JPH08311022A - Prostaglandins - Google Patents

Abstract

PURPOSE: To obtain the subject new compound exhibition excellent antiethanol ulcer action, extremely weak platelet aggregation-suppressing action as a serious adverse effect and useful as a remedy and a preventive of ulcer. CONSTITUTION: A compound of formula I or its salt [R<1> is a (protected carboxy, a tetrazolyl, a (substituted) carbamoyl, etc.,; R<2> and R<3> are each H or an OH- protecting group; R<4> is H or a1-4C alkyl, R<5> is a (substituted) alkyl; a (substituted) alkenyl or a (substituted) alkinyl, etc.; A is an ethylene group, a vinylene group or an ethynylene group, etc.; m is 2; n is 2-5]. For instance, 4,9-dioxo-11α,15α-dihydroxy-16-phenoxy-17,18,19,20-tetranolprost-13(E)-enic acid methyl ester. The compound of the formula I is obtained by using a compound of formula II (R<2> a and R<7> are each an OH-protecting group) as a starting material, subjecting to Witting rearrangement, reduction and R<7> -deprotection to obtain a compound of formula III, then oxidizing and further deprotecting R<2> a , a necessary.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel prostaglandin or a salt thereof which selectively has an excellent antiulcer action.

[0002]

2. Description of the Related Art As prostaglandin derivatives having a carbonyl group on the α side chain, for example, the 6-oxo and 7-oxo compounds shown below are known to have antiulcer action and the like (Japanese Patent Application Laid-Open No. 2000-242242). 52-83524, JP-A-58-58
4762).

[0003]

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However, these compounds have an antiulcer action and a platelet aggregation inhibitory action at the same time, and the action is not sufficiently separated, so that they are not always satisfactory as desirable antiulcer agents.

[0005]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies for many years on the synthesis of a prostaglandin derivative and its antiulcer action, and as a result, have a carbonyl group at a specific position on the α side chain. The present invention has been completed by finding that the compound exhibits an excellent anti-ulcer effect and exhibits only an extremely weak inhibitory effect on platelet aggregation.

[0006]

The novel compound according to the present invention has the general formula

[0007]

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It has

In the above formula, R ¹ is an optionally protected carboxy group, a tetrazolyl group, an optionally substituted carbamoyl group, an optionally protected hydroxymethylcarbonyl group or an optionally protected hydroxy. A methyl group, R ² and R ³ are the same or different and each represents a hydrogen atom or a hydroxyl-protecting group, and R ⁴ is a hydrogen atom or C
_{1 to} C _{4 is} an alkyl group, and R ⁵ is an optionally substituted alkyl group, an optionally substituted alkenyl group (including a dienyl group), an optionally substituted alkynyl group or the formula -B. -R group [wherein with ^6, B is a single bond or an oxygen atom, a sulfur atom or an alkylene group optionally C ₁ -C ₆ also include a vinylene group (linear or branched), R ⁶ Represents an optionally substituted C ₃ -C ₁₀ cycloalkyl group, aryl group, heterocyclyl group or heteroaryl group. ], A represents an ethylene group, a vinylene group, an ethynylene group or a group having the formula —O—CH ₂ — or —S—CH ₂ —, m represents an integer of 2, and n represents 2 to Indicates an integer of 5.

The protecting group for the carboxy group of R ¹ is not particularly limited as long as it is a commonly used protecting group for the carboxy group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and n-. Pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n
A C ₁ -C ₁₀ alkyl group such as decyl;
_{3 to} C ₇ cycloalkyl group; aralkyl group such as benzyl, 4-bromobenzyl, benzhydryl; aryl group such as phenyl and naphthyl (the aryl group may have a substituent, and these may be substituted by C ₁ ~ C ₄ alkyl groups, C ₂ such as acetylamino, propionylamino
To C ₅ aliphatic acylamino group, benzoylamino, 4-
C ₁ -C ₄ alkyl such as methylbenzoylamino, 3-methoxybenzoylamino, 4-methoxybenzoylamino, 4-hydroxybenzoylamino, C ₁ -C
₄ is a benzoylamino group optionally substituted by alkoxy or hydroxy, a carbamoyl group, or a mono- or di-C ₁ -C ₄ alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl. ); A phenacyl group or a geranyl group may be mentioned, and a C ₁ -C ₁₀ alkyl group, an optionally substituted phenyl group or a naphthyl group is preferable.

Examples of the optionally substituted carbamoyl group for R ¹ include a carbamoyl group and a mono- or di-substituted carbamoyl group, and examples of the substituent include C ₁ -C ₄ which may be substituted. Alkyl group [(C ₁ -C ₄ alkyl group represents a straight-chain or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, and n-butyl, and the substituent is carboxy. Group, C ₁ -C ₄ alkoxycarbonyl group, hydroxyl group, phenyl group, etc.),
Hereinafter, the C ₁ -C ₄ alkyl group has the same meaning. ], An optionally substituted phenyl group such as phenyl, tolyl, an acyl group such as acetyl, trifluoroacetyl, benzoyl, or C ₁ -C such as methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and 4-toluenesulfonyl. ₄ alkane or arylsulfonyl group can be mentioned, but mono (optionally substituted C ₁ -C ₄ alkyl group) substituted carbamoyl group,
A carbamoyl group or a methanesulfonylcarbamoyl group, particularly preferably mono (optionally substituted C _1-
C ₄ alkyl group) A substituted carbamoyl group or a methanesulfonylcarbamoyl group.

The protective group for the hydroxymethyl group or hydroxymethylcarbonyl group of R ¹ or the protective group for the hydroxyl group of R ² or R ³ is not particularly limited as long as it is a commonly used protective group for the hydroxyl group, for example, acetyl, propionyl, Butyryl, isobutyryl, valeryl, benzoyl,
Aliphatic or aromatic acyl group C ₂ -C _5, such as naphthoyl; benzyl, 4-nitrobenzyl, aralkyl groups such as 4-methoxybenzyl; 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 4-methoxytetrahydropyran 5- to 6-membered cyclic heterocyclic group having an oxygen atom or a sulfur atom in the ring, which has or does not have an alkoxy group such as pyran-4-yl and 2-tetrahydrothiopyranyl as a substituent; methoxymethyl, methylthio Methyl,
A methyl group having an alkoxy group such as ethoxymethyl and benzyloxymethyl, an alkylthio group or an aralkyloxy group as a substituent; 1-methoxyethyl, 1
1-alkoxyethyl groups such as ethoxyethyl; trimethylsilyl, triethylsilyl, tri-n-propylsilyl, t-butyldimethylsilyl, diphenyl t-
Can be mentioned alkyl tri C ₁ -C ₄ or diaryl -C ₁ -C ₄ alkylsilyl group or trityl group such as butylsilyl, preferably a protecting group is a silyl group of hydroxymethyl group in R ^1, R ² and R ³
The protective group for the hydroxyl group of is a 2-tetrahydropyranyl group or 2
A tetrahydrofuranyl group.

The alkyl moiety of the optionally substituted alkyl group for R ⁵ is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, n-hexyl, n-heptyl, 1,1-dimethylpentyl, 1,1-dimethylhexyl, 1,1-dimethylheptyl, 2-methylhexyl, 2,6-dimethylheptyl, n-octyl, 1,
1,6-trimethylheptyl, 2-methyloctyl, n
-Nonyl, 2-methylnonyl, 2-ethyloctyl, n
- decyl, 2-methyldecyl or 2-ethyldecyl C ₁ -C may be mentioned alkyl groups of _12, such as, preferably an alkyl group having C ₃ -C _10, for example isopropyl,
n-butyl, isobutyl, t-butyl, n-pentyl,
Isopentyl, 1-methylpentyl, 2-methylpentyl, n-hexyl, n-heptyl, 1,1-dimethylpentyl, 1,1-dimethylhexyl, 2-methylhexyl, 1,1-dimethylheptyl, 2,6- Dimethylheptyl, n-octyl, 1,1,6-trimethylheptyl, 2-methyloctyl or 2-ethyloctyl group, more preferably n-pentyl, 1,1-dimethylpentyl, n-hexyl, 1, 1-dimethylhexyl,
It is a 1,1-dimethylheptyl, 2-methylhexyl or 1,1,6-trimethylheptyl group.

The substituent of the optionally substituted alkyl group, alkenyl group or alkynyl group of R ⁵ is, for example, a halogen atom such as fluorine, chlorine or bromine, or methoxy, ethoxy, n-propoxy, isopropoxy, n-.
A C ₁ -C ₄ alkoxy group such as butoxy can be mentioned, and a fluorine atom, a chlorine atom, a methoxy group or an ethoxy group is preferable.

The alkenyl moiety of the optionally substituted alkenyl group for R ⁵ is 1-butylvinyl, allyl, 2-propylallyl, 2-butenyl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl. Four
-Methyl-3-pentenyl, 1-methyl-4-pentenyl, 1,1-dimethyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 1-methyl -5-hexenyl,
1,1-dimethyl-5-hexenyl, 6-methyl-5-
Heptenyl, 1,6-dimethyl-5-heptenyl, 2,
6-dimethyl-5-heptenyl, 1,1,6-trimethyl-5-heptenyl, 6-methyl-5-octenyl,
2,6-dimethyl-5-octenyl, 6-ethyl-5-
Increase the alkenyl group of C ₃ -C _12, such as a nona-3,7-dienyl - octenyl, 2-methyl-6-ethyl-5-octenyl, 2,6-diethyl-5-octenyl, 3,8-dimethyl it can, preferably alkenyl groups C ₅ -C _10, for example, 1-Buchirubiniru, 2-propyl allyl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl 1
-Methyl-4-pentenyl, 1,1-dimethyl-4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-
Dimethyl-3-pentenyl, 5-heptenyl, 1-methyl-5-hexenyl, 1,1-dimethyl-5-hexenyl, 6-methyl-5-heptenyl, 1,6-dimethyl-
5-heptenyl, 2,6-dimethyl-5-heptenyl,
It is 1,1,6-trimethyl-5-heptenyl.

The alkynyl moiety of the optionally substituted alkynyl group for R ⁵ is, for example, propargyl or 2-
Butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 1-methyl-2-
Pentynyl, 1-methyl-3-pentynyl, 1,1-dimethyl-2-pentynyl, 1,1-dimethyl-3-pentynyl, 1,1-dimethyl-2-hexynyl, 1-methyl-3-hexynyl, 1, 1-dimethyl-5-hexynyl, 1,1-dimethyl-3-C ₃ ~ like octynyl
C ₁₀ alkynyl group may be mentioned, preferably C ₅
To C ₁₀ alkynyl groups such as 2-pentynyl, 3-pentynyl, 1,1-dimethyl-2-pentynyl, 1,1
-Dimethyl-5-hexynyl, 1,1-dimethyl-3-
It is a pentynyl or 1,1-dimethyl-3-octynyl group, more preferably a 1-methyl-3-pentynyl group.

Examples of the C _{1 to} C ₆ alkylene group (straight or branched) which may contain an oxygen atom, a sulfur atom or a vinylene group of B in R ⁵ include, for example, methylene, ethylene, methylmethylene, Trimethylene, dimethylmethylene, tetramethylene, 1-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,
1-dimethyl trimethylene, hexamethylene, oxymethylene (-CH ₂ -O-), oxy ethylidene (-C
_{(CH 3) H-O-)} , thiomethylene (-CH ₂ -S
-), methyleneoxy methylene (-CH ₂ -O-CH ₂
-), an arylene (-CH ₂ -CH = CH-) can be exemplified, preferably an oxygen atom or an alkylene group of good C ₁ -C ₄ contains a sulfur atom, such as methylene,
It is ethylene, methylmethylene, trimethylene, dimethylmethylene, oxymethylene, oxyethylidene or thiomethylene.

Examples of the optionally substituted C ₃ -C ₁₀ cycloalkyl group for R ⁶ include cyclopropyl and 1-n-
Pentyl cyclopropyl, cyclobutyl, cyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 3-
Propylcyclohexyl, 4-methylcyclohexyl,
Cycloheptyl, bicyclo [4.3.0] nonane-7-
Yl may have an alkyl group of C ₁ -C _6, such as adamantyl as substituents, which may be a condensed C ₃ be -C ₁₀
Examples of the cycloalkyl group include, preferably C ₅
To C ₁₀ cycloalkyl group, more preferably cyclopentyl group or cyclohexyl group.

The aryl group of R ⁶ includes phenyl, 4 and
-Hydroxyphenyl, 2-tolyl, 3-tolyl, 4-
Trilyl, 4-ethylphenyl, 2,5-dimethylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 3-n-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, Two
-Ethoxyphenyl, 3-methylthiophenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4
-Chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3,4-dimethylphenyl, 3-
Fluoro-4-methylphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, N-acetyl-2-aminophenyl, N-acetyl-3-amino Phenyl, hydroxy such as N-acetyl-4-aminophenyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, halogen atom, trifluoromethyl or nitrogen atom is C ₂ -C. _{5 A} phenyl group, a naphthyl group, or a biphenyl group, which may have 1 or 2 amino groups which may be substituted with an aliphatic acyl group as a substituent, may be mentioned, preferably C _{1 to} C ₄
Alkyl group, C ₁ -C ₄ alkoxy group, halogen atom or phenyl group which may be substituted with trifluoromethyl, more preferably methyl, ethyl, methoxy, fluorine atom, chlorine atom or trifluoromethyl. It may be a phenyl group.

Examples of the heterocyclyl group of R ⁶ include, for example, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidyl, morpholinyl, morpholino, a 5- or 6-membered heterocyclic group containing an oxygen, sulfur or / and nitrogen atom. Examples thereof include a cyclic group, and preferably a 2-tetrahydrofuryl group or 2
A tetrahydropyranyl group.

Examples of the heteroaryl group for R ⁶ include furyl, thiophenyl, pyrrolyl, imidazolyl,
An optionally condensed 5- to 10-membered cyclic aromatic heterocyclic group containing an oxygen, sulfur or / and nitrogen atom such as oxazolyl, thiazolyl, isoxazolyl, pyridyl, quinolyl and indolyl can be mentioned, but it is preferable. Is
It is a 2-thiophenyl group, a 3-thiophenyl group, a 3-indolyl group or a 1-imidazolyl group.

R ⁴ is preferably a hydrogen atom or a methyl group. A is preferably a trans-vinylene group. n
Is preferably 2 or 3.

Among the compounds of the present invention represented by the general formula (I), the compound in which R ¹ is a carboxy group can be made into a salt form, if necessary. Examples of such salt forms include salts of alkali metals or alkaline earth metals such as sodium, potassium, magnesium and calcium;
Ammonium salt; tetramethylammonium, tetraethylammonium, benzyltrimethylammonium,
Quaternary ammonium salts such as phenyltriethylammonium, methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, Salts of alkyl, cycloalkyl or aralkylamines such as ethylenediamine; heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine, pyridine, 1-methylpiperazine, 4-ethylmorpholine and their C's.
₁ salts of alkyl derivatives of -C _4; monoethanolamine, ethyl diethanolamine, may be mentioned 2-amino-1-amine salts including such hydrophilic groups as butanol.

The compound (I) of the present invention is α-, β
It can also be used by forming an inclusion compound with a host compound such as-, γ-cyclodextrin. In addition,
In the compound having the general formula (I), there are optical isomers based on the asymmetric carbon of the cyclopentane ring and its side chain or geometric isomers based on the double bond when R ⁵ is an alkenyl group. Therefore, when the compound having the above-mentioned general formula (I) is obtained as a mixture of these stereoisomers, each isomer can be obtained by separation and resolution according to a conventional method. In the general formula (I), mixtures of these optical isomers and stereoisomers are all represented by a single formula, but the scope of the present invention is not limited thereto.

In the general formula (I), preferred compounds include: 1) R ¹ is a carboxy group, a C ₂ -C ₁₀ alkoxycarbonyl group, an optionally substituted phenoxycarbonyl group, or naphthoyloxy. Carbonyl group, carbamoyl group, mono- or di-substituted carbamoyl group (wherein the substituent is
It is an optionally substituted C _{1 to} C ₄ alkyl group, a phenyl group or a methanesulfonyl group. ), A compound which is a hydroxymethylcarbonyl group or a hydroxymethyl group, 2) a compound in which R ² and R ³ are hydrogen atoms, 3) a compound in which R ⁴ is a hydrogen atom or a methyl group, 4) R ⁵ is fluorine Atoms, chlorine atoms or C ₃ -C ₁₀ alkyl groups which may be substituted with C ₁ -C ₄ alkoxy groups, C ₅ -C ₁₀ alkenyl groups, C ₅ -C ₁₀ alkynyl groups or formula-B A group having —R ⁶ (in the formula, B is a C _{1 to} C ₄ alkylene group which may contain a single bond or an oxygen atom or a sulfur atom, and R ⁶ is a C _{5 to} C _{10 group;}
Cycloalkyl group, heteroaryl group or C ₁ -C ₄
Is an alkyl group, a C ₁ -C ₄ alkoxy group, a trifluoromethyl group, a C ₂ -C ₅ aliphatic acylamino group or a phenyl group which may be substituted with a halogen atom. ), 5) A is trans-vinylene, 6) n is 2 or 3, 7) R ¹ is a carboxy group, a C ₂ -C ₁₀ alkoxycarbonyl group, which is substituted. Good phenoxycarbonyl group, naphthoyloxycarbonyl group, carbamoyl group,
A mono- or di-substituted carbamoyl group (the substituent is an optionally substituted C ₁ -C ₄ alkyl group, a phenyl group or a methanesulfonyl group), a hydroxymethylcarbonyl group or a hydroxymethyl group; R ² and R ³ are hydrogen atoms; R ⁴ is a hydrogen atom or a methyl group; R ⁵ is a fluorine atom, a chlorine atom or C ₁ -C
_A C _{3 to} C ₁₀ alkyl group which may be substituted with ₄ alkoxy groups, a C _{5 to} C ₁₀ alkenyl group, a C _{5 to} C ₁₀ alkynyl group or a group having the formula —B—R ⁶ (wherein , B
Is a C ₁ -C ₄ alkylene group which may contain a single bond or an oxygen atom or a sulfur atom, and R ⁶ is C ₅
To C ₁₀ cycloalkyl group, heteroaryl group, or C
Alkyl group of ₁ -C _4, a C ₁ -C ₄ alkoxy group, a trifluoromethyl group, C ₂ -C ₅ aliphatic acylamino group or a phenyl group optionally substituted with a halogen atom. ); A is a trans-vinylene group; a compound in which n is 2 or 3; 8) R ¹ is a carboxy group, a C ₂ -C ₁₀ alkoxycarbonyl group, a mono-substituted carbamoyl group or is substituted. Is also a phenoxycarbonyl group; R ² and R ³
Is R ^4, a hydrogen atom or a methyl group; There is a hydrogen atom R ⁵ is, C ₅ -C ₁₀ alkyl, C alkenyl group ₅ -C _10, alkynyl group, or the formula C ₅ -C ₁₀ -BR
A group having ⁶ (in the formula, B is a C _{1 to} C ₄ alkylene group which may contain a single bond or an oxygen atom or a sulfur atom, and R ⁶ is a C _{5 to} C ₁₀ cycloalkyl group; Heteroaryl group or halogen, trifluoromethyl, C
It is a phenyl group which may be substituted with _{1 to} C ₄ alkyl, C _{1 to} C ₄ alkoxy or C _{2 to} C ₅ aliphatic acylamino. ), A is trans-vinylene, and n is 3.

The above-mentioned general formula (I) obtained by the present invention
As the compound having, for example, the compounds described in Table 1 to Table 6 below can be mentioned.

[0027]

[Chemical 4]

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

[0033]

[Table 6]

Of the above-exemplified compounds, preferred compounds include compounds 7, 10, 11 and 12. Further, preferable compounds include 6, 10 and 1
Two compounds can be mentioned.

[0035]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) according to the present invention can be produced according to the following method.

[0036]

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[0037]

[Chemical 6]

[0038]

[Chemical 7]

[0039]

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[0040]

[Chemical 9]

[0041]

[Chemical 10]

[0042]

[Chemical 11]

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R
⁵ , m, A and n have the same meanings as described above, R
¹ _a represents an optionally protected carboxy group, a tetrazolyl group or an optionally protected hydroxymethyl group, R ¹ _b represents an optionally protected carboxy group, R ² _a , R ³ _a , R ⁷ and R ⁸ represent a hydroxyl-protecting group, A ′ represents a vinylene or ethynylene group, Y represents a hydrogen atom or a halogen atom, and p represents an integer of 2. A
The method is a method for producing compound (I).

The first step of Method A is a step of producing a compound having the general formula (III). The aldehyde derivative having the general formula (II) has the following two general formulas.

[0045]

[Chemical 12]

(In the formula, R ¹ _a and m have the same meanings as described above, and R ⁹ is C ₁ -C ₄ such as methyl and butyl.
Or an aryl group such as phenyl or tolyl, and M is an alkali metal such as lithium or sodium. This is achieved by reacting a Wittig or modified Wittig reagent having

The Wittig or modified Wittig reagent having the above-mentioned general formula (XXVI) or (XXVII) used in the reaction can be prepared by the following two general formulas in the presence of a solvent according to a conventional method.

[0048]

[Chemical 13]

(Wherein R ¹ _a , R ⁹ and m have the same meanings as described above, and X represents a halogen atom such as chlorine or bromine), and sodium hydride or potassium hydride is added to the compound. Alkali metal hydrides such as or sodium methoxide, sodium ethoxide, potassium t
alkali metal alkoxides such as ert-butoxide, alkali metal amides such as sodium amide, potassium amide, alkyl alkali metal such as n-butyl lithium, alkali metal dimethyl sulfoxide anion such as sodium dimethyl sulfoxide anion,
It can be obtained by reacting an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, or an alkali metal base such as an alkali metal carbonate such as potassium carbonate or sodium carbonate. As the solvent to be used, a solvent used in a general Wittig reaction is used without particular limitation, and examples thereof include ethers such as ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; thioethers such as sulfolane; benzene, toluene and hexane. Hydrocarbons such as: Dialkyl sulfoxides such as dimethyl sulfoxide; Fatty acid dialkylamides such as dimethylformamide, dimethylacetamide; Halogenated hydrocarbons such as dichloromethane, chloroform; Hexamethylphosphoryltriamide (HMPA) Examples thereof include phosphoric acid triamides; alcohols such as methanol and ethanol; water or a mixed solvent of two or more of the above solvents.

The reaction is also preferably carried out in an inert gas such as nitrogen, argon or helium. The reaction temperature is not particularly limited, and is usually from −10 ° C. to the reflux temperature of the solvent, preferably around room temperature. The reaction time varies depending on the reaction temperature and the like, but is usually 6 to 50 hours.

The starting compound (II) in this step is publicly known or can be easily produced according to publicly known methods (for example, RA Johson et al., J. Org. Che.
m ,. 45 , 1121 (1980)).

After completion of the reaction, the target compound of the Wittig reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, ice water is added to the reaction mixture, and then, if necessary, an acid treatment is performed, an organic solvent such as ether is added and extracted, and the obtained organic solvent layer is washed with water and dried. It is obtained by distilling off the solvent.

The second step is a step of producing a compound having the general formula (IV) and is accomplished by reducing the double bond of the α, β-unsaturated carbonyl group of compound (III).

The reaction in this step is not particularly limited as long as it selectively reduces the double bond of the α, β-unsaturated carbonyl group, but a catalytic reduction reaction is preferred. The catalyst used is, for example, palladium-carbon, platinum-carbon, rhodium-carbon, platinum oxide, RhCl (Ph
₃ P) ₃ etc. can be mentioned.

The solvent used is, for example, methanol,
Mention may be made of alcohols such as ethanol, hydrocarbons such as hexane, benzene, toluene or esters such as ethyl acetate. Reaction temperature is usually −
The reaction time is 30 ° C to room temperature, and the time required for the reaction is
It is 10 minutes to 2 hours, depending on the reaction temperature and the like.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is filtered off, the solvent is distilled off under reduced pressure, ice water is added, the mixture is extracted with a water-immiscible organic solvent, and the organic solvent is distilled off.

The third step is a step of producing a compound having the formula (V) by removing the hydroxyl-protecting group R ⁷ of the compound (IV), and the reaction depends on the nature of the hydroxyl-protecting group.

When the hydroxyl-protecting group is a lower aliphatic or aromatic acyl group, its removal is carried out by a usual hydrolysis or solvolysis reaction. The acid or base used in the general hydrolysis reaction or solvolysis reaction is used as the acid or base is not particularly limited, usually, for example lithium hydroxide, sodium hydroxide,
It is preferably carried out under basic conditions using alkali metal and alkaline earth metal hydroxides such as potassium hydroxide, calcium hydroxide, barium hydroxide or alkali metal carbonates such as potassium carbonate. As the solvent to be used, a solvent used for the hydrolysis reaction is used without any particular limitation, for example, alcohols such as methanol, ethanol, n-propanol and isopropyl alcohol; ethers such as ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane. And dialkyl sulfoxides such as dimethyl sulfoxide and mixed solvents of these organic solvents and water. The reaction temperature is not particularly limited, and is usually from about room temperature to the reflux temperature of the solvent. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 12 hours.

When the hydroxyl-protecting group is an aralkyl group, it is achieved by bringing the corresponding compound into contact with a reducing agent in an inert solvent. Examples of the reducing agent used include alkali metals such as lithium, sodium and potassium. The reaction is preferably carried out in liquid ammonia or a mixed solvent of liquid ammonia and ethers such as ether and tetrahydrofuran. The reaction temperature is −
78 ° C to -20 ° C, and the reaction time is usually 2
It is from 0 minutes to 6 hours.

Further, when the protecting group is a 4-methoxybenzyl group, it can be removed by treating it with cerium ammonium nitrate and water-containing acetone at around room temperature.
Alternatively, it is also removed by an oxidizing agent such as dichlorodicyanoquinone or sodium persulfate. When the hydroxyl-protecting group is a heterocyclic group, a methyl group having a substituent of alkoxy or aralkyloxy, a 1-alkoxyethyl group, or a trityl group, it can be easily achieved by contact with an acid. Examples of the acid used include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, oxalic acid, malonic acid,
Organic acids such as methanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid and camphorsulfonic acid; mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are preferably used.
The reaction is carried out in the presence or absence of a solvent, but it is preferable to use a solvent to smoothly carry out the reaction, and the solvent used is not particularly limited as long as it does not participate in the reaction, for example water. Alcohols such as methanol and ethanol; Ethers such as tetrahydrofuran and dioxane; Ketones such as acetone and methyl ethyl ketone; or mixed solvents of these organic solvents and water are preferably used. The reaction temperature is not particularly limited, and the reaction is carried out from room temperature to the reflux temperature of the solvent. The time required for the reaction is 30 minutes to 10 hours. Alternatively, the methylthiomethyl group is also removed by treatment with mercuric chloride in aqueous acetonitrile.

When the hydroxyl-protecting group is a tri-lower alkyl or diaryl-lower alkylsilyl group, it can be easily achieved by bringing it into contact with water or water containing an acid or a base. When water containing an acid or a base is used, examples of the acid or base contained include organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid and malonic acid; hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Acids such as mineral acids or alkali metal and alkaline earth metal hydroxides such as potassium hydroxide and calcium hydroxide; bases such as alkali metal and alkaline earth metal carbonates such as potassium carbonate and calcium carbonate It is used without particular limitation. In the reaction, if water is used as a solvent, other solvents are not particularly required. When other solvents are used, for example, a mixed solvent of water with an organic solvent such as ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol is used. Although the reaction temperature is not particularly limited, it is usually preferably carried out at room temperature. The time required for the reaction is 30 minutes to 5 hours. When the protecting group is a t-butyldimethylsilyl group or a diphenyl-t-butylsilyl group, it can be achieved by treatment with tetrabutylammonium fluoride in the presence of an ether such as tetrahydrofuran or dioxane.

After completion of the reaction, the target compound of the reaction for removing the hydroxyl-protecting group is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is appropriately distilled off under reduced pressure,
By distilling the reaction mixture into ice water without distilling and neutralizing as necessary, then adding an appropriate organic solvent for extraction, washing the extract with water and drying, and then distilling the solvent from the extract. can get. In this step, a protecting group for R ⁷ is selected, and the removal reaction is appropriately carried out under acidic, alkaline or neutral conditions to protect other hydroxyl protecting groups, that is, those contained in R ¹ _a , R ² _a and R ^{2. 3} as distinct from _a, it is possible to remove the reaction.

The fourth step is a step of producing a compound having the formula (VI) and is accomplished by oxidizing the compound (V).

Examples of the oxidizing agent used include chromic anhydride and chromic anhydride-pyridine complex salt (Collin).
s reagent), chromic anhydride-concentrated sulfuric acid-water (Jones reagent), chromic acids such as sodium dichromate, potassium dichromate; N-bromoacetamide, N-bromosuccinimide, N-bromophthalimide, N-chloro-
4-toluenesulfonamide, N-chlorobenzenesulfonamide and other organic active halogen compounds; aluminum-tert-butoxide, aluminum isopropoxide and other aluminum alkoxides; dimethylsulfoxide-dicyclocarbodiimide; pyridine-sulfuric anhydride; active acyl derivatives (For example, oxalic acid dichloride, trifluoroacetic anhydride) -dimethyl sulfoxide-organic amine (for example, triethylamine, pyridine, etc.) and the like, and preferably, chromic anhydride-pyridine complex salt, pyridine-sulfuric acid anhydride, oxalic acid dichloride. -Dimethylsulfoxide-organic amine.

The reaction is preferably carried out in an inert organic solvent, and examples of the solvent to be used include methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ether, tetrahydrofuran and dioxane. Examples thereof include ethers, ketones such as acetone and methyl ethyl ketone, or sulfoxides such as dimethyl sulfoxide. The reaction temperature is -70 ° C to room temperature, and the reaction time is usually 30 minutes to 3 minutes.
Time. After completion of the reaction, the desired oxo compound is collected from the reaction mixture according to a conventional method. For example, after the reaction
When an insoluble matter is present, it can be obtained by filtering off, pouring in ice water, neutralizing appropriately, extracting with a water-immiscible organic solvent, and distilling off the solvent. Further, in the reaction of this step, the protecting group of the hydroxyl group may be removed at the same time.

The fifth step is a step which is carried out as desired, and R
Deprotection reaction of hydroxyl group contained in ¹ _a; esterifying the resulting carboxy group; the resulting hydroxymethyl group was oxidized to a formyl group, further reaction to oxidize the reaction or directly carboxy group is oxidized to a carboxy group Reaction; Reaction of converting carboxy or ester into carbamoyl group which may be substituted; Reaction of converting ester into carboxy group; Reaction of removing protective group for hydroxyl group of R ² _a and / or R ³ _a ; It includes a reaction for converting a group to a hydroxymethylcarbonyl group (including a hydroxyl group protection reaction), and these reactions can be carried out in an appropriate order. Also, the order can be changed from the third step and the fourth step.

The reaction for removing the hydroxyl-protecting group is carried out according to the above-mentioned A.
It is performed in the same manner as the third step of the method. The reaction for converting a hydroxymethyl group to a carboxy group is carried out according to a conventional method for oxidizing a primary alcohol to a carboxylic acid. On this occasion,
R ² _a and R ³ _a must be hydroxyl-protecting groups.
Examples of the oxidizing agent used include chromic anhydride-concentrated sulfuric acid-water (Jones reagent), chromic anhydride, potassium permanganate, sodium hydroxide or sodium carbonate,
Examples thereof include silver oxide and potassium dichromate-sulfuric acid. The reaction is usually carried out in a ketone such as acetone, water or a mixed solvent of water and alcohol such as methanol or ethanol, or a mixed solvent of water and pyridine. The reaction temperature is -30 ° C to 100 ° C, and the time required for the reaction is usually 30 minutes to 50 hours. Alternatively, a compound having a hydroxymethyl group may be oxidized in the same manner as in the fourth step to obtain a formyl compound, and then treated in the same manner as in the above reaction to obtain a carboxy compound.

After completion of the reaction, the desired carboxy compound is collected from the reaction mixture by a conventional method. For example, the reaction mixture can be obtained by pouring the reaction mixture into ice water, and when the solution is alkaline, acidifying with dilute acid, extracting with a water-immiscible organic solvent, and distilling off the solvent.

The reaction for esterifying a carboxy group is carried out by contacting with an esterifying agent in the presence or absence of a solvent. As the esterifying agent used, an esterifying agent used when converting to a carboxylic acid or ester is used without particular limitation. Examples of the esterifying agent used include diazoalkanes such as diazomethane, diazoethane, diazo-n-propane, diazoisopropane and diazo-n-butane; methanol,
Alcohols forming an ester group such as ethanol, n-propanol, isopropyl alcohol, n-butanol, n-hexanol, n-decanol, cyclopentanol, cyclohexanol, benzyl alcohol and geraniol, and hydrochloric acid, hydrobromic acid or sulfuric acid. Mineral acids such as or organic acids such as methanesulfonic acid, benzenesulfonic acid or 4-toluenesulfonic acid; alkyl halides such as methyl bromide, ethyl bromide, butyl bromide and sodium hydroxide, potassium hydroxide, sodium carbonate Such bases are preferably used. When diazoalkanes are used, the reaction is suitably carried out in the presence of a solvent.
The solvent used is not particularly limited as long as it does not participate in this reaction, and ethers such as ethyl ether and dioxane are preferable. Although the reaction temperature is not limited, it is preferably carried out at a relatively low temperature in order to suppress side reactions and to prevent decomposition of diazoalkanes, and usually it is preferably carried out under ice cooling. When alcohols are used in the presence of an acid, excess alcohols are usually preferably used as a solvent. The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or around the reflux temperature of the alcohol used. The reaction time varies depending on the reaction temperature and the kind of alcohol used, but is about 1 hour to 2 days.

In addition, sodium salts of carboxylic acids may be converted to halides such as benzyl bromide, 4-methoxybenzyl chloride, phenacyl bromide, benzhydryl chloride and bases such as triethylamine, pyridine, 4-
The corresponding aralkyl, phenacyl or benzhydryl ester is produced by treating in the presence of (N, N-dimethylamino) -pyridine according to a conventional method, and the carboxylic acid is a halogenating agent such as thionyl chloride or phosphorus pentachloride. It is treated with an acid halide such as pivaloyl chloride or ethyl chloroformate according to a conventional method to obtain a reaction active substance such as a corresponding acid halide or acid anhydride, and then treated in an inert solvent (for example, ether such as ether). Ethers, amides such as dimethylformamide, nitrites such as acetonitrile), in the presence of a base (eg, triethylamine, organic amines such as DBU), optionally substituted phenols or alcohols mentioned above. Reaction at room temperature for 30 minutes to 3 hours Tel is produced.

After completion of the reaction, the target compound for the esterification reaction is collected from the reaction mixture according to a conventional method. For example, by removing the solvent from the reaction mixture after completion of the reaction,
Further, if necessary, the product is dissolved in an organic solvent, the organic solvent layer is washed with an aqueous solution of sodium bicarbonate or an aqueous solution of alkali carbonate such as an aqueous solution of sodium carbonate and dried, and then the solvent is distilled off from the organic solvent layer. Obtained by

When a carboxy compound is used as a starting material, the reaction for converting a carboxy or an ester into a carbamoyl group which may be substituted is carried out by using a mixed acid anhydride or dicyclohexylcarbodiimide (DCC).
By reacting with an amine compound by a method using The method using a mixed acid anhydride is carried out, for example, in an inert organic solvent (halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as ether, tetrahydrofuran and dioxane) or in water or without a solvent, and a tertiary amine is used. (Pyridine, triethylamine,
In the presence of N, N-dimethylaminopyridine, picoline, etc., acid halides (pivaloyl halide, tosyl halide, mesyl halide, oxalyl halide, etc.) or acid derivatives (ethyl chloroformate, isopropyl chloroformate, isobutyl chloro) Formate), and the resulting mixed acid anhydride and amine compound are reacted in an inert organic solvent. When an ester compound is used as a raw material, the reaction is performed by heating in the presence of an amine compound. Examples of the amine compound used include ammonia or methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, aniline, 4-methylaniline, dimethylamine, methylethylamine, diethylamine, N-methylaniline, N- Ethylaniline,
Primary or secondary amino acids such as N-methyl-3-methylaniline, glycine, alanine, phenylalanine, serine, isoleucine and their esters, or 2
A primary amine can be mentioned. The reaction is usually 0 ° C to 1
The reaction time is 1 hour to 24 hours.
Time.

In the method using DCC, the above amine compound is used in an inert organic solvent (the same as above) or without solvent in the presence or absence of a tertiary amine, using DCC,
It is carried out by reacting at 0 ° C to 100 ° C.
All of these reactions were carried out under an inert gas (argon,
It is preferable to carry out the reaction under an anhydrous condition under an atmosphere such as nitrogen.

The reaction for converting a carboxy group into an N-acylcarbamoyl group is carried out by bringing it into contact with an acylisocyanate such as acetylisocyanate, trifluoroacetylisocyanate or benzoylisocyanate in an inert solvent. The solvents used are, for example, hydrocarbons such as benzene, toluene, xylene or ethers, ethers such as tetrahydrofuran, dimethoxyethane. The reaction temperature is usually room temperature,
The time required for the reaction is 30 minutes to 10 hours.

The reaction for converting a carboxy group into an N-sulfonylcarbamoyl group is carried out by converting into an active amide derivative in an inert solvent, and then converting into a sulfonic acid such as methanesulfonic acid amide, benzenesulfonic acid amide or 4-toluenesulfonic acid amide. It is carried out by reacting with an amide.
The active amide derivative is obtained by reacting the corresponding compound with an N-hydroxyimide such as N-hydroxysuccinimide or N-hydroxyphthalimide in the presence of a condensing agent such as dicyclohexylcarbodiimide, usually at room temperature for 30 minutes to 10 hours. Is manufactured by The reaction between the active amide derivative and the sulfonic acid amide is carried out in the presence of a base such as sodium methoxide, sodium ethoxide and potassium t-butoxide for 30 minutes to 15 at room temperature.
It is done by reacting for a time.

Both the above reactions are preferably carried out in an inert solvent, and examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, tetrahydrofuran and dimethoxyethane. Examples thereof include amides such as dimethylformamide and dimethylacetamide; or sulfoxides such as dimethylsulfoxide.

After completion of the reaction, the desired amide compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture can be obtained by pouring the reaction mixture into iced water, neutralizing if necessary, extracting with a water-immiscible organic solvent, and distilling off the solvent. Further, if necessary, it can be purified by a conventional method, for example, silica gel column chromatography, recrystallization method and the like.

The reaction for converting an ester to a carboxy group is preferably carried out using an enzyme. That is, the ester compound is dissolved (suspended) in a buffer solution such as acetone and a phosphate buffer solution, and esterase is used. The reaction is usually performed at room temperature for 30 minutes to 5 hours.

The reaction for converting a hydroxymethyl group into a hydroxymethylcarbonyl group is the same as the reaction in the fourth step, except that the hydroxymethyl group is converted into a formyl group and reacted with the anion of the protected hydroxymethyltin compound. It is carried out by converting the 2-position hydroxyl group to a protected 1,2-di-hydroxyethyl group, followed by oxidation and removal of the protecting group. In this step, preferably,
The carbonyl group of compound (VI) is protected, and examples of the protecting group include

[0079]

Embedded image

(Wherein R ¹⁰ represents a C ₁ -C ₄ alkyl group, and T represents C ₂ -such as ethylene, propylene, trimethylene, butylene, tetramethylene and 2,2-dimethyltrimethylene. C _{5 represents} an alkylene group,
G represents an oxygen atom or a sulfur atom. Group having a) can be mentioned, and the protection and deprotection are carried out according to a conventional method.

The reaction for converting the formyl compound into the 1,2-dihydroxyethyl compound in which the hydroxyl group at the 2-position is protected is carried out by converting the formyl compound in an inert solvent into a compound of the general formula

[0082]

[Chemical 15]

[0083] (wherein, R ⁹ and M are the same meanings as described above, R ¹¹ is 1-methoxyethyl, 1-a 1- (C ₁ -C ₄ alkoxy as ethoxyethyl) C ₁ ~ C
_{4 represents} an alkyl group. ) With an anion having Compound (XXVIII) can be prepared by a known method, for example, The Journal of American Chemical Society, 100 , 1481 (1978).
Year): J. Am. Chem. Soc. , 100 , 148
1 (1978) and then purified in the reaction solution.

Examples of the inert solvent used include ethers such as ether, tetrahydrofuran and dimethoxyethane, and amides such as hexamethylphosphoryltriamide, and the reaction temperature is -78.
The temperature is from 0 ° C to 0 ° C, and the time required for the reaction is from 5 minutes to 2 hours. Oxidation of the 1,2-dihydroxyethyl derivative in which the hydroxyl group at the 2-position is protected is carried out by treating with the above Collins reagent according to a conventional method, and the deprotection reaction of the hydroxyl group is the same as the above deprotection reaction of the corresponding hydroxyl group. Done.
Alternatively, if necessary, the carbonyl group is deprotected. The desired hydroxymethylcarbonyl compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is poured into ice-water and neutralized appropriately, and after extraction with a water-immiscible organic solvent,
It can be obtained by distilling off the solvent. further,
If necessary, it can be further purified by a conventional method such as column chromatography or recrystallization.

Method B is a compound (VI) in which R ¹ _a is an optionally protected carboxy group (R ¹ _b ).
_{This is a} method of separately manufacturing _a ). The sixth step of Method B is a step of producing a compound having the formula (VIII) and is accomplished by iodolactonization of the compound having the formula (VII).

This reaction is carried out in the presence of a base in an inert solvent,
It is carried out by treating the compound (VII) with iodine-alkali iodide (eg, sodium iodide, potassium iodide, etc.). Examples of the base used include alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate and potassium hydrogen carbonate.

The inert solvent used is, for example,
Examples thereof include alcohols such as methanol, ethanol and isopropanol, ethers such as ether, tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, water or a mixed solvent thereof. Reaction temperature is usually 0 ° C to 5
The temperature is 0 ° C., and the time required for the reaction is 30 minutes to 5 hours, varying depending on the reaction reagent, the reaction temperature, and the like.

After completion of the reaction, the target compound of this step is collected from the reaction mixture by a conventional method. For example, after the reaction is completed, the solvent is distilled off under reduced pressure, ice water is added, the mixture is extracted with a water-immiscible organic solvent, and the organic solvent is distilled off.

The seventh step is a step for producing a compound having the formula (IX) and is accomplished by treating the compound (VIII) with a reducing agent in an inert solvent. The reducing agent used is not particularly limited as long as it reduces an iodine atom to a hydrogen atom, but preferably includes tri-lower alkyl tin hydrides such as trimethyl tin hydride and tributyl tin hydride. .

The inert solvent used is, for example,
There may be mentioned hydrocarbons such as hexane, benzene and toluene, ethers and ethers such as tetrahydrofuran. Further, this reaction is suitably carried out using a radical initiator such as azobisisobutyronitrile or benzoyl peroxide as a catalyst. Reaction temperature is usually 0 ° C to 6
The temperature is 0 ° C., and the time required for the reaction is 10 minutes to 2 hours, depending on the reaction reagent, the reaction temperature and the like. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, it is obtained by adding diluted alkaline water, extracting with a water-immiscible organic solvent, and distilling off the organic solvent.

The eighth step is a step for producing a compound having the formula (X), which is achieved by hydrolyzing or alcohololyzing the compound (IX) and, if necessary, removing the hydroxyl-protecting group R ^7. To be done. The hydrolysis reaction is performed in the same manner as in the case where the hydroxyl-protecting group is an acyl group in the third step of Method A.

The alcoholysis reaction is carried out in an inert solvent,
In the presence of a base, the compound (IX) is converted into the compound represented by the general formula R ¹² OH (XXIX) (wherein R ¹² is a C _{1 to} C ₁₀ alkyl group, C _{3 to} C ₇
Represents a cycloalkyl group, an aralkyl group, a phenacyl group or a geranyl group. ). As the base used, for example,
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium methoxide, potassium t
-Alkali metal alkoxides such as butoxide can be mentioned.

The inert solvent used is, for example,
Examples thereof include aromatic hydrocarbons such as benzene and toluene, ethers, and ethers such as tetrahydrofuran. Further, the reaction preferably proceeds even when a large excess of alcohol (XXIX) is used also as a solvent. The reaction temperature is usually 0 ° C. to 50 ° C., and the time required for the reaction is 1 hour to 24 hours, varying depending on the reaction reagent, the reaction temperature and the like. After completion of the reaction, the target compound of this step is prepared according to a conventional method.
Taken from the reaction mixture. For example, after completion of the reaction, ice water is added, extraction is performed with a water-immiscible organic solvent, and the organic solvent is distilled off.

[0094] Further, in the compound obtained in the above reaction, when R ⁷ is not removed, the following Method A third step can be eliminated R ^7, when R ¹ _b is a carboxy group, If desired, the hydroxyl group is protected in the same manner as in Method C, Step 13 described below, the carboxy group is esterified according to the corresponding reaction in Method A, Step 5, and the hydroxyl group protecting group is removed according to Method A, Step 3. Alternatively, after protecting the carboxy group with, for example, a silyl group to protect the hydroxyl group, the protecting group for the carboxy group may be removed, and then esterification of the carboxy group and removal of the protecting group for the hydroxyl group may be performed.

The ninth step is a step for producing the compound (VI _a ) and is accomplished by oxidizing the compound (X),
This step is performed in the same manner as the above-mentioned Method A fourth step.

Method C is a method for separately producing compound (X _a ) in which A is vinylene or ethynylene group (A ′) in compound (X). The tenth step of the C method is the formula (XI
This is accomplished by iodolactonization of the compound of formula (XI) in the step of producing the compound of formula (I), and this step is carried out in the same manner as in the method B, step 6.

The starting compound (XI) in this step is a known compound or can be easily produced by a known method (for example, Ogawa et al., Te.
trahedron Letters, 25 , 1067
(1984)).

The eleventh step is a step for producing a compound having the formula (XIII) and is achieved by reducing the compound (XII), and this step is performed in the same manner as the seventh step of the method B.

The twelfth step is a step for producing a compound having the formula (XIV), which is accomplished by hydrolyzing or alcohololyzing the compound (XIII), and this step is the same as the eighth step of Method B. To be done.

The thirteenth step is a step for producing a compound having the formula (XV) and is accomplished by protecting the hydroxyl group of the compound (XIV). The reaction for protecting the hydroxyl group is carried out by bringing compound (XIV) into contact with a compound forming a protecting group according to a conventional method. Examples of the compound forming a protective group used include acetic acid, propionic acid, butyric acid, benzoic acid, carboxylic acids such as naphthalenecarboxylic acid or reactive derivatives thereof; benzyl chloride, benzyl bromide, 4-nitrobenzyl bromide, 4- Aralkyl halide compounds such as methoxybenzyl bromide; trityl chlorides, trityl halides such as trityl bromide; dihydropyran, dihydrothiopyran, dihydrothiophene, 4-methoxy-5,6-dihydro- (2
H) 5- or 6-membered cyclic hetero compounds such as pyran;
Methoxymethyl chloride, methylthiomethyl chloride,
Alkoxy, alkylthio or aralkyloxy substituted alkyl halide compounds such as ethoxyethyl chloride and benzyloxymethyl chloride; unsaturated ethers such as methyl vinyl ether and ethyl vinyl ether; hexamethyldisilazane, trimethylsilyl chloride, tri-n-propylsilyl chloride Examples of suitable compounds include silyl compounds such as t-butyldimethylsilyl chloride and t-butyldimethylsilyl chloride. When a carboxylic acid compound is used, it is suitably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide.

As the reactive derivative of carboxylic acid, for example, acetic acid chloride, acetic acid bromide, benzoyl chloride,
Examples thereof include acid halide compounds such as benzoyl bromide and naphthoyl chloride, and acid anhydrides such as acetic anhydride, propionic anhydride and benzoic anhydride. When this derivative is used, triethylamine, pyridine,
-N, N-dimethylaminopyridine, quinoline, N, N
-Preferably carried out in the presence of an organic base such as dimethylaniline.

This reaction is carried out in the presence of a solvent. Examples of the solvent used include hydrocarbons such as benzene, toluene, xylene, n-hexane, methylene chloride,
Chloroform, carbon tetrachloride, halogenated hydrocarbons such as chlorobenzene, ether, tetrohydrofuran,
Examples thereof include ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, and hydrocarbons are preferable. The reaction temperature is usually 0 ° C to 100
The reaction time is 30 minutes to 6 hours, depending on the reaction reagent, reaction temperature, solvent, etc.

When the aralkyl halide compound, trityl halide, alkoxy, alkylthio or aralkyloxy substituted alkyl halide compound or silyl compound is used, the compound (XIV) is treated with sodium hydride or potassium hydride in an inert solvent. It is achieved by reacting with an alkali metal hydride to produce an alkali metal salt of compound (XIV), and then reacting with a corresponding halide compound or a silylating reagent such as disilazane.

The inert solvent to be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether, tetrahydrofuran, dioxane, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoryltriamide, acetonitrile. , Nitrites such as benzonitrile or sulfoxides such as dimethyl sulfoxide,
Preferred are amides. Reaction temperature is 0 ℃ to 100 ℃
The reaction time is usually 10 minutes to 3 hours, varying depending on the reaction agent and the reaction temperature.

In addition, triethylamine, pyridine, 4-
Compound (XIV) in the presence of an organic base such as N, N-dimethylaminopyridine or imidazole or an inorganic base such as sodium hydroxide, potassium hydroxide or potassium carbonate.
It is also possible to react a halide compound corresponding to
When using a 5- or 6-membered cyclic heterocyclic compound or unsaturated ethers, the reaction is carried out in the presence or absence of an inert solvent with a small amount of an acid such as a mineral acid such as hydrochloric acid or hydrobromic acid. It is carried out in the presence of an organic acid such as picric acid, trifluoroacetic acid, benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but ethers such as ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride or benzene. Aromatic hydrocarbons such as toluene and xylene can be mentioned, but halogenated hydrocarbons are preferable. The reaction is also carried out by using an excess of a heterocyclic compound or a vinyl ether compound also as a solvent in the absence of an inert solvent. The reaction temperature is usually 0 ° C. to 50 ° C., and the time required for the reaction is 30 minutes to 3 hours, varying depending on the reaction reagent and the reaction temperature.

After completion of each of the above reactions, the target compound having a protected hydroxyl group is collected from the reaction mixture according to a conventional method.
For example, if the reaction mixture is poured into ice water and insoluble matter is present, it is filtered off, and if the solution is acidic or alkaline, it is appropriately neutralized and extracted with a water-immiscible organic solvent, and then the solvent is distilled off. It can be obtained by If necessary, it can be further purified by a conventional method such as column chromatography, thin layer chromatography, recrystallization method and the like. Further, when R ¹ _b is a carboxy group, esterification can be carried out according to the corresponding reaction in the above-mentioned Method A, step 5.

The 14th step is a step for producing a compound having the formula (XVI), which is accomplished by removing R ⁸ of the compound (XV), and this step is carried out in the same manner as the 3rd step of Method A. Be seen. In this step, R ⁸ can be selectively removed by appropriately selecting the protecting groups R ⁷ and R ² _a for other hydroxyl groups. The combination of protecting groups in this case is
R ² _a , R ⁷ and R ⁸ are protecting groups that are removed under acidic, alkaline and neutral conditions, for example, R ⁷ is a group that is removed under basic conditions such as an acyl group, R ² _a
Is a heterocyclic group, a substituted methyl group, a 1-alkoxyethyl group,
R is a group such as a trityl group which is removed under acidic conditions, and R
⁸ is a tri-substituted silyl group (dimethyl-t-butylsilyl,
Diphenyl-t-butylsilyl, etc.) and an aralkyl group, which are protective groups that can be removed under neutral conditions.

The fifteenth step is a step for producing a compound having the formula (XVII), which is accomplished by removing R ⁸ of the compound (XIII). This step is the third step of the A method and the third step of the C method. It is performed in the same manner as the 14th step.

The sixteenth step is a step for producing a compound having the formula (XVIII) and is accomplished by oxidizing the compound (XVII), and this step is carried out in the same manner as the ninth step of Method B.

The 17th step is a step for producing a compound having the formula (XIX) and is accomplished by oxidizing the compound (XVI). This step is the same as the 9th step of the B method and the 16th step of the C method. To be done.

The eighteenth step is a step for producing a compound having the formula (XX), which comprises adding the following two general formulas to the compound (XVIII):

[0113]

Embedded image

(Wherein R ⁵ , R ⁹ , M and Y have the same meanings as defined above), and the reaction can be accomplished by reacting a Wittig or modified Wittig reagent, the process comprising: The method is performed in the same manner as the first step.

The nineteenth step is a step for producing a compound having the formula (XXI), which is the same as the compound (XIX) of the general formula (XXX) or (XX
XI) is carried out by reacting a Wittig reagent or a modified Wittig reagent having C.
It is performed in the same manner as the 8 steps.

The twentieth step is a step for producing a compound having the formula (XXI), which is accomplished by hydrolyzing or alcohololyzing the compound (XX) and then protecting the hydroxyl group. It is performed in the same manner as the 12th and 13th steps.

The twenty-first step is a step for producing a compound having the formula (XXII), in which the compound (XX) is added with a reducing agent or a general formula R ⁴ _a —Mg—X (XXXII) (wherein, X is as described above). Has the same meaning as that of R ⁴ _a
Shows the C ₁ -C ₄ alkyl group. A compound having R ⁴ is a hydrogen atom and R ⁴ is a C ₁ -C ₄ alkyl group. The compound is produced.

The reaction with the reducing agent is usually carried out in an inert solvent. The reducing agent used is not particularly limited as long as it is a reducing agent that converts only a carbonyl group into a hydroxyl group, and for example, sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, trihydrogen hydride. t
ert-butoxy aluminum lithium, lithium methoxytrimethoxyaluminum, hydrogenated metal compounds such as sodium cyanoborohydride or aluminum isopropoxide, diisobutyl- (2,6-di-t-butyl-4-methylphenoxy) aluminum Such aluminum compounds can be mentioned, but sodium borohydride is preferred. In addition, cerium chloride or the like can be added to suppress the reduction of the double bond.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but in the reaction with a reducing agent, alcohols such as methanol, ethanol, n-propanol, n-butanol, t-butanol or Examples thereof include ethers such as ether, tetrahydrofuran, dioxane, and mixed solvents thereof, preferably alcohols, particularly methanol, and ethers in the reaction with the compound (XXXII).

The reaction temperature is usually 0 ° C. to room temperature, and the time required for the reaction varies depending on the reaction reagent, reaction temperature, etc.
It is from 0 minutes to 2 hours. After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the solvent is distilled off under reduced pressure, ice water is added, the mixture is extracted with a water-immiscible organic solvent, and the organic solvent is distilled off.

The twenty-second step is a step for producing a compound having the formula (XXIII), which is accomplished by reacting the compound (XXI) with a reducing agent or a compound having the general formula (XXXII), and this step is the above-mentioned C This is performed in the same manner as the 21st step of the method.

The twenty-third step is a step for producing a compound having the formula (XXIII), which is accomplished by hydrolyzing or alcohololyzing the compound (XXII), and then protecting the hydroxyl group. It is performed in the same manner as the 12th and 13th steps.

The 24th step is a step for producing a compound having the formula (XXIV) and is accomplished by protecting the hydroxyl group of the compound (XXII). When Y represents a halogen atom, the halovinylene group can be optionally converted to an ethylene group prior to the protection of the hydroxyl group.

The desired step, the reaction of converting a halovinylene group to an ethynylene group, is accomplished by treating the corresponding compound (XXII) with a base in an inert solvent.

Examples of the base used include alkali metal alkoxides such as sodium methoxide, potassium ethoxide, potassium t-butoxide and sodium t-pentoxide, or alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples thereof include strong bases such as potassium t-butoxide, sodium t-pentoxide and potassium hydroxide.

The inert solvent to be used is not particularly limited as long as it does not participate in the reaction, but preferred examples include alcohols such as methanol, ethanol and t-butanol, or ethers, and ethers such as tetrahydrofuran. be able to. The reaction temperature is usually room temperature to the reflux temperature of the solvent, and the time required for the reaction is 30 minutes to 5 minutes.
Time.

After completion of the reaction, the desired compound is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is appropriately distilled off under reduced pressure, or the reaction mixture is neutralized if necessary by pouring the reaction mixture into ice water without distilling, and then an appropriate organic solvent is added for extraction to obtain an extract. It is obtained by washing with water and drying, and then distilling off the solvent from the extract. Further, if necessary, it can be further purified by a conventional method, for example, silica gel column chromatography.

Protection of the hydroxyl group is carried out in the same manner as in the 13th step of Method C. Further, when R ¹ _b is a carboxy group, it can be protected by esterification in the same manner as the corresponding reaction in the above-mentioned Method A fifth step, and when R ¹ _b is a protected carboxy group, After removing the protecting group by hydrolysis or the like, it may be protected by another protecting group by esterification or the like.

The 25th step is a step for producing a compound having the formula (XXV) and is accomplished by protecting the hydroxyl group of the compound (XXIII). When Y represents a halogen atom, the halovinylene group can be optionally converted to an ethynylene group prior to the protection of the hydroxyl group. This step is performed in the same manner as the 24th step of Method C.

The 26th step is a step for producing a compound having the formula (XXV), which is accomplished by hydrolyzing or alcohololyzing the compound (XXIV) and then protecting the hydroxyl group. It is performed in the same manner as the 12th and 13th steps.

The 27th step is a step for producing a compound having the formula (X _a ). After removing R ⁷ of the compound (XXIV), hydrolysis or alcoholysis is carried out, or removal and hydrolysis of R ⁷ are carried out. This is achieved by simultaneously carrying out the decomposition or alcoholysis, and this step is carried out in the same manner as the above-mentioned A method third step and / or C method twelfth step.

The 28th step is a step for producing compound (X _a ), which is accomplished by removing R ⁷ of compound (XXV), and this step is carried out in the same manner as the third step of Method A. When the target compound thus obtained is obtained as a mixture of various geometrical isomers and optical isomers, these isomers can be separated and resolved at an appropriate synthetic step.

Test Example 1 In Vitro Platelet Aggregation Inhibitory Action Blood was collected from Japanese white rabbits and immediately 1/10 volume of 3.8%.
Mixed with sodium citrate. After centrifugation at 95 g for 15 minutes at room temperature, platelet-rich plasma (PRP) was obtained from the upper layer. The remaining blood was further centrifuged at 1000 g for 15 minutes to obtain platelet poor plasma (PPP) from the upper layer. An appropriate amount of PRP and PPP were mixed, and the final platelet number of PRP was adjusted to 600,000 per μl. The aggregation of platelets can be performed by the method of Bourne et al.
R. Born J. Physiol. , 62 , 67-6
8 (1962)) using an aglycometer to measure the increase in transmitted light. 25 μl of the test drug solution was added to 250 μl of PRP, and 2 minutes later, 25 μl of ADP was added, and then observed for 5 minutes to confirm the aggregation inhibitory effect. The inhibition rate was determined for the aggregation when a physiological saline solution was used instead of the test solution, and the IC ₅₀ was calculated from the dose-response curve.

Test Example 2 Preventive Effect on Ethanol Ulcer in Rats As animals, SD male rats (Charles River Co., Ltd.) with a body weight of about 180-200 g were fasted for about 42 hours and used. Each test compound was orally administered to rats, and 1 hour later, 1 ml of absolute ethanol was orally administered to induce gastric mucosal damage. One hour after the administration of ethanol, the rats were killed with dry ice and the stomach was removed. After fixing the stomach with formalin, the damage area (mm ² ) formed on the gastric mucosa induced by ethanol was measured by VIP (video image pro).
The inhibitory rate of gastric mucosal damage for each test compound was calculated. Incidentally, 6- which is a known compound
Of the oxo form and the 7-oxo form, the following 6-oxo form compounds, which are more similar to the compounds of the present invention, were used as control compounds.

[0135]

[Chemical 17]

The results of the above two tests are summarized in Table 7.

[0137]

[Table 7]

As described above, the compound (I) of the present invention or a salt thereof exhibits an excellent anti-ethanol ulcer action, and
It is extremely useful as a therapeutic and preventive agent for ulcers because it has a significantly weaker platelet aggregation inhibitory action, which is a serious side effect when it is carried out as a drug, compared with the 6-oxo compound which is a control compound. Examples of the dosage form include oral administration such as tablets, capsules, granules, powders, syrups and fat emulsions (liposome preparations) and parenteral administration such as injections and suppositories. These preparations are manufactured by a well-known method using additives such as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent. The amount used varies depending on symptoms, age, weight, etc., but is usually about 0.0 per day for adults.
001 mg to 100 mg, preferably about 0.00 per day
It is 1 mg to 10 mg, and can be administered once or several times a day. Next, the present invention will be described more specifically with reference to Examples and Reference Examples.

[0139]

【Example】

Example 1 4,9-Dioxo-11α, 15α-dihydroxypro
St-13 (E) -enoic acid methyl ester (a) 1-decarboxy-1-hydroxymethyl-4-
Oxo-9α-hydroxy-11α, 15α-di (teto
Lahydropyran-2-yloxy) prost-5
(E), 13 (E) -dienoic acid di (dimethyl-t-butyl)
Rusilyl) ether 1α- (tetrahydropyran-2-
Iloxy) -2β- (3α-tetrahydropyran-2
-Yloxy-1-octenyl) -3α- (2-oxoethyl) -4α- (dimethyl-t-butylsilyloxy) cyclopentane 500 mg, dimethyl 2-oxo-5- (dimethyl-t-butylsilyloxy) pentylphosphonate 470 mg Was treated and treated in the same manner as in Reference Example 2 (a) (reaction temperature was room temperature) to obtain 637 mg of the target compound as an oil. IR spectrum (liquid film); 1692, 1668, 1626cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.91 (18H, s), 4.66 (2H, br.
s), 5.45 (2H, m), 5.8 ~ 7.2 (2H, m). (B) 1-decarboxy-1-hydroxymethyl-4-
Oxo-9α-hydroxy-11α, 15α-di (teto
Lahydropyran-2-yloxy) prost-13
(E) -Di (dimethyl-t-butylsilyl) enoate
Ether enone body (the compound of Example 1 (a); 100 mg) is stirred and dissolved in benzene 5ml chlorotris (triphenylphosphine) rhodium (I) under an atmosphere of hydrogen added 200 mg 15 hours. The catalyst is removed from the reaction and the catalyst is washed with ethyl acetate. When the solvent was distilled off, 210 mg of a residue was obtained, which was subjected to silica gel chromatography (eluent: 7
-11% ethyl acetate-hexane). 78m
g of the oily target compound was obtained. IR spectrum (liquid film); 1714 cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.90 (18H, s), 4.64 (2H, br.
s), 5.38 (2H, m). (C) 1-decarboxy-1-hydroxymethyl-4-
Oxo-9α-hydroxy-11α, 15α-di (teto
Lahydropyran-2-yloxy) prost-13
To a tetrahydrofuran solution (1.4 ml) of the (E) -silyl enoate (compound of Example 1 (b); 70 mg) was added 1M tetrabutylammonium fluoride in tetrahydrofuran solution.
Add 93 ml and stir at room temperature for 16 hours. After completion of the reaction, the reaction solution is poured into brine and extracted with ethyl acetate. The extract is washed with brine and dried over sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel chromatography (eluent: 70-
44m when refined with 100% ethyl acetate-hexane)
g of an oily target product was obtained. IR spectrum (liquid film); 3450, 1708cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.89 (3H, br.t), 4.68 (2H, b
rs), 5.42 (2H, m). (D) 4,9-dioxo-11α, 15α-di (tetra
Hydropyran-2-yloxy) prost-13 (E)
-Enoic acid methyl ester alcohol compound (compound of Example 1 (c); 310 mg)
5 ml of the methylene chloride solution prepared in step 1 above is added to a Collins reagent prepared from 1.18 g of chromic anhydride, 1.90 ml of pyridine and 11 ml of methylene chloride under ice cooling and stirred for 30 minutes.
After completion of the reaction, the mixture is poured into ether to remove precipitates, and the ether layer is washed with water and dried. The solvent was distilled off, and the resulting residue was dissolved in 8.1 ml of acetone and added to an acetone solution (5.4 ml) of Jones reagent (0.58 ml) at -30 to -10 ° C and stirred for 30 minutes. After completion of the reaction, isopropyl alcohol is added, the mixture is poured into ice water, and extracted with ethyl ether. The extract is washed with water, dried and the solvent is distilled off. The obtained residue is esterified with diazomethane and then purified by silica gel chromatography (eluent: 20-36% ethyl acetate-hexane). 240 mg of oily target product was obtained. IR spectrum (liquid film); 1735, 1714 NMR spectrum (CDCl ₃ ) δ; 0.87 (3H, br.t), 3.64 (3H,
s), 4.69 (2H, br.s), 5.55 (2H, m). (E) 4,9-dioxo-11α, 15α-dihydroxy
Cyprost-13 (E) -enoic acid methyl ester pyranyl compound (compound of Example 1 (d); 230 mg) was dissolved in 1 ml of tetrahydrofuran and 2.4 ml of acetic acid, water (5.1 ml) was added, and the mixture was stirred at 40 ° C. for 3 hours. To do. Meanwhile, 13 ml of water was added. The reaction solution is poured into ice water and extracted with ethyl acetate. The extract is washed with brine, dried and the solvent is distilled off. The residue was purified by silica gel chromatography (eluent: 60-100% ethyl acetate-hexane) to give 134 mg of the desired product as an oil. IR spectrum (liquid film); 3330, 1752, 1740, 1708cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.90 (3H, br.t), 3.68 (3H,
s), 5.66 (2H, m) [α] ²⁴ _D = -52.9 (C = 1, MeOH).

Example 2 4,9-Dioxo-11α, 15α-dihydroxy-1
6-phenoxy-17,18,19,20-tetranor
Prost-13 (E ) -enoic acid methyl ester 1α- (tetrahydropyran-2-yloxy) -2β
-[(3α-tetrahydropyran-2-yl) oxy-
4-phenoxy-1-butenyl] -3α- (2-oxoethyl) -4α- (dimethyl-t-butylsilyloxy) cyclopentane (1.97 g) was used to carry out the reaction in the same manner as in Example 1 to obtain 139 mg of an oily substance. The target compound was obtained. IR spectrum (liquid film); 3400, 1740, 1718 (sh), 972c
m ^-1 NMR spectrum (CDCl ₃ ) δ; 3.66 (3H, s), 5.82 (2H, m),
6.8-7.5 (5H, m) [α] ²⁴ _D = -56.9 (C = 1, MeOH).

Example 3 4,9-Dioxo-11α, 15α-dihydroxy-1
6,16-Dimethylprost-13 (E) -methanoic acid
Glycol ester 1.alpha.-(tetrahydropyran-2-yloxy) -2Beta
-[(3α-tetrahydropyran-2-yl) oxy-
4,4-Dimethyl-1-octenyl] -3α- (2-oxoethyl) -4α- (dimethyl-t-butylsilyl-
When the reaction treatment was sequentially carried out in the same manner as in Example 1 using 0.60 g of (oxy) cyclopentane, 134 mg of the oily target compound was obtained. IR spectrum (liquid film); 3440, 1738, 1714 (sh), 972c
m ^-1 NMR spectrum (CDCl ₃ ) δ; 0.85 (3H, s), 0.87 (3H, s),
3.68 (3H, s), 5.7 (2H, m). [Α] ²⁴ _D = -34.8 (C = 1, MeOH).

Example 4 4,9-Dioxo-11α, 15α-dihydroxy-1
6- (4-chlorophenoxy) -17,18,19,2
Methyl ether of 0-tetranorprost-13 (E) -enoate
Ester 1.alpha.-(tetrahydropyran-2-yloxy) -2Beta
-[(3α-tetrahydropyran-2-yl) oxy-
4- (4-Chlorophenoxy) -1-butenyl] -3α
When 2.23 g of-(2-oxoethyl) -4α- (dimethyl-t-butylsilyl-oxy) cyclopentane was sequentially reacted and treated in the same manner as in Example 1, 273 mg of the oily target compound was obtained. IR spectrum (liquid film); 3430, 1738, 1714 (sh), 971c
m ^-1 NMR spectrum (CDCl ₃ ) δ; 3.65 (3H, s), 5.82 (2H, m),
6.88 (1H, d), 7.28 (1H, d) [α] ²⁴ _D = -54.0 (C = 1, MeOH).

Reference Example 15-oxo-16-phenoxy-17,18,19,2
0-tetranorprostaglandin E ₁ methyl ester (A)1α-hydroxy-2α- (6-carboxy-2
(Z) -Hexenyl) -3β-dimethyl-t-butyloxy
Ryloxymethyl-4α- (2-tetrahydropyrani
) Oxycyclopentane 1α-hydroxy-2α- (6-methoxycarbonyl-
2 (Z) -hexenyl) -3β-dimethyl-t-butyl
Silyloxymethyl-4α- (tetrahydropyran-2
-Yl) oxycyclopentane 10.0 g of methanol
Solution (500 ml) and 5% aqueous sodium hydroxide (25
(0 ml) was stirred at room temperature for 1.5 hours. Reaction liquid
After cooling, add concentrated hydrochloric acid to neutralize, and distill the solvent under reduced pressure.
Leave. Add ice water, weakly acidify with concentrated hydrochloric acid, and add ethyl acetate.
Extract with stell. After washing the extract with saline,
Dried with sodium acidate. 8.6 when the solvent was distilled off
7 g of the oily title compound was obtained. IR spectrum (liquid film); 3450, 1708, 1030cm^-1 NMR spectrum (CDCl₃) δ; 0.89 (9H, s), 4.70 (1H, br.
s), 5.45 (2H, m). (B)1α-acetoxy-2α- (6-carboxy-2
(Z) -Hexenyl) -3β-dimethyl-t-butyloxy
Ryloxymethyl-4α- (2-tetrahydropyranyl
Oxy) cyclopentane Hydroxy form (Compound of Reference Example 1 (a); 8.64 g)
Acetic anhydride (10 ml) was added to the pyridine solution (20 ml)
Then, a catalytic amount of 4-dimethylaminopyridine was added.
Eh, it was left at 0 ° C. for 100 hours. Water (10 m
l) was added and the mixture was stirred for 30 minutes at room temperature and then poured into ice water 3
Acidify with% hydrochloric acid and extract with ethyl acetate. Extraction
The liquid was washed with saline and dried with sodium sulfate.
I do. The solvent was distilled off and the residue was subjected to silica gel column chromatography.
Purify with Raffy. Hex containing 20-45% ethyl acetate
From the sun outflow part, 8.23 g of the oily target compound was obtained.
Was. IR spectrum (liquid film); 1742, 1718, 1252, 1022cm^-1 NMR spectrum (CDCl₃) δ; 0.90 (9H, s), 2.02 (3H, s),
4.65 (1H, br.s), 5.08 (1H, m), 5.45 (2H, m). (C)1α-acetoxy-2α- [2-iodo-2 (6
-Oxotetrahydropyran-2-yl) ethyl] -3
β-dimethyl-t-butylsilyloxymethyl-4α-
(Tetrahydropyran-2-yloxy) cyclopenta
The Of carboxylic acid (compound of Reference Example 1 (b); 7.21 g)
0.5N charcoal in isopropanol solution (47.6ml)
Add 47.6 ml of sodium hydrogen carbonate solution at room temperature and add 10.
Stir for minutes. Iodine-potassium iodide solution in the reaction mixture
(Iodine (11.01 g), potassium iodide (21.60
g) and water (prepared from 65.0 ml)), and then 30
Stir at ~ 38 ° C for 2 hours. The reaction solution was diluted with 10% sodium thiosulfate.
Pour into thorium solution (W / V: 700 ml) and ethyl acetate
Extract with. Wash the extract with saline and wash with sodium sulfate.
To dry. When the solvent was distilled off, the oily target product (8.97) was obtained.
g) was obtained as a mixture of two isomers. IR spectrum (liquid film); 1740, 1242, 1022cm^-1 NMR spectrum (CDCl₃) δ; 0.91 (9H, s), 2.09 (3H, s),
4.60 (1H, br.s), 5.18 (1H, m). (D)1α-acetoxy-2α- [2- (6-oxothene
Trahydropyran-2-yl) ethyl] -3β-dimethyl
Ru-t-butylsilyloxymethyl-4α- (tetrahy
Doropyran-2-yloxy) cyclopentane A sample of iodine (compound of Reference Example 1 (c); 8.94 g)
Tributyltin hydride in solution (180 ml)
(5.70 ml) and catalytic amount of α, α'-azobisdiiso
Add butyronitrile, heat to 40 ° C and stir for 20 minutes.
It Dilute the reaction mixture with saturated sodium hydrogen carbonate solution and add acetic acid.
Extract with ethyl. After washing the extract with saline,
Dry with sodium acidate. Distill off the solvent and remove the residue.
Purify by Kagel chromatography. 25-35% vinegar
5.83 g of oily eyes from the hexane-containing hexane outlet.
The target was obtained. IR spectrum (liquid film); 1740, 1250, 1024cm^-1 NMR spectrum (CDCl₃) δ; 0.90 (9H, s), 4.62 (1H, br.
s), 5.15 (1H, m). (E)1α-hydroxy-2α- [3-hydroxy-6
-Methoxycarbonylhexyl) -3β-dimethyl-t
-Butylsilyloxymethyl-4α- (tetrahydropi
Lan-2-yloxy) cyclopentane Acetyl derivative (compound of Reference Example 1 (d); 6.67 g)
3.80 g of anhydrous potassium carbonate was added to a methanol solution (200 ml),
Stir at room temperature for 20 hours. Pour the reaction solution into ice water and add hydrochloric acid.
Acidify and extract with ethyl acetate. Wash the extract with saline
After the separation, the solvent is distilled off. Dissolve the residue in ether, part
The hydrolyzed product is esterified with diazomethane.
The solvent was evaporated and the residue was chromatographed on silica gel.
Purify. Hexane outflow part containing 45-90% ethyl acetate
5.15 g of the oily target compound is a mixture of two isomers.
Obtained as a mixture. IR spectrum (liquid film); 3450, 1746, 1258, 1022cm^-1 NMR spectrum (CDCl₃) δ; 0.90 (9H, s), 3.68 (3H, s),
4.70 (1H, br.s). (F)1α-acetoxy-2α- [3-acetoxy-6
-Methoxycarbonylhexyl) -3β-dimethyl-t
-Butylsilyloxymethyl-4α- (tetrahydropi
Lan-2-yloxy) cyclopentane Hydroxy form (Compound of Reference Example 1 (e); 5.14 g)
Was dissolved in pyridine (12 ml) and 12 ml of acetic anhydride was added.
The mixture is allowed to stand at room temperature for 7 hours and at 0 ° C. for 15 hours. End of reaction
After that, add water, and then add ice-cold hydrochloric acid water, and add ethyl acetate.
Extract. After washing the extract with saline,
Dry with um. The solvent was distilled off and the residue was washed with silica gel.
Purify by ram chromatography. 18-26% acetic acid
5.49 g of oil from the hexane outlet containing ethyl
The compound is obtained. IR spectrum (liquid film); 1742, 1248, 1020cm^-1 NMR spectrum (CDCl₃) δ; 0.90 (9H, s), 2.04 (6H, s),
3.68 (3H, s), 4.62 (1H, br.s), 4.85 (1H, m), 5.10 (1H, m)
 . (G)1α-acetoxy-2α- (3-acetoxy-6
-Methoxycarbonylhexyl) -3β-hydroxyme
Tyl-4α- (tetrahydropyran-2-yloxy)
Cyclopentane The silyl compound (compound of Reference Example 1 (f); 5.47 g)
1M tetrabutyrate in trahydrofuran solution (110 ml)
Lumonium fluoride solution in tetrahydrofuran
(23.9 ml) is added, and the mixture is stirred at room temperature for 3 hours. reaction
The solution is poured into brine and extracted with ethyl acetate. Extract the salt
After washing with water, it is dried with sodium sulfate. Distill the solvent
Purify the residue by silica gel column chromatography
I do. From the outflow part of hexane containing 50-80% ethyl acetate
4.29 g of the oily target compound was obtained. IR spectrum (liquid film); 3450, 1732, 1374, 1240, 10
18 cm^-1 NMR spectrum (CDCl₃) δ; 2.06 (6H, s), 3.68 (3H, s),
4.4 to 5.0 (2H, m), 5.10 (1H, m). (H)1α-acetoxy-2α- (3-acetoxy-6
-Methoxycarbonylhexyl) -3β-formyl-4
α- (Tetrahydropyran-2-yloxy) cyclope
Tan Alcohol (compound of Reference Example 1 (g); 1.0 g)
Dissolve in dimethyl sulfoxide (10 ml),
Luamine (6.1 ml) was added. Under stirring to the reaction mixture
Dimethyl sulphate of pyridine-sulfuric acid anhydride complex (7.4g)
Add the hydroxide solution (5 ml) at room temperature and stir for 20 minutes.
Was. The reaction solution is poured into ice water and extracted with ethyl acetate. Extraction
The solution is saline, 2% hydrochloric acid containing ice, and then saline.
Wash and dry with sodium sulfate. Evaporate the solvent
Then, an oily crude target compound (1.03 g) was obtained. IR spectrum (liquid film); 2700, 1730, 1240, 1020cm^-1 NMR spectrum (CDCl₃) δ; 2.03 (3H, s), 2.07 (3H, s),
3.68 (3H, s), 5.15 (1H, m), 9.82 (1H, m). (I)5,9α-diacetoxy-11α- (tetrahydr
Ropran-2-yloxy) -15-oxo-16-fu
Enoxy-17,18,19,20-tetranorpros
To-13 (E) -enoic acid methyl ester 0.29 g of 55% oily sodium hydride with hexane
Wash and suspend in tetrahydrofuran (45 ml).
Under ice cooling, dimethyl-2-oxo-3-phenoxypropionate
Luphosphonate (2.54 g) was added, then 1 at room temperature.
Stir for hours. Aldehydes under ice cooling (Reference Example 1 (h)
A compound (1.34 g) in tetrahydrofuran (1
5 ml) is added. After the reaction solution was heated under reflux for 2 hours,
Cool, dilute with ice water, acidify with concentrated hydrochloric acid and ethyl acetate.
Extract with. After washing the extract with saline,
Dry with rium. The solvent is distilled off and the residue is silica gel.
Purify by column chromatography. 30-40% vinegar
1.35 g of oily eyes from the hexane outlet containing ethyl acidate
The target compound was obtained. IR spectrum (liquid film); 1738, 1696, 1624, 1602, 15
92, 1242cm^-1 NMR spectrum (CDCl₃) δ; 2.00 (3H, s), 2.07 (3H, s),
3.67 (3H, s), 4.3 ~ 5.3 (5H, m), 6.3 ~ 7.5 (7H, m). (J)5,9α-diacetoxy-11α- (tetrahydr
Ropyran-2-yloxy) -15α-hydroxy-1
6-phenoxy-17,18,19,20-tetranor
Prost-13 (E) -enoic acid methyl ester and its
15β-isomerCerium chloride heptahydrate (850mg)
Of methanol solution (8 ml) under ice-cooling with enone form (reference
A solution of the compound of Example 1 (i); 1.33 g) in methanol
(12.0 ml) is added. Then Natriborohydride
Umium (85 mg) was added at an internal temperature of -5-1 ° C for 15 minutes.
Stir. Dilute the reaction mixture with ice water and extract with ethyl acetate.
It The extract is washed with water and dried with sodium sulfate.
The solvent was distilled off and the residue was chromatographed on a silica gel column.
To purify. Run off with hexane containing 50% ethyl acetate
520 mg of 15β- than the less polar part
420 mg of 15 than the isomer and the more polar part
The α-isomer was obtained.15α-isomer IR spectrum (liquid film); 3460, 1734, 1600, 1588, 12
42 cm^-1 NMR spectrum (CDCl₃) δ; 2.00 (3H, s), 2.06 (3H, s),
3.67 (3H, s), 5.12 (1H, m), 5.72 (2H, m), 6.8 ~ 7.5 (5H,
m). 15β-isomer IR spectrum (liquid film); 3460, 1736, 1602, 1588, 12
42 cm^-1 NMR spectrum (CDCl₃) δ; 2.01 (3H, s), 2.05 (3H, s),
3.68 (3H, s), 5.13 (1H, m), 5.63 (2H, m), 6.8 ~ 7.5 (5H,
m). (K)5,9α-diacetoxy-11α, 15α-di
(Tetrahydropyran-2-yloxy) -16-fe
Noxy-17,18,19,20-tetranorprost
-13 (E) -enoic acid methyl ester 15 α-alcohol compound (Compound of Reference Example 1 (j); 40
0 mg) in methylene chloride solution (2 ml) with dihydro
Pyran (0.1 ml) and catalytic amount of p-toluenesul
Fononic acid is added and left at room temperature for 20 minutes. After the reaction, vinegar
After adding ethyl acetate and washing with water, dry with sodium sulfate.
Dry. When the solvent was distilled off, 0.48 g of an oily target compound was obtained.
The thing was obtained. IR spectrum (liquid film); 1738, 1600, 1588, 1242, 10
33 cm^-1 NMR spectrum (CDCl₃) δ; 1.95, 1.97 (3H, 2 peak),
2.03 (3H, s), 3.65 (3H, s), 5.15 (1H, m), 5.65 (2H, m), 6.
8 to 7.5 (5H, m). (L)5,9α-dihydroxy-11α, 15α-di
(Tetrahydropyran-2-yloxy) -16-fe
Noxy-17,18,19,20-tetranorprost
-13 (E) -enoic acid methyl ester Acetyl derivative (compound of Reference Example 1 (k); 460 mg)
To a methanol solution (9.2 ml) was added anhydrous potassium carbonate (1
90 mg), and the mixture is heated with stirring at 40 ° C. Two hours later,
The reaction mixture was diluted with ice water, neutralized with concentrated hydrochloric acid, and then diluted with ethyl acetate.
To extract. Wash the extract with saline and wash with sodium sulfate.
To dry. The solvent was distilled off and the residue was washed with silica gel column.
Purify by chromatography. 60-90% ethyl acetate
337 mg of the target product was found to be an oily substance from the hexane containing effluent.
It was obtained. IR spectrum (liquid film); 3450, 1738, 1600, 1588, 10
18 cm^-1 NMR spectrum (CDCl₃) δ; 3.66 (3H, s), 5.2〜5.9 (2
H, m), 6.8-7.5 (5H, m). (M)5-oxo-16-phenoxy-17,18,1
9,20-Tetranorprostaglandin E ₁ 11,
15-di (tetrahydropyran-2-yl) ether
Chill ester Oxalic acid dichloride (0.52 ml) dissolved in methylene chloride
Liquid (8 ml) was added to dimethyl sulfoxide (0.
85 ml of methylene chloride solution (1.6 ml) was added.
Get Then a hydroxy form (compound of Reference Example 1 (l);
320 mg of methylene chloride solution (3.2 ml)
Add at -65-55 ° C and stir for 15 minutes. In the reaction liquid
Triethylamine (3.77 ml) was added at 70-60 ° C.
Add and stir at room temperature for about 30 minutes. Dilute with saline and add acetic acid.
Extract with chill. The extract was brine, chilled 2% hydrochloric acid,
Wash with saline and dry with sodium sulfate.
It The solvent was distilled off and the residue was subjected to silica gel column chromatography.
Purify with Raffy. Hex containing 24-40% ethyl acetate
264 mg of oily target compound was obtained from the outflow part of the sun.
Was. IR spectrum (liquid film); 1738, 1712, 1600, 1583, 10
28 cm^-1 NMR spectrum (CDCl₃) δ; 3.65 (3H, s), 5.6 ~ 6.1 (2
H, m), 6.8-7.5 (5H, m). (N)5-oxo-16-phenoxy-17,18,1
9,20-Tetranorprostaglandin E ₁ Methyle
Steal Pyranyl compound (Compound of Reference Example 1 (m); 250 mg)
To a tetrahydrofuran solution (1.0 ml) was added acetic acid (2.5
ml) and water (6.8 ml) and heated to 40 ° C., at 3:00
Stir for a while. During that time, 33 ml of water was added. End of reaction
After that, the reaction solution is diluted with saline and extracted with ethyl acetate. Extraction
Wash the exudates with saline solution and dry with sodium sulfate.
It The solvent was distilled off and the residue was chromatographed on silica gel.
Purify with. Hexane outflow containing 65-90% ethyl acetate
From the part, 134 mg of the oily target compound was obtained. IR spectrum (liquid film); 3400, 1736, 1720 (sh), 159
8, 1584, 1240, 970cm^-1 NMR spectrum (CDCl₃) δ; 3.63 (3H, s), 5.77 (2H, m),
6.7 to 7.5 (5H, m). [Α]^{twenty five} _D = -50.7 (C = 1, MeOH).

Reference Example 2 5-oxo-16,16-dimethylprostaglandin
E ₁ methyl ester and its 15R-isomer (a) 5,9α-diacetoxy-11α- (tetrahydr
Ropran-2-yloxy) -15-oxo-16,1
Methyl 6-dimethylprost-13 (E) -enoate
Tel. 0.12 g of 55% oily sodium hydride is washed with hexane and suspended in tetrahydrofuran (30 ml).
After 820 mg of dimethyl-2-oxo-3,3-dimethylheptylphosphonate was added under ice cooling, the mixture was stirred at room temperature for 1 hour. A solution of an aldehyde derivative (compound of Reference Example 1 (h); 960 mg) in tetrahydrofuran under ice cooling (10 m
1) is added and stirred at 10 ° C. for 3 hours. After the completion of the reaction, the same treatment as in Reference Example 1 (i) was performed to obtain 1.12 g of the oily target compound. IR spectrum (liquid film); 1738, 1692, 1626, 1240, 10
20 cm ^-1 NMR spectrum (CDCl ₃ ) δ; 1.13 (6H, s), 2.01 (3H, s),
2.07 (3H, s), 3.68 (3H, s), 4.55 (1H, m), 4.70 (1H, m), 5.
15 (1H, m), 6.72 (2H, m). (B) 5,9α-diacetoxy-11α- (tetrahydr
Ropran-2-yloxy) -15-hydroxy-1
6,16-Dimethylprost-13 (E) -methanoic acid
The reaction and treatment were carried out in the same manner as in Reference Example 1 (j) using a luester ketone body (Compound of Reference Example 2 (a); 1.10 g) and sodium borohydride, to obtain 1.03 g of the oily target compound. . IR spectrum (liquid film); 3530, 1740, 1242, 1020cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.82 (3H, s), 0.86 (3H, s),
2.00 (3H, s), 2.05 (3H, s), 3.66 (3H, s), 5.15 (1H, m), 5.
62 (2H, m). (C) 5,9α-diacetoxy-11α, 15-di (te
Trahydropyran-2-yloxy) -16,16-di
Methylprost -13 (E) -enoic acid methyl ester alcohol compound (Compound of Reference Example 2 (b); 1.01 g)
Then, by reacting and treating with dihydropyran in the same manner as in Reference Example 1 (k), 1.22 g of the oily target compound was obtained. IR spectrum (liquid film); 1740, 1242, 1020cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.85 (3H, s), 0.90 (3H, s),
2.01 (3H, s), 2.05 (3H, s), 3.66 (3H, s), 5.45 (2H, m). (D) 5,9α-dihydroxy-11α, 15-di (te
Trahydropyran-2-yloxy) -16,16-di
Methylprost -13 (E) -enoic acid methyl ester acetyl derivative (Compound of Reference Example 2 (c); 1.20 g) and potassium carbonate were reacted in the same manner as in Reference Example 1 (l),
Upon treatment, 872 mg of the oily target compound was obtained. IR spectrum (liquid film); 3420, 1740, 1016cm ^-1 NMR spectrum (CDCl ₃ ) δ; 3.67 (3H, s), 4.68 (2H, br.
s), 5.45 (2H, m). (E) 5-oxo-16,16-dimethylprostagla
Engine E ₁ 11,15- di (tetrahydropyran-2
A) Mixture of ether methyl ester and 15R-isomer
Compound alcohol compound (Compound of Reference Example 2 (d); 850 m
g), oxalic acid dichloride and dimethyl sulfoxide were reacted and treated in the same manner as in Reference Example 1 (m) to yield 526 m.
g of the oily target compound was obtained. IR spectrum (liquid film); 1746, 1718, 1022, 978cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.7 to 1.1 (9H, m), 3.67 (3
H, s), 4.68 (2H, br.s), 5.55 (2H, m). (f) 5-oxo-16,16-dimethylprostalangeline E ₁ methyl ester and
And its 15R-isomer ketone compound (compound of Reference Example 2 (e); 520 mg) and acetic acid were reacted and treated in the same manner as in Reference Example 1 (n) to give 64 mg of oily 15R isomer from the less polar portion. , Then melting point 60-65 ° C than the more polar part
72 mg of the desired compound having a IR spectrum (liquid film); 3410, 1738, 972cm ^-1 NMR spectrum (CDCl ₃ ) δ; 0.7 to 1.05 (9H, m), 3.66 (3
H, s), 5.67 (2H, m) [α] ²⁴ _D = -35.3 (c = 1, MeOH). 15R-isomer: IR spectrum (liquid film form); 3450, 1740, 975 cm ^-1 .

[0145]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention or a salt thereof has an excellent anti-ethanol ulcer activity and is extremely weak in the inhibitory effect on platelet aggregation, which is a serious side effect when it is used as a drug. It is extremely useful as a therapeutic and preventive agent for ulcer.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Keiichi Tabata 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Yoshiyoshi Iwata 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents an optionally protected carboxy group,
A tetrazolyl group, an optionally substituted carbamoyl group, an optionally protected hydroxymethylcarbonyl group or an optionally protected hydroxymethyl group, wherein R ² and R ³ are the same or different and each is a hydrogen atom or a hydroxyl group. And R ⁴ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, and R ⁵ represents an optionally substituted alkyl group or an optionally substituted alkenyl group (including a dienyl group). , An optionally substituted alkynyl group or a group having the formula —B—R ⁶ [wherein B may be a single bond or an oxygen atom, a sulfur atom or a vinylene group;
_{1 to} C ₆ alkylene group (straight or branched), R
⁶ represents an optionally substituted C ₃ -C ₁₀ cycloalkyl group, aryl group, heterocyclyl group or heteroaryl group. ], A is an ethylene group, a vinylene group, an ethynylene group or a formula —O—CH ₂ — or —S—.
Represents a group having CH ₂ —, m represents an integer of 2, and n
Represents an integer of 2 to 5. ] Or a salt thereof.