-) Linol-15-methyl-9
(0) -Memenome 4.6(9")-Prostaglandin ■111.15-bis-t-butyldimethylsilyl ether CI)CRs) : NMR(δTMs 0.7-1.0(2H+m)+1. 20 (3H1s)
+2.7-3.3 (IH, br), 3.5-4.0
(IH, m). 4.7-5.3(2H+m)+s, 3-5.7(3
H, m). 6.50 (IH, dd, J=18■Z, 10Hz)I
R(λne&t+cm-'): aX 1257.1110.967.13:15.775Ma
ss (EI, m/e): 518 (M+) + 461 Example 1 1.2.3-) Re/ Rou 9(0) -1 Ta/
-Δ””9a'-Prostaglandin I, 11. J5-
Bis-t-butyldimethylsilyl ether [Compound (I
i) ) 1 m(2) of 504119 was bath-deposited on dry tetrahydrofuran (5 caps), purged with nitrogen, cooled on ice, and then purified with 0.0 m of 9-polavisic+-(3,3,1]nona7 (9-LIBN). 5M tetrahydrofuran #j solution 3a was added and stirred for 2rgf under water cooling. Then 5N hydroxide) IJ
Add 11Lt of hydrogen peroxide solution and 1m of hydrogen peroxide solution to
The mixture was heated and stirred at 50 to 60°C for 30 minutes. Water (20V) was added, and after extraction with ethyl acetate (2×30μ), the organic layer was washed with saturated brine and dried over magnesium sulfate. 1!6
After distilling off the solvent, the residue was purified by silica gel column chromatography, and 433M9 (yield: 839) of 1.2.3-)dinol-4-hydroxy- was found in the 5X ethyl acetate-n-hexane eluate. 9(0)-methano-△6(9a)
-Prostaglandin I, 11.15-t-butyldimethylsilyl ether (compound (+i+)) was obtained. NMR (δC is 3): MS O,71,0(21H)I2.73. J(IH+br)
. 3.5-4.3 (4H7m) + 5.2-5.7 (3
H9m) IR (A ``at+CIR'): +nax 3350.1255.11!2,1002.972°8
35, 775 Mass (El, m/e): 522 (M+
) + 504 + 465 The following compounds were obtained in the same manner. (17S)-1,2,3-trinor-4-hydroxy-17,20-dimethyl-9(0)-methano-muro(9
a)-Prostaglandin I, 11.15-bis-1-
Butyldimethylsilyl ether CDα,) NMR (δ'l' IVI S 0.7-1.0 (24H), 2.7-3.3 (IH
,br). 3.5 4.3(4H+m)+5.2 5-7(3
H+m)I R(2neat, C11-'): na
x 335011255.1110,1004.970°8
35.775 Mass (h:I, m/e): 550 (M+), 53
2,493(17R)-1,2,3-)dinol-4-
Hydroxy-17,20-dimethyl-9(O)-methano-Δ6(9a)-prostaglandin I, 11115-
Bis-t-7'tyldimethylsilyl ether NMR (δCDα3): MS 0.7-1.0 (24H), 2.7-3.3 (IH, b
r). 3.5-4.3 (4H+m), 5.2-5.7 (3H+
m) IR(””t+3-1): nla! 3370.1252.1112,1002,970°8
35.775 Mass (EI, m/e): 550 (M→-), 532
,4931.2.3-)su/ru-4-hydroxy-16
-Methyl-9(0)-methano-Δ6(9a)-prostaglandin I, 11115-bis-t-7'tildi, methylsilyl ether methane in st6 δSt \ 0.7-1.1 (24H), 2.7-3.3 (IH,b
r). 3.5 4.2(4H, m>+ 5.2-5.7(3
H9m) I R(2ne"+5311-') ax 3380 .1255.1112+1004 .970
+837.777 Mass (EI +m/e): 536(
M+), 5]8. 479112.3116. ]]7.
18,19.20-octule-15cyclobenti-4-hydroxy-9(0)-methano-muro(9(X)
-Prostaglandin 1,11゜15-histo-t-gtyldimethylinyl ether NMR (J CLl"): MS O-71,0 (18H) + 2.7-3.J (IHL)
br). 3.5-4.1(4H+m)+5.2-5.7(3
11+m)1R(A ''+G11') :ma
X 3360.1255. Ill2.1UO2,972°8
37.775 Mass (El +lTl713):52(IfM
+)+502.4631.2.3,15.16,17.
18,19.20-year-old ctano-15-cyclohexyl-4-hydroxy-9(0)-methano-Δ6 (9a
) - Prostaglandin ■. If, 15-bis-L-butyldimethylsilyl ether NMR (δ(:DC13,. T~tS 0.7-1.0 (18H), 2.7-3.3 (IH,
br). 3.5-4.2 (4H, m) + 5.2-5.7 (3H
, m) IR (l neat, cIRl): maX 337011255.1112110001968°8
35.975 Mass (EI +m/ @): 534(M+)+
51b+4771.2.3- Trinor-4-hydroxy-15-methyl-9(0)-MeknoΔ6(9a)-
Prostaglandin I, 11135-His-t-
-j tildimethylsilyl ether NMR (δCDα1): MS 0.7-1.0 (21H, m), 1.20 (3H, s
). 2.7-3.3(IH+br)+3.5-4.0(3
H+m)+5.2-5.7(3H,m) (R(2neat,,-1): nax 338011256.1112,970,836°Ma
ss (EI +m/e): 536 (M+) + 18
1479 (Ill)
(IV) Sodium hydride (539 oil dispersion) 13019 (2.9 mmol) was washed with pentane under a nitrogen atmosphere and made cloudy with KM in 7 l of dry dimethylform. 1,2.3-) Reflow 4
-Human ρoxy-9(0)-methano-Δ6(9a)-prostaglandin I, 11.15-bis-1-butyldimethylsilyl ether (compound (Ill)) 300 Da (0.58 mmo/ ) Dry dimethylpolamide solution (11 Lt) was added and stirred at room temperature for 30 minutes. t-Butyl bromoacetate 470μA' (2,9m
After stirring at room temperature for 6 hours, saturated ammonium chloride solution #4 (203114) was added, and ether (2
X20JIj). The combined single layer was sequentially washed with an aqueous potassium hydrogen sulfate solution, 4 parts water, and 1 part brine, and then dried over magnesium sulfate, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography to yield n-hexane-ethyl acetate (99:1 to 98:2).
) Elution part IC81119 (yield 229) 9(0) −
)p/-Δ6(9")-3-oxaprostaglandin I, -butyl ester 11.15-bis-t-butyldimethylsilyl ether (compound (IV)) was obtained. NMR (δCDCIs): MS 7-7-1-0 (21H) + 1-46 (9H1a)
+2.7-3.3 (11Lbr), 3.4-4.3 (
6H, m). 5.2-5.7 (3H+m) Mass (EI+m/e): 636 (M+), 579 The following compounds were obtained in the same manner. (17S)-17,20-dimethyl-9(0)-Δ
6 (9a) a-oxaprostaglandin I,
t-Butyl ester 11.15-bis-t-butyldimethylsilyl ether 5i07tsH♂jn. NMR (δCDα・): MS 0.7-1.1 (24H), 1.43 (9H, s)
. 2.7 3.3 (IHlbr), 3.4 4.3 (6H
9m) +5.2-5.7 (3H, m) Mass (El, m/e): 664 (M+), 60
7(17R)-17,20-dimethyl-9(0)-methano-Δ6(9a) 3-year-old xabrostaglandin 1
1t-Butyl ester 11.15-bis-t-7' thyldimethylsilyl ether NMR (δCD (J): MS Ll, 7-J, 1 (24H), 1.44 ('JH,
s). 2.7-: 1J (HLbr), 3.4--+, 3(
6H, m). 5.2-5.7 (3H, m) Mass (El + m/e): 664 (M”) + 60
7] 6-Methyl-9(0)-methano-6M9a) 3
-Oxaprostaglandin I, t-butyl ester 11.15-bis-t-butyldimethylsilyl ether% ゝ, SiO7cSIQ riCDα, ) engineering NMR (δTMS 0.7-1.024H), ]. 42 (9H, s). 2.73.3 (IH+br) + 3.44.3 (6H9
m). 5.2-5.7 (3H, m) Mass (EI +m/e): 650 (M”), 593
16.17.18,19.20-pentanol-15-cyclopentyl-9(0)-mekno△6(9a) 3
-Oxafrostaclandin I, t-phthyl ester 1
1.15-bia, -t-butyldimethylsilyl ether NMI (δCDα·): M S 0.7-1. H1811) + 1.43 (91”l+s
)+2.7-3.3(IH,br)+3.4-4.3
(4) 1+m)+J, 92(2H,s)+5.25
．． 6(3H+m)I R(2neaL+3-1): 118X 1755.2555,972,835,775Mass
(El, ryI/e): 634 (M+), 577.5
6516.17,18. l'J, 20-pentanol-1
5-Cyclo to *shiru 9 (0)) evening/-mu”9a)
-3-f Xaprustabrandin I, t-butyl ester 11.15-His-t-butyldimethylsilyl ether NMR (δCL) C1,. MS 0.7-LH]8HL 1.44 (911,a). 2.73.3(lH+br)+3. s 4.3 (6H
, mL5.2-5.7 (3H, m) Mass (EI +m/e): 648 (M") +
591.56515-) f Roux 9(0)-) Evening/-△"9a'-3-Oxaprostaglandin I
, t-butyldimethylsilyl ether NMR (δCC10: TMS (1,71,0(21H1m), 1.20(3H+s
)+1.44+9H9s)s 3.7-J, 3(IH
lbr). 3.5-4.3 (51Lm), 5.2-5.7 (3H,
m) Mass (EI + m/e): 1i50
(M+), 593 Example 3 (nl) (v) Perform the same operation as in Example 1 except for using methyl bromoacetate instead of t-butyl bromoacetate under the conditions of Example 10. By this, 9(0)-methano-Δ6(9a)-3-oxab-ρ staglandin I
, methyl ester 11. IS-bis-t-butyldimethylsilyl ether (compound (V)) was obtained. NMR (δC: TMS 0.7-1.0 (21H), 2.7-3.3 (IH,
br). 3.4-4.3 (6H, mL 3.66 (31118)
15.2-5.6 (3H, m) 10) Mass (EI, m/e): 594 (M, 537
The following compounds were obtained in the same manner. It = (/CH1Y to 7\CHs [Compound (V-1)) Hl = I, CH\7 to 7. (Compound (V-
3> )=+−Q (compound tv
-4))(178)-17,20-dimethyl-9(0)
-Methano-Δ6(9")-3-year-old xabrostaglandine, methyl ester 11.15-bis-t-7' tyldimethyllinyl ether [Chemical 1 (product (V-1)) (,:
1) C1, NMR (15TMs 0.7-1.024H), 2.73.3 (IH+br)
. 3.4-4.3((iH,m), 3.69(3H,a)
. 5.2-5.7 (3H, m) Mass (EI, m/e): 622 (M”), 565
(17R)-17,20-dimethyl-9(O)-methano-86(Qa) 3-oxabrostaglandin I,
Methyl ester 11.15-bis-t-butyldimethylsilyl ether (compound (V-2'))): NMR (δTMS 0.7-1.1 (2411), 2.7-3.3 (
L) I, br). 3.4-4-3(6H+rn), 3.68(3)1. s
). 5.2-5.7 (3H, m) Mass (EI +m/e): 622 (M+1
, 56516-methyl-9(0)-'tanome 6(9a
)-3-oxab p-staglandine, methyl ester/
11゜15-bis-t-butyldimethylsilyl ether (compound (V-33) N MR (a CDCl, s): Mb 0.7-1.024H), 2.7-3.3 (LH, b
r). 3.4-4.3 (6H, m), 3.69 (3H, s)
. 5.2-5.7 (3H, m) Mass (El, m/a): 608 (M+), 5511
6.17.18,19.20-pentanol-15-cyclopentyl-9(0)-methano-6(9a) 3-
Oxab p-staglandine, methyl ester 11゜l
s-His-1-butyldimethylsilyl ether [Compound (V-4)) CDC1s ・NMR (δ ] 6 MS 0.7-1.0(18H), 2.7-:(,3(l)
H, br). 3.4-4.2 (6H, m), 3.68 (3H+a)
+5.25.7+3H+m) Mass (EI, m/e): 592(M+
), 535,52316.17.1L19120-pentanol-16-cyclohexyl-9(0)-methanol-Δ
6(9")-3-oxaprostaglandin 11 methyl ester 15-bis-t-gutiline methylsilyl ether (compound (V-5)) CuO. NMR (δ): MS 0.7-1.0 ( 18H), 2.7-3.3(lH+
br). 3.4-4.2 (6H, m), 3.67 (3H, s)
. 5.2-5.7 (3H, m) Mass (EI tm/e ): 606 (M+), 5
49.52315-methyl-9(0)-methaneme fi
(9a): s-oxaprostaglandin 1, methyl ester 11115-bis=t--j tildimethylsilyl ether [Compound (V-6)) NMR (a CD''): MS 0.7-1.0 ( 21H,m), 1.20(3H,s
). 2.7-3.3(HLbr)+ 3.44.3(5H+
m)+3.67(3H,s), 5.2-5.7(3H
+rn) Mass (El +m/e): 608 (M+)
, 551 Example 4 (IV) (Vl)9(0)-methano-Δ6(9″)-3-year-old xabrostaglandin 1
1t-Butyl ester 11.15-bis-t-gutiline methylsilyl ether [Compound (IV)) 190~
(0.3 ml) was added with 1.5 mL of a solution of tetra n-butylammonium fluoride in IM-tetrahydrofuran, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of 7-72tam chloride (12 g) was added, and ethyl acetate (2X2011
After extraction with j), the organic ltI was washed with saturated negative brine, then dried over magnesium sulfate. When the residue obtained by distilling off the solvent was purified by silica gel column coomadography, 9(0) of 105 my (yield: 54 sa circles) was found in the eluate of vinegar-modified ethyl-n-hexane (1:1 to 1:3). -methano-
Δ6(9″)-3-oxaprostaglandin I, t
-butyl ester (compound (Vll) was obtained. NMR (δCDCl5): MS 0.7-1.0 (3H), 1.43+9)I, s). 2.7-3.3(IH+br), 3.4-4.2(
4H, m) +3.92 (2H9s) + 5.2-5.
7(3H,m)IR(J”at): ax 3400.1750.1140,9fj8Mass (
E I, m/e): 390 (MH, 0)
+346 The following compound was obtained by applying the same pressure. (178)-17,20-dimethyl-9(0)-mero(
9 Red g) Tanome-3-oxaprostaglandin I,
t-Butyl ester Hδ HO Mountain CDCL. NMR (δ): MS 0.7-1.1 (6H, m), 1.43 (911, s
). 2.7-3.3 (IH, br), 3.4-4.2 (4
1Lm). 3.9] (2H + a) + 5.2-5.7 (311, m
1IR(λnejL ax 3400.1750,11:(8,970Mass(E
I, m/e): 418 (M-11,0), 374 (]
7R)-17,20-dimethyl-9(0)-methane-△
6(9a) a-Oxaprostaglandin■1t-
Butyl ester NMlt (δCDCJ: ′l″Mδ 0.7 1-1-1 (Lili1+ 1.43<9H
,s). 2.7-3.3 (11 I, brl+J, 44.2 (4)
11m>. 3.92 (2H, s), 5.2-5.7 (3H, m
)neat・IR(λ)・ax 3400.1750.1138.968Masa (E
I, m/e): 418 (MH, 0), 3
7 416-Methyl-9(0)-methano-Δ6(9a)
3-Oxaprostaglandin I, t-glutyl ester 110 OH NMR (CD Tsuru): MS 41.7-1.1 (6H+m), 1.43 (9H
,5)+2.7-d,3<IH,brB 3.4-4
．． 2 (4JLn+3+!1.93(2)1+s),
5.2-5.7 (3H, +n) Mass (El
, m/e): 404 (M-H,0
) + 36 016+17+18+I9+20-
Hair f/Rue 15-cyyμbenthyl-3-oxaclostaglandin I. t-Gutyl ester Hδ Mu NMR (-〇1): MS 1.43 (9H, s), 2.7-3.3CIH*br
)+3.4 5.2(4H+rn>+ 3.92(
2Hrs) +5, 2-5, 7 (3kl +m)
I R (J ne", c, -"): maχ 3400.1750+1138.966.840Mas
s (EI + m/e): 388 (M-Bti
), 344.33216.17118119.20-pe7ri/R15-cipRhexyl-9(o)-mek/
-Muro(9")-3-oxabrostaglandine, t
-Butyl ester OH NMR (δCDCl, . MS 1.43 (iJH,s), 2.7-3.3 (]H+b
rL3.4-5.2 (4H, m), 3.91 (
2H, s) +5, 2-5.7 (3H, m) Mass (EI +m/e): 402 (M-H, 0) +
35815-methyl-9(o)-methano-Δb (9
a) -3-3-oxaprostaglandin I, t
-Butyl ester 0.7-1.0(3H,m)>1.20(3H,s
). 1.43(9H+g), 2.7-:(,3(IH9br
L3.4-5.2 (3H+mL 3.93(2)1,
8)+5.2-5.7+3)1. s) Mass (EI I m/e): 404 IM
-HP○), 31i0 & Example 5'') (Vll) 9(0)-Meta/-Δ6(9a) -3-Oxaprostaglandin 11th methyl ester, 15-bis-t-
Butyldimethylsilyl ether [compound (ψ)] was desilylated under the same conditions as in Example 3, and 9(0),...
, 6 (9ct) 3-oxaprostaglandin 11
Methyl ester [compound (Vll)] was obtained. CL) C1C1 1JN (δ): MS O, 71,0 (3H1bt +J"5tlz), 2.
7-3.3 (IH9br) +3.4 4.3 (6)
ilmL 3.66 (3H1s) + 5.2-5.7 (
3)1. m) Mass (EI+m/e): 348 (M-HI3) 13
04 Similarly, obtain the following compound: HO6H R=(/CH to/ν to CH, (compound@compound(vu-1))δ
8flu=l/CHC compound (vn-3)) (178)-17,20-dimethyl-9(O)-methano-Δ6(9")-3-oxab p-staglandine, methyl ester (compound (Vll-11 )CDα, ),
. NMIL(δTMS 0.7-1.0(6H+m)+2.7-3.3(IH
+br)+3.4-4.3(6H+m)+3.67
(3H+s)+5, 2-5, 7 (3HlIn)
Mass (EI, m/e): 376 (M
-11,0) ,332(17R) -17,20-
') Methyl-9(0)-methano-Δ6(9a) 3-
Oxaprostaglandin 11 methyl ester [compound (Vll-2)) NMR (δCDCjLs); MS 0.7-1.0 (6fLm), 2.7-3.3 (IH
,br). 3.4-4.3(6H+m)+3.68(3H,s)
+5.2-5.7 (3H, m) Mass (El, m/e) : : (76 (M-
H,O), 33216-methyl-9(0)-methano-Δ6(9a)-3-oxaprostaglandin 11
Methyl ester [Compound (vu-3)] NMR (δCDCJL!): MS 0.7-1. H6H+m), 2.7-3.3(IH+
br)+3.44.3(6H+m)13-69(3H9
s). 5.25.7 (3H+m) Mass (El, m/'e): 362 (M-H, 0)
, 31816117.18,19.20-pentanol-15-cyclohexyl-9(0)-) l/-L
, 6(9a'-3-oxaprostaglandin 11 methyl ester [compound (U-4)) CL)CQs NMI also (6): MS 2.7-3.3 (IR, hr), 3.4 −4.2(
6Lm)+3.68(3H+s), 5.2-5.7
(3H, m) Mnsa (EI, m/e): 3
46 (M-H, (J), 30216.17.18 +
] 9+ 20-pentanol-15-cyclohexyl-
9(0)-Methano-Δ6(9a) 3-oxaprostaglandin 11 methyl ester (compound (vu-51
) CDα. NMR (δ): 'L'MS 2-7-J, 3 (IH9br) + J-44, 2 (6H
9rn). 3.68 (3H+s), 5.2-5.7 (3H, m)
Mass (El + m/e): 402CM-H,Q
) +35615-) Chill-9(U)-)l/-Δb
(9a)-3-Oxaprostaglandin 11 thyl ester [Compound (vl+-6)) CDα. NMR (δ): MS O, 71.0 (3H9m)+1.21 (3H+s). 2.7-3.3 (IH, br) + 3.4-4.3 (5
1Lm). 3.69 (3H, s), 5.2-5.7 (3H, m)
Mass (EI, m/e): 362 (
M-MtO), 31 B Example 6 (Vl) (VlN) 9(0)-methanol-Δb(9a) a-oxaprostaglandin I, t-butyl ester [Example Section] 56 N (0,
14 mmol) was dissolved in methanol (1.51 Lj), 0.5 ml of 1N sodium hydroxide water bath solution was added, and the mixture was stirred at room temperature for 3 hours. Methanol was purified under reduced pressure, water (1
0517) and ethyl acetate (10ml) and stirred] Normal hydrochloric acid was added to make the aqueous layer acidic.The aqueous layer was extracted again with ethyl acetate (15V), and the combined organic layers were washed with saturated brine. It was ILL dried with red sea bream sium sulfate. When the residue obtained by distilling off the solvent was purified by silica gel column chromatography, 9(
0)-Methanomuro(9a) 3-oxaprostaglandin I, (Compound (Vll):] 39 Ik
g (yield 803+61 was obtained. NMR (11Cvα3): 1'MS O, 71,0 (JH, bt-J"5LIz) + 2.
7-3.3 (IH+br). 3.4-4.3<6H,rn), 5.3-5.7(3
1Lm) IR (2neat, -1): ax 3380.2800-2300.1725, 1128°Mass (FDtm/e): 353 (M+1), 3
35 was treated in the same manner to obtain the following compound. HOδ□ R=(/CHsゝ?heno\CHs (compound Ql(
vu+-1)]δruHsR=IyCHNha/(Compound (Vllll-3))
f7=1-0 (compound (vm-4
)) (178)-17,20-dimethyl-9(0)-MekunorΔ6(9a) 3-Oxaprostaglandin I. [Compound (vm-1)] NMR (to δ0): MS 0.7-1.1 (6H, m), 2.7-3.3 (IH
,br). 3.5-4. :(((iH, m>, 5.3-5.7(3
H+m) 11 ((λ0e11t, cIn-1): nax 3390.2) 100-2300.1728, 1128
゜Mass (FD, m/e) 2381 (M+1), 36
3(171ζ)-17,20-dimethyl-9(0)-methano-muro(9cr)-3-oxaprostaglandin I. (Compound (Vlll-2)) NMR (δCDC1a): MS 0.7-1. H6H,m), 2.7-3.3(11
1,br). 3.5-4.3 (6H9m), 5.3-5.7 (3
H,m)ZR(2neat,c,]): ax 338(1,2800-231)0. 1 728.
1 1 28. Masa (t'L), m/e): 3
8] (M + 1 3, 36, j
16-Methyl-old 0)-methano-muro(9a) 3
-Oxaprostaglandin 1. (Compound (Vllll
-3>) NMR (a CD”): MS 0.7-1.1 (6H, rn) + 2.7-3.3 (I
H,br)t3.5-4.3(6H,m), 5.3-
5.7 (31Lm) neat -1. IR(λ +c11)-ax 3380, Sl+00-2300+1728,
l 128 +Mass (F”D, m/e)
: 367 (M+1)16.17,18. I9.2
U-pentanol-15-cyclopentyl-9(0)-mecnorme 6(9α)-3-oxaprostaglandin L
(Compound (Vlll-4)) NMR (J CDc
): MS 2.7-3.3 (IH, br), 3.5-4.3 (6
H, m). 5.3-5.7 (3H, m) I R (2neat+3-”): ax 3380.2800-2300.1728.1128゜Mass (FD+m/e): 351 (M+1), 333
16+J7+18+19+2 (1-be/Tafuru 15-
Cyclohexyl-9(0)-methano-Δ6(9a)
3-oxaprostaglandin II (compound (Vll
-5)) NMR (aCD''): MS 2.7-3.3 (IH, br), 3.5-4.3 (
6H, m) +s, a-5,7 (3H+m) I R (2neat+(m-') : mJL! 3380.2800-2300.1730.1130°Mass (FD, m/e): 365 (M+
1), 34715-methyl-9(0)-methano-Δ
6(9a) 3-oxaprostaglandin I,
(Compound (Vlll-6)) C8 NMR (δ): MS O,7J,O(3H1m), 1.21 (3klts). 2.7-3.3 (IH, br), 3.5-4.3 (5
H, mL5.3-5.7 (3H, m) I R (2neat, alM-1): naX 3380.2800-2300.1727,968Ma
ss(PL), m/@): 367 (M+1)
Example 7 The in vitro platelet aggregation JK inhibitory effect of the test mulberry was assayed using rabbits. That is, blood was collected from the ear vein of a Japanese American white-breasted rabbit weighing 2.5 to 3.5 mm at a ratio of 90 to 3.8 circles of trisodium citrate bath solution.
After centrifugation for 0 rpm, the upper layer is PIζP (platelet-rich plasma).
It was set aside as Lower part is Sara K 2800rpm
After centrifugation for 10 minutes, the upper layer, which was disposed of in two layers, was separated as PPP (platelet poor plasma). Platelet count is fiX10
'/μl 1) Diluted with PP 1AJl t. Add 25 μl of tested mulberry to 250 μl of adjusted PRP and mix 37
ADP 1μ after 2 min preinguation at °C.
Add M (final) and measure xt with an acribometer!
Excessive 0) changes were recorded. The test drug was dissolved in ethanol to a concentration of 10~/V, and then dissolved in phosphate buffer (
It was used after being diluted sequentially at pH 7.4). The aggregation inhibition rate was determined using the Ac formula below. I! I11@rate (9) = (1--)XI 00'r
0 'ro: (') Excessive reaction of the acid buffer solution addition system) 'L': Excessive reaction of the test drug addition system) I C ，
. Shown as a value,
-Oxaprostaglandin I, XC of the compound (Vlll-4>) of (Example 6). The value is 9.2 nl
/111. In addition, prostaglandin f, (
)'Gr,) has an rcSo value of 5.4 ny/ILt.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼…………[I] [In the formula, R^2^1 and R^3^1 are the same or different, Represents a group that forms an acetal bond with a tri(C_1 to C_7) hydrocarbon silyl group or the oxygen atom of a hydroxyl group, R^4 represents a hydrogen atom or a methyl group, and R^5 represents a straight group that may contain an oxygen atom. Chain or branched C_1-C_1_0 alkyl group; straight-chain or branched C_2-C_1_0 alkenyl group; straight-chain or branched C_2-C_1_0 alkynyl group; optionally substituted C_3-C_1_0 cycloalkyl group; even if substituted It represents a phenyl group that may be substituted; or a phenyl group that may be substituted; a straight chain or branched C_1 to C_5 alkyl group substituted with a phenoxy group or a C_3 to C_1_0 cycloalkyl group; When R^4 is a hydrogen atom, the configuration at position 15 is the configuration shown by ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and when R^4 is a methyl group, it is the (R) configuration. (S) represents a configuration and a mixture thereof in any proportion. ] 1,2,3-trinor-Δ^4-isocarbacyclines having the natural configuration represented by are subjected to a water addition reaction to form the following formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼… ......[II] [In the formula, the definitions of R^2^1, R^3^1, R^4, R^5 and 15th position are the same as the above definitions. ] 1,2,3-trinor-4-hydroxyisocarbacyclines having the natural configuration represented by the formula [III] are obtained, and then the following formula [III] [In the formula, X represents a chlorine atom, a bromine atom, or an iodine atom, R^1^1 is a hydrogen atom, C_1 to C
Represents a _1_0 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C_3-C_1_0 cycloalkyl group, or a substituted or unsubstituted phenyl (C_1-C_2) alkyl group. The following formula [IV] is characterized by reacting haloacetic acids represented by ] in the presence of a base, and subjecting it to deprotection and/or hydrolysis reaction and/or esterification reaction and/or salt formation reaction as necessary. ▲There are mathematical formulas, chemical formulas, tables, etc.▼………… [IV] [In the formula, R^1 is a hydrogen atom, C_1 to C_1_0 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C_3 to C_1_0 cycloalkyl group,
Represents a substituted or unsubstituted phenyl (C_1-C_2) alkyl group or 1 equivalent cation, R^2 and R^3 are the same or different, a hydrogen atom,
Represents a tri(C_1 to C_7) hydrocarbon silyl group or a group that forms an acetal bond or an ester bond with the oxygen atom of a hydroxyl group, and the definitions of the steric configuration at the R^4, R^5 and 15th positions are the same as the above definitions. be. ] A method for producing 3-oxisocarbacycline having a natural configuration represented by: 2. The method for producing 3-oxisocarbacycline having a natural configuration according to claim 1, wherein the water addition reaction is a hydroboration reaction followed by an oxidation reaction. 3. The following formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼…………[IV] [In the formula, R^1 is a hydrogen atom, C_1 to C_1_0 alkyl group substituted or unsubstituted phenyl group, substituted or unsubstituted C_3-C_1_0 cycloalkyl group,
Represents a substituted or unsubstituted phenyl (C_1-C_2) alkyl group, or 1 equivalent of a cation, R^2 and R^3 are the same or different, a hydrogen atom, a tri(C_1-C_7) hydrocarbon silyl group, or a hydroxyl group represents a group that forms an acetal bond or ester bond with an oxygen atom, R^4 represents a hydrogen atom or a methyl group, and R^4 represents a hydrogen atom or a methyl group;
^5 is a straight chain or branched chain C_1 to C_1_0 alkyl group that may contain an oxygen atom; straight chain or branched chain C
_2~C_1_0 alkenyl group; straight chain or branched chain C
_2 to C_1_0 alkynyl group; optionally substituted C_3 to C_1_0 cycloalkyl group; optionally substituted phenyl group; optionally substituted phenoxy group; or optionally substituted phenyl group, phenoxy group, or Represents a straight chain or branched chain C_1 to C_5 alkyl group substituted with a C_3 to C_1_0 cycloalkyl group. In addition, when R^4 is a hydrogen atom, the configuration at position 15 is expressed as ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and when R^4 is a methyl group, it is expressed as (
R)-configuration, (S)-configuration and mixtures thereof in arbitrary proportions. ] A 3-oxisocarbacycline having a natural configuration represented by: 4. 3-oxisocarbacyclines having a natural configuration according to claim 3, wherein R^1 is a hydrogen atom, a methyl group, or a cation of one equivalent. 5. 3 having the natural configuration according to claim 3 or 4, wherein R^2 and R^3 are both hydrogen atoms.
-Oxisocarbacyclines. 6, R^5 is n-pentyl group, 1-methylpentyl group,
A 3-oxisocarbacycline having a natural configuration according to any one of claims 3 to 5, which is a 2-methylhexyl group, a cyclopentyl group, or a cyclohexyl group.