JP2788657B2 - New compound Cornegistin derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Purpose] (Industrial application field) The present invention relates to a novel Cornegistin derivative having excellent seed germination inhibitory action, plant growth inhibitory action and herbicidal activity.

(Problems to be Solved by the Invention) The present inventors have conducted intensive studies on the synthesis and activity of a new compound, a cornegistin derivative, for many years, and as a result, the novel compound of the present invention was found to be excellent in seed The present invention was found to have a germination inhibitory action, a plant growth inhibitory action and a herbicidal activity, and completed the present invention.

[Constitution] The novel Cornegistin derivative of the present invention has the following general formula (1) [Wherein, R ¹ and R ² are the same or different and represent a carboxy group or a carbamoyl group, or together form a general formula (Wherein X, Y and Z are the same or different and each represent an oxygen atom or an imino group), and R ³ and R ⁶ are the same or different and are a hydroxyl group, a mercapto group, or an amino group. Or a halogen atom, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a hydroxyl group, or R ⁴ and R ⁵ together represent an oxo group or an imino group, and A represents an oxygen atom Or a single bond. Or a derivative in which a hydroxyl group, a mercapto group, an amino group, a carboxy group, a carbamoyl group or / and an imino group in the molecule is protected, and a salt thereof, and (2) the above (1). (3) a compound in which the protecting group for the hydroxyl group and / or the mercapto group of the compound of (1) is protected by a protecting group selected from the following groups A, B and C; (4) a compound of the amino group, the carboxy group, the carbamoyl group and / or the imino group in which the protecting group is protected by a protecting group selected from the following group A; [Wherein, R ¹ ′ and R ² ′ are the same or different and each represent a carboxy group which may be protected or an carbamoyl group which may be protected, or together form a general formula (Wherein X, Y and Z are the same or different and each represent an oxygen atom or an imino group which may be protected), and R ³ ′ and R ⁶ ′ are the same or different. Represents an optionally protected hydroxyl group, an optionally protected mercapto group, an optionally protected amino group or a halogen atom, and R ⁴ ′ and R ⁵ ′ are the same or different and are a hydrogen atom or a protected R ⁴ ′ and R ⁵ ′ together represent an oxo group or an imino group which may be protected, and A represents an oxygen atom or a single bond. Or (5) general formula In the formula, R ¹ ′ and R ² ′ are the same or different and may be protected carboxy groups (the protecting groups include the following A
Shows a group selected from the group. ) Or a carbamoyl group which may be protected (the protecting group is a group selected from the following group A) or together form a general formula [Wherein, X, Y and Z are the same or different and each represent an oxygen atom or an imino group which may be protected (the protecting group is a group selected from the following group A). ]
R ³ ′ and R ⁶ ′ are the same or different and each may be a protected hydroxyl group (for the protective group, a group selected from the following group A, group B and group C) ), A mercapto group which may be protected (for the protecting group, the following groups A and B
The group selected from the group and group C is shown. ), An amino group which may be protected (the protecting group is a group selected from the following group A) or a halogen atom, and R ⁴ ′ and R ⁵ ′ are the same or different; A hydrogen atom or a hydroxyl group which may be protected (the protecting group is a group selected from the following groups A, B and C), or R ⁴ ′ and R ⁵ ′ together Represents an oxo group or an imino group which may be protected (the protecting group is a group selected from the following group A), and A represents an oxygen atom or a single bond. It is represented by｝.

However, [3S ^* , 4R ^* , 7R ^* ]-3-n-propyl-4,7
-Dihydroxy-5-oxo-8 (Z) -ethylidene-
1-cyclononene-1,2-dicarboxylic anhydride and [3S ^* ,
4R ^* , 7R ^* ]-3-n-propyl-4,7-dihydroxy-
Excluding 5-oxo-8 (Z) -ethylidene-1-cyclononene-1,2-dicarboxylic acid and salts thereof.

Group A lower alkyl group; silyl lower alkyl group; aliphatic acyl group; aromatic acyl group; lower alkoxy lower aliphatic acyl group; aryloxy lower aliphatic acyl group; aralkylcarbonyl group; aralkyl group; aromatic acyl lower alkyl group Disubstituted lower alkoxyphosphinyl group; disubstituted lower alkoxythiophosphinyl group; disubstituted lower alkoxyphosphinyl lower alkyl group; disubstituted lower alkoxythiophosphinyl lower alkyl group; lower alkanesulfonyl group; Lower alkanesulfonyl group; arylsulfonyl group; lower alkanesulfonyl lower alkyl group; fluorinated lower alkanesulfonyl lower alkyl group; arylsulfonyl lower alkyl group; alkoxycarbonyl group; alkenyloxycarbonyl group; An aralkyloxycarbonyl group;
Lower alkenyl group; lower alkynyl group; lower alkoxy lower alkyl group; carbamoyl group which may be substituted; aminosulfonyl lower alkyl group which may be substituted; sulfonamide group which may be substituted; carboxy lower alkyl group; Protected carboxy lower alkyl groups. Group B heteroarylcarbonyl group; heteroarylthiocarbonyl group; silyl group. Group C As divalent protecting groups, oxomethylene; thioxomethylene; lower alkylidene group; aralkylidene group; alkoxyethylidene group; divalent sulfonyl group; divalent phosphinyl group; divalent thiophosphinyl group; divalent silyl group . In the above formula, the “halogen atom” in the definition of R ³ and R ⁶ indicates a halogen atom such as fluorine, chlorine, bromine and iodine.

"Imino group" wherein X, Y and Z are the same or different
Represents the formula = NH or -NH-.

The “imino group” represented by R ⁴ and R ⁵ together has the formula: NH
Is shown.

The "lower alkyl group" in the definition of Group A includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl,
A straight or branched chain having 1 to 6 carbon atoms such as 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl Represents an alkyl group, preferably an alkyl group having 1 to 4 carbon atoms.

The “silyl lower alkyl group” in the definition of Group A is
The “silyl group” described below indicates a group substituted by the “lower alkyl group”, for example, a trimethylsilylmethyl group, 1-
Examples thereof include a (trimethylsilyl) ethyl group and a dimethylisopropylsilylmethyl group.

The “aliphatic acyl group” in the definition of Group A is an optionally substituted alkylcarbonyl or unsaturated alkylcarbonyl group (the substituent may be the aforementioned halogen atom or methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy) , S-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy,
-Methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3- It represents a linear or branched lower alkoxy group having 1 to 6 carbon atoms such as dimethylbutoxy, and is preferably a halogen atom or an alkoxy group having 1 to 4 carbon atoms. ), For example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
Pivaloyl, valeryl, isovaleryl, octanoyl,
Alkylcarbonyl groups such as lauroyl, myristoyl, tridecanoyl, palmitoyl and stearoyl; halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl; lower alkoxyalkylcarbonyl groups such as methoxyacetyl; ) -2-Methyl-2-butenoyl and the like, and an unsaturated alkylcarbonyl group, such as an alkylcarbonyl group, is preferred.

The “aromatic acyl group” in the definition of Group A represents an arylcarbonyl group, and the “aryl group” is an aromatic hydrocarbon group having 5 to 12 carbon atoms such as phenyl and naphthyl. The group may have 1 to 4 substituents selected from the following on the ring, and the substituent on the ring includes an amino group; a nitro group; a cyano group; A carboxy group optionally substituted with a lower alkyl halide or an aralkyl described below; a carbamoyl group; the halogen atom; the lower alkyl group; the lower alkoxy group; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl , Fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl , 2-fluoroethyl, 2,2
Halogenated lower alkyl groups such as dibromoethyl; the above-mentioned aliphatic acyl groups and alkylenedioxy groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy and propylenedioxy; Examples thereof include arylcarbonyl groups such as benzoyl, α-naphthoyl and β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl,
A lower alkylated arylcarbonyl group such as toluoyl, a lower alkoxylated arylcarbonyl group such as 4-anisoyl, a nitrated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl,
A lower alkoxycarbonylated arylcarbonyl group such as (methoxycarbonyl) benzoyl, an arylated arylcarbonyl group such as 4-phenylbenzoyl and the like can be mentioned, and an arylcarbonyl group is preferable.

The term "lower alkoxyaliphatic acyl group" in the definition of Group A refers to a group in which the "lower alkoxy group" has been substituted by the "aliphatic acyl group", for example, methoxyacetyl, methoxypropionyl, ethoxybutyryl. Groups.

The “aryloxyaliphatic acyl group” in the definition of Group A refers to a group in which the “aryloxy group” in which the “aryl group” is bonded to an oxygen atom is an oxygen atom and is substituted by the “aliphatic acyl group”. Examples thereof include a phenoxyacetyl group, a 2,4-dichlorophenoxyacetyl group, a phenoxypropionyl group, and a naphthyloxybutyryl group.

The “aralkyl group” in the definition of Group A indicates a group in which the “aryl group” has been substituted with the “lower alkyl group”, for example, a benzyl group, a 4-methoxybenzyl group,
Examples thereof include a 4-dimethoxybenzyl group, a phenethyl group, a phenylpropyl group, and a diphenylmethyl group.

The “aralkylcarbonyl group” in the definition of Group A indicates a group in which the above “aralkyl group” has been substituted with a carbonyl group, and examples thereof include a phenylacetyl group, a phenylpropionyl group, and a phenylbutyryl group.

"Aromatic acyl lower alkyl group" in the definition of Group A
Means a group in which the "aromatic acyl group" is substituted with the "lower alkyl group", and examples thereof include a benzoylmethyl group, a 4-bromobenzoylmethyl group, a 4-toluoylmethyl group, and a benzoylethyl group. Can be.

The term “di-substituted lower alkoxyphosphinyl group” in the definition of Group A refers to a group in which two molecules of the “lower alkoxy group” are substituted by a phosphinyl group, for example, a dimethoxyphosphinyl group, a diethoxyphosphonyl group. Groups such as a finyl group, a methoxyethoxyphosphinyl group, a dipropoxyphosphinyl group, and a methoxypropoxyphosphinyl group can be exemplified.

The term "di-substituted lower alkoxythiophosphinyl group" in the definition of Group A refers to a group in which two molecules of the above "lower alkoxy group" are substituted by a thiophosphinyl group, such as a dimethoxythiophosphinyl group, Ethoxythiophosphinyl group, methoxyethoxythiophosphinyl group,
Groups such as a dipropoxythiophosphinyl group and a methoxypropoxythiophosphinyl group can be exemplified.

The “disubstituted lower alkoxyphosphinyl lower alkyl group” in the definition of Group A refers to a group in which the “disubstituted lower alkoxyphosphinyl group” is substituted with the “lower alkyl group”. Examples include a phosphinylmethyl group, a diethoxyphosphinylmethyl group, a methoxyethoxyphosphinylethyl group, a dipropoxyphosphinylethyl group, and a methoxypropoxyphosphinylmethyl group.

The “disubstituted lower alkoxythiophosphinyl lower alkyl group” in the definition of Group A means that the “disubstituted lower alkoxythiophosphinyl group” is the “lower alkyl group”
And represents, for example, a dimethoxythiophosphinylmethyl group, a diethoxythiophosphinylmethyl group, a methoxyethoxythiophosphinylethyl group, a dipropoxythiophosphinylethyl group, a methoxypropoxythiophospho group. Groups such as a finylmethyl group can be mentioned.

The term "lower alkanesulfonyl group" in the definition of Group A refers to a group in which the aforementioned "lower alkyl group" has been substituted with a sulfonyl group. Can be mentioned.

The term “fluorinated lower alkanesulfonyl group” in the definition of Group A refers to a group in which the lower alkane part of the above “lower alkanesulfonyl group” is substituted with fluorine, for example, trifluoroethanesulfonyl group, pentafluoroethane Groups such as a sulfonyl group can be mentioned.

The “arylsulfonyl group” in the definition of Group A is
The "aryl group" represents a group substituted by a sulfonyl group, and examples thereof include groups such as a benzenesulfonyl group and a p-toluenesulfonyl group.

The term “lower alkanesulfonyl lower alkyl group” in the definition of Group A refers to a group in which the above “lower alkane sulfonyl group” has been substituted with a “lower alkyl group”, for example, methanesulfonylmethyl group, ethanesulfonylmethyl group,
And groups such as -propanesulfonylmethyl group, methanesulfonylethyl group, ethanesulfonylethyl group and 1-propanesulfonylethyl group.

The “fluorinated lower alkanesulfonyl lower alkyl group” in the definition of Group A refers to a group in which the “fluorinated lower alkanesulfonyl group” is substituted with the “lower alkyl group”, for example, trifluoromethanesulfonyl Examples of such groups include a methyl group, a pentafluoromethanesulfonylmethyl group, a trifluoromethanesulfonylethyl group, and a pentafluoroethanesulfonylethyl group.

The “arylsulfonyl lower alkyl group” in the definition of Group A refers to a group in which the “arylsulfonyl group” has been substituted with the “lower alkyl group”, for example, benzenesulfonylmethyl group, p-toluenesulfonylmethyl group, benzene Groups such as a sulfonylethyl group and a p-toluenesulfonylethyl group can be exemplified.

The term "alkoxycarbonyl group" in the definition of Group A refers to a group in which the above "lower alkoxy group" has been substituted with a carbonyl group, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, an isobutoxycarbonyl group. Such groups can be mentioned.

The term “alkenyloxycarbonyl group” in the definition of Group A refers to a group in which the “lower alkenyl group” described below is substituted with an oxycarbonyl group, for example, having 3 to 7 carbon atoms such as vinyloxycarbonyl group and allyloxycarbonyl group. Alkenyloxycarbonyl groups.

“Aryloxycarbonyl group” in the definition of Group A
"" Means a group in which the above "aryl group" is substituted with an oxycarbonyl group, and examples thereof include groups such as a phenoxycarbonyl group, a naphthyloxycarbonyl group and a p-chlorophenoxycarbonyl group.

The “aralkyloxycarbonyl group” in the definition of Group A refers to a group in which the “aralkyl group” has been substituted with an oxycarbonyl group, for example, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3,4
Groups such as a -dimethoxybenzyloxycarbonyl group, a 2-nitrobenzyloxycarbonyl group, and a 4-nitrobenzyloxycarbonyl group.

The term "lower alkenyl group" in the definition of Group A means at least one double bond such as vinyl group, 1-butenyl group, 2-butenyl group, 1-propenyl group and 2-propenyl group, Shows a group contained in the molecule.

The “lower alkynyl group” in the definition of Group A is 1-
Butynyl group, 2-butynyl group, 1-propynyl group, 2-
A group having at least one triple bond such as a propynyl group in the molecule of a lower alkyl group.

The “lower alkoxy lower alkyl group” in the definition of Group A refers to a group in which the “lower alkoxy group” has been substituted with a “lower alkyl group”, for example, a methoxymethyl group,
1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group,
Examples include groups such as a butoxymethyl group, a t-butoxymethyl group, a 1-ethoxyethyl group, and a 1- (isopropoxy) ethyl group.

The “pyranyl group” in the definition of Group A is a 3-halogenotetrahydropyranyl group such as a 2-tetrahydropyranyl group or a 3-bromotetrahydropyranyl group, a 2-tetrahydrothiopyranyl group, or a 4-methoxytetrahydropyranyl group. Groups such as a 4-lower alkoxytetrahydropyranyl group such as a methyl group and a 4-lower alkoxytetrahydrothiopyranyl group such as a 4-methoxytetrahydrothiopyranyl group.

The “furanyl group” in the definition of Group A includes groups such as a 2-tetrahydrofuranyl group and a 2-tetrahydrothiofuranyl group.

The “optionally substituted carbamoyl group” in the definition of Group A indicates a group in which one or two carbamoyl groups may be substituted with the following substituents.
The "lower alkyl group", the "lower alkenyl group",
The “lower alkynyl group”, the “lower alkoxy group”, the “aralkyloxy group” or the “aryl group” can be exemplified.

The “aminosulfonyl lower alkyl group which may be substituted” in the definition of Group A is an aminosulfonylmethyl group, an aminosulfonylethyl group, an aminosulfonylpropyl group, an aminosulfonylbutyl group, an aminosulfonylpentyl group, an aminosulfonylhexyl group And the like, the amino group of "aminosulfonyl lower alkyl group" is substituted with the substituent described in the definition of "carbamoyl group which may be substituted".

The “optionally substituted sulfonamido group” in the definition of Group A is the same as the “substituted carbamoyl group” described above in that the nitrogen atom of the “sulfonamido group” is substituted. The following groups are shown.

The term "carboxy lower alkyl group" in the definition of Group A refers to a group in which a carboxy group is substituted with the above "lower alkyl group", for example, carboxymethyl group, carboxyethyl group, carboxypropyl group, carboxybutyl group,
Examples include a carboxypentyl group and a carboxyhexyl group.

The term "protected carboxy lower alkyl group" in the definition of Group A refers to a group in which the carboxy group of the above "carboxy lower alkyl group" is protected by the following protecting group, and the protecting group includes the aforementioned "lower alkyl group"",The" halogeno lower alkyl group ", the" aralkyl group ", the" lower alkoxy lower alkyl group ", an acetoxymethyl group, a propionyloxymethyl group, a butyryloxymethyl group,
Aliphatic acyloxymethyl group such as pivaloyloxymethyl group or 1-methoxycarbonyloxyethyl group,
1-ethoxycarbonyloxyethyl group, 1-propoxycarbonyloxyethyl group, 1-isopropoxycarbonyloxyethyl group, 1-butoxycarbonyloxyethyl group, 1-isobutoxycarbonyloxyethyl group, 1-cyclohexyloxycarbonyloxyethyl group And a 1-lower alkoxycarbonyloxyethyl group.

"Heteroarylcarbonyl group" in the definition of Group B
Is a group in which a “heteroaryl group” is substituted with a carbonyl group, and the “heteroaryl group” is a 5- to 7-membered aromatic heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms. A group such as furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3
-Oxadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, pyridyl group, pyridazinyl group,
Examples thereof include a pyrimidinyl group, a quinolyl group, and an isoquinolyl group, which preferably contain at least one nitrogen atom and may contain an oxygen atom or a sulfur atom.
A membered heterocyclic group, for example, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-oxadiazolyl group,
Triazolyl group, tetrazolyl group, thiadiazolyl group,
Examples include a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a quinolyl group, and an isoquinolyl group.

The “heteroarylthiocarbonyl group” in the definition of Group B represents the same group as the above-mentioned “heteroarylcarbonyl group” in which the carbonyl group has become a thiocarbonyl group.

The “silyl group” in the definition of Group B may be any group bonded by a silicon atom, and includes, for example, trimethylsilyl,
Triethylsilyl, isopropyldimethylsilyl, t-
Butyldimethylsilyl, methyldiisopropylsilyl,
Tri-lower alkylsilyl groups such as methyldi-t-butylsilyl and triisopropylsilyl; 1 such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl
Tri-lower alkylsilyl groups substituted with 1 to 2 aryl groups; tri-lower alkylsilyl groups substituted with 1 to 2 halogen atoms such as chloromethyldimethylsilyl, chloromethyldiisopropylsilyl, di (chloromethyl) methylsilyl Groups; tri-lower alkylsilyl groups substituted with alkenyl groups such as allyldimethylsilyl and vinyldimethylsilyl.

The “lower alkylidene group” in the definition of Group C includes, for example, groups such as methylidene, ethylidene and isopropylidene.

The “aralkylidene group” in the definition of Group C includes, for example, a benzylidene group.

The “alkoxyethylidene group” in the definition of Group C includes, for example, methoxyethylidene and ethoxyethylidene groups.

The “divalent sulfonyl group” in the definition of Group C indicates a group having the formula —SO ₂ —.

The “divalent phosphinyl group” in the definition of Group C is
For example, "lower alkyl" such as methylphosphinyl
A phosphinyl group [-P (= 0) (lower alkyl)-],
A "lower alkoxy" phosphinyl group [-P (= 0) (lower alkoxy)-] such as methoxyphosphinyl; an [aryl] phosphinyl group [-P (= 0) (aryl)-such as phenylphosphinyl; ], An "aryl" oxyphosphinyl group such as phenoxyphosphinyl [-
P (= 0) (aryloxy)-] and the like.

The “divalent thiophosphinyl group” in the definition of Group C is, for example, a “lower alkyl” thiophosphinyl group such as methylthiophosphinyl [—P (＝ S) (lower alkyl) —], methoxythiophosphinyl Such as "lower alkoxy" thiophosphinyl group [-P (= S) (lower alkoxy)-], "aryl" thiophosphinyl group such as phenylthiophosphinyl [-P (= S) (aryl)-], phenoxythio Groups such as "aryl" oxythiophosphinyl groups such as phosphinyl [-P (= S) (aryloxy)-] can be mentioned.

The “divalent silyl group” in the definition of Group C includes, for example, di “lower alkyl” silyl groups such as dimethylsilyl [—Si (lower alkyl) (lower alkyl) —] and “phenylmethylsilyl” such as phenylmethylsilyl. Aryl, lower alkyl, silyl group [-Si (aryl) (lower alkyl)
-], Di "aryl" silyl groups such as diphenylsilyl [-Si (aryl) (aryl)-], di "lower alkoxy" silyl groups such as dimethoxysilyl [-Si (lower alkoxy) (lower alkoxy)- And the like.

The “optionally protected carboxy group” in the definition of R ¹ ′ and R ² ′ is a carboxy group which may be protected by a carboxy group protecting group commonly used in a reaction or as a prodrug. And the protecting group is preferably a group selected from the group A.

The `` carbamoyl group which may be protected '' in the definition of R ¹ ′ and R ² ′ is a protecting group for a carbamoyl group usually used in a reaction or as a prodrug,
It represents a carbamoyl group which may be protected, and the protecting group is preferably a group selected from the group A.

The "optionally protected imino group" in the definition of X, Y and Z indicates an imino group which may be protected by a protecting group for an imino group commonly used in a reaction or as a prodrug. The protecting group is preferably a group selected from the group A.

The “optionally protected hydroxyl group” in the definition of R ³ ′, R ⁴ ′, R ⁵ ′ and R ⁶ ′ is a protected hydroxyl group commonly used in a reaction or as a prodrug. Represents a hydroxyl group which may be, as such a protecting group,
Preferably, it is a group selected from the groups A, B and C.

The “optionally protected mercapto group” in the definition of R ³ ′ and R ⁶ ′ is a mercapto group which may be protected by a mercapto group-protecting group commonly used in a reaction or as a prodrug. And the protecting group is preferably a group selected from the above-mentioned groups A, B and C.

The “optionally protected amino group” in the definition of R ³ ′ and R ⁶ ′ refers to an amino group which may be protected by a protecting group for an amino group usually used in a reaction or as a prodrug. And the protecting group is preferably a group selected from the group A.

The `` optionally protected imino group '' represented by R ⁴ ′ and R ⁵ ′ together may be an imino group which may be protected by a protecting group for an imino group commonly used in a reaction or as a prodrug. It shows a good imino group, and such a protecting group is preferably a group selected from the group A.

Note that the stereoscopic display indicated by the symbol * indicates one enantiomer of the relative structure, for example, [3
The notation [S ^* , 4R ^* , 7R ^* ] means that either the compound having the absolute structure of [3S, 4R, 7R] or the compound having the absolute structure of [3R, 4S, 7S] is an optically active compound. It shall indicate the enantiomer. This is because the absolute structure of cornegistin obtained from nature, which is the raw material compound of the present invention, has not been determined yet. In the present application, [3S ^* , 4R ^* , 7R
^* ] ^Indicates that the compound has the same absolute structure as natural Cornegistin.

The compounds of the present invention may be in the form of a salt, preferably a salt of an alkali metal or alkaline earth metal such as a sodium, potassium or calcium salt; an ammonium salt; Salts, aliphatic amine salts such as diethylamine salt; aromatic amine salts such as aniline salt; hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide , Nitrates, perchlorates, sulfates, phosphates and other inorganic salts; lower alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfonate; Aryl sulfonates such as toluene sulfonate, fumarate, succinate,
Organic salts such as citrate, tartrate, oxalate and maleate and amino acid salts such as glutamate and aspartate can be mentioned.

The compound of the present invention has an asymmetric carbon in the molecule, and there are stereoisomers each having S-coordinate and R-coordinate, and each of them or a mixture thereof is included in the present invention. You.

Among the compounds of the present application, preferred compounds include: (1) a compound whose steric configuration is [3S ^* , 4R ^* , 7R ^* ].

(2) A compound wherein 8-position is Z when A represents a single bond.

(3) The compound in the formula (I), wherein R ¹ and R ² are the same or different and each is a carboxy group.

(4) In the general formula (I), R ¹ and R ² are taken together to form a general formula [In the formula, X, Y and Z each represent an oxygen atom. ] The compound which is a group which has this.

(5) The compound in the formula (II), wherein R ¹ ′ and R ² ′ are the same or different and each is an optionally protected carboxy group.

(6) In the general formula (II), one of R ¹ ′ and R ² ′ is
A compound which is a carboxy group or a carbamoyl group, and the other is a protected carboxy group.

(7) The compound in the formula (I), wherein R ³ , R ⁴ and R ⁶ are hydroxyl groups.

(8) In the general formula (II), R ³ ′, R ⁴ ′ and R ⁶ ′
A compound which is a hydroxyl group which may be protected.

(9) The compound of the formula (I), wherein R ⁵ is a hydrogen atom.

(10) The compound in the formula (I), wherein A is a single bond.

(11) In the general formula (I), R ⁴ and R ⁵ together
A compound that is an oxo group.

Can be mentioned.

The Cornegistin derivative of the present invention can be produced by the method described below.

In the above formula, R ³ ′ and R ⁶ ′ have the same meaning as described above.

R ³ ″ and R ⁶ ″ represent the same groups as the “protected hydroxyl group” included in the definitions of R ³ ′ and R ⁶ ′;
A hydroxyl group protected by a protecting group selected from the group and group C, wherein R ⁷ and R ⁸ are the same or different and are a hydrogen atom or the above-mentioned “amino, carbamoyl or / and imino group-protecting group”; It shows the same group and shows a protecting group selected from the group A.

R ⁹ and R ¹⁰ are the same or different and represent the same group as the “protecting group for carboxy group”, and represent a protecting group selected from Group A.

R ¹¹ represents a group selected from the above “aryl group” and the above “arylsulfonyl group”.

 Hal represents the aforementioned “halogen atom”.

[Method] is Cornegistin (III)
Is a method for protecting the hydroxyl group at the 4-position and / or the 7-position.

The protection of the hydroxyl group is performed according to a conventional method, for example,
As a method by acylation, R ¹² OH (where R ¹²
Has the same significance as the acyl residue selected from Group A and Group B. Is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole.

In addition, the activated reagent R ¹² -Q (where R ¹² is
A group selected from the group selected from the group, group B and group C;
Generally radicals having OR ^12; chlorine, bromine, halogen atom such as iodine; acetoxy, propionyloxy alkylcarbonyloxy group such as oxy, chloro acetyloxy, dichloroacetyl oxy, trichloroacetyloxindole, the trifluoroacetyloxy A halogenated alkylcarbonyloxy group, a lower alkoxyalkylcarbonyloxy group such as methoxyacetyloxy,
(E) an aliphatic acyloxy group such as an unsaturated alkylcarbonyloxy group such as 2-methyl-2-butenoyloxy; an arylcarbonyloxy group such as benzoyloxy, 2-bromobenzoyloxy, and 4-chlorobenzoyloxy; Halogenated arylcarbonyloxy group, 2,4,6-trimethylbenzoyloxy, lower alkylated arylcarbonyloxy group such as 4-toluoyloxy, lower alkoxylated arylcarbonyloxy group such as 4-anisoyloxy, Aromatic acyloxy groups such as nitrated arylcarbonyloxy groups such as 4-nitrobenzoyloxy and 2-nitrobenzoyloxy; trihalogenomethyloxy groups such as trichloromethyloxy; methanesulfonyloxy and ethanesulfonyloxy Lower alkanesulfonyl group; trifluoromethanesulfonyloxy, halogeno lower alkanesulfonyloxy groups such as pentafluoroethane sulfonyloxy; benzenesulfonyloxy,
A leaving group such as an arylsulfonyloxy group such as p-toluenesulfonyloxy is shown. ) In a solvent in the presence of a base.

The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform, or carbon tetrachloride; an ether such as ether, dioxane, or tetrahydrofuran; hexane. Hydrocarbons such as benzene; aromatic hydrocarbons such as benzene and toluene; esters such as ethyl acetate;
Examples include polar solvents such as dimethyl sulfoxide and dimethylformamide.

The base used is preferably an alkali metal hydride such as sodium hydride or potassium hydride; an alkali metal carbonate such as potassium carbonate or sodium carbonate; an alkali metal amide such as sodium amide;
Inorganic bases such as alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; or tri-lower alkylamines such as triethylamine and diisopropylethylamine; heteroaromatics such as pyridine and N, N-dimethylaminopyridine Aliphatic tertiary amines; alicyclic cyclic amines such as DBU, DBN and DABCO; and organic bases such as aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline. .

The reaction is carried out at a temperature of 0 ° C to 100 ° C, preferably 20 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of solvent used, but is usually from 10 minutes to 24 hours.

 Specifically, this is performed as follows.

In the case of silylation, a solvent that does not inhibit the reaction is preferably used, and dimethylformamide, amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, and ether are preferable. , Tetrahydrofuran, ethers such as dioxane, ethyl acetate, esters such as propyl acetate, methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane and tetrachloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, and ketones such as acetone and methyl ethyl ketone are used. The reagents used are preferably lower trialkylsilyl halides, which are usually readily available. As the base to be used, imidazole, triethylamine, pyridine and the like are used, but the present invention is not particularly limited thereto, and the reaction is carried out at −20 to 50 ° C.
The amount of the silyl halide to be used with respect to Cornegistin depends on whether only one of the two hydroxyl groups is protected or both are protected, but is 1 to 5 equivalents. It is preferable that the base used is also changed in accordance with the amount of silyl halide used.

When acylating with an acid anhydride, the solvent used is not particularly limited as long as it does not inhibit the reaction, and an acid anhydride as a reaction reagent can also be used.
Toluene, aromatic hydrocarbons such as xylene, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, ethers such as ether, tetrahydrofuran, dioxane, esters such as ethyl acetate and propyl acetate, Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and tetrachloroethane, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide are used. The reagent used is a lower aliphatic carboxylic anhydride or an aromatic carboxylic anhydride. The reaction proceeds in the presence or absence of a base, and pyridine, triethylamine, or the like is used as the base to be used, but is not particularly limited thereto. Addition of a catalytic amount of a strong base, such as 4- (dimethylamino) pyridine, in addition to the above base may be effective to drive the reaction and is carried out at -20 to 50C.

When reacting with an acyl halide such as methoxyacetyl chloride, the reaction is carried out in the presence of a base, and the reaction is exactly the same except that an acid halide is used instead of the above acid anhydride. Examples of the acid halides used include lower aliphatic acyl halides, aromatic acyl halides, lower alkoxy aliphatic acyl halides, aryloxy lower aliphatic acyl halides, lower alkoxycarbonyl halides, and carbamoyl halides which may be substituted. be able to.

Such a hydroxyl-protecting reaction can be selectively carried out at the 4- or 7-position based on steric factors. For example, as a reagent, a bulky trialkylsilyl such as t-butyldimethylsilyl chloride is used. When a halide is used, the fact that the 7-position hydroxyl group is an active allyl alcohol, that the 4-position hydroxyl group is inactivated by the steric influence of the adjacent n-propyl group, and that the reagent itself is bulky. Therefore, compound (IV) in which only position 7 is selectively protected can be produced (first step).

Further, for example, when a sulfonyl chloride such as methanesulfonyl chloride or p-toluenesulfonyl chloride is used as a reagent, the 4- and 7-positions are simultaneously protected due to the high reactivity of the reagent. As is generally known, the compound is an unstable allyl sulfonate, and can be easily decomposed to produce a compound (V) in which only the 4-position is selectively protected (step 3) ).

Further, the compound (IV) or (V) selectively produced above
Is protected in the same manner with the same or another protecting group, whereby compound (VI) can be produced (second step,
Fourth step).

On the other hand, the hydroxyl groups at the 4- and 7-positions of the compound (III) can be simultaneously protected with the same protecting group according to the above, and when the hydroxyl groups are adjacent to each other, particularly, when R ⁴ or R ⁵ is When it is a hydroxyl group, the diol can be simultaneously protected with the divalent protecting group described in the above-mentioned Group C (fifth step).

Such protection of the diol is carried out according to a conventional method, for example, as follows.

When the protecting group is an oxomethylene group, the solvent used is preferably an aromatic hydrocarbon such as benzene or toluene; a halogenated hydrocarbon such as dichloroethane, methylene chloride or chloroform; Ethers such as tetrahydrofuran, dioxane and dimethoxyethane; amides such as dimethylformamide, dimethylacetamide, and hexaphosphorotriamide; sulfoxides such as dimethylsulfoxide or esters such as ethyl acetate and methyl acetate; The reagent used is preferably phosgene; a carbonate such as diethyl carbonate or dimethyl carbonate or a carbonyldiazole such as carbonyldiimidazole.

The reaction is carried out at a temperature of 0 to 150 ° C., and the reaction time is usually 10 minutes to 10 hours, although it depends mainly on the reaction temperature, the kind of the starting compound and the type of the solvent used.

When the protecting group is a thioxomethylene group, the solvent used, the reaction temperature, and the reaction time are the same as when the protecting group is an oxomethylene group, and the reagent used is preferably thiophosgene. Or thiocarbonyldiazoles such as thiocarbonyldiimidazole.

When the protecting group is a lower alkylidene group, an aralkylidene group or an alkoxyethylidene group, the solvent used is preferably an aromatic hydrocarbon such as benzene or toluene; or a solvent such as dichloroethane, methylene chloride or chloroform. Halogenated hydrocarbons; ethers,
Ethers such as tetrahydrofuran, dioxane and dimethoxyethane; amides such as dimethylformamide, dimethylacetamide and hexaphosphorotriamide; sulfoxides such as dimethylsulfoxide or nitriles such as acetonitrile. Are preferably ketones such as acetone, aldehydes such as benzaldehyde, carbonates such as diethyl carbonate and dimethyl carbonate, ketals such as dimethoxypropane or benzaldehyde dimethyl acetal, which correspond to the protecting group. Acetals like this.

The reaction is carried out at a temperature of 0 to 180 ° C., and the reaction time is usually 30 minutes to 20 hours, although it depends mainly on the reaction temperature, the type of the starting compound and the type of the solvent used.

When the protective group is a divalent sulfonyl group, a divalent phosphinyl group, a divalent thiophosphinyl group or a divalent silyl group, the solvent used is preferably an aromatic solvent such as benzene or toluene. Aliphatic hydrocarbons such as hexane; halogenated hydrocarbons such as dichloroethane, methylene chloride and chloroform;
Ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; esters such as ethyl acetate and methyl acetate; amides such as dimethylformamide, dimethylacetamide and hexaphosphorotriamide; sulfoxides such as dimethyl sulfoxide or acetone And ketones such as methyl ethyl ketone, the reaction temperature is from 0 to 180 ° C., and the reaction time is
Although it depends mainly on the reaction temperature, the starting compound and the type of solvent used, it is usually from 10 minutes to 15 hours.

When the protecting group is a divalent sulfonyl group, the reagent used is a sulfonyl halide or a sulfamide such as a sulfonyl chloride; and when the protecting group is a divalent phosphinyl group, Lower alkyl phosphate dihalides such as methyl phosphate dichloride and ethyl phosphate dibromide; lower alkyl dihalogeno phosphites such as methyl dichlorophosphite, methyl dibromophosphite and ethyl dichlorophosphite; aryl phosphate dichloride and aryl phosphate dibromide When arylphosphoric dihalides or aryldihalogenophosphites such as phenyldichlorophosphite, phenyldibromophosphite and naphthyldichlorophosphite, and the protective group is a divalent thiophosphinyl group,
Lower alkylthiophosphoric dihalides such as methylthiophosphoric acid dichloride and ethylthiophosphoric acid dibromide; lower alkyl dihalogenothiophosphites such as methyldichlorothiophosphite, methyldibromothiophosphite and ethyldichlorothiophosphite; arylthiophosphoric dichloride and arylthiophosphoric acid An arylthiophosphoric acid dihalide such as dibromide or an aryl dihalogenothiophosphite such as phenyldichlorothiophosphite, phenyldibromothiophosphite or naphthyldichlorothiophosphite, wherein the protecting group is a divalent silyl group. Is a dihalogenodi lower alkyl such as dichlorodimethylsilane, dibromodiethylsilane, dichlorodiethylsilane, iododimethylsilane, iododiethylsilane Silanes;
Dihalogenodi lower alkoxysilanes such as dichlorodimethoxysilane, dibromodiethoxysilane, dichlorodiethoxysilane, iododimethoxysilane, and iododiethoxysilane; dichlorodiphenylsilane;
Dihalogenodiaryl silanes such as dibromodiphenylsilane, iododiphenylsilane and iododinaphthylsilane; dihalogenoaryl lower alkylsilanes such as dichlorophenylmethylsilane, dibromophenylmethylsilane, iodophenylmethylsilane and iodonaphthylmethylsilane; Dihalogenoaryl lower alkoxysilanes such as dichloromethoxyphenylsilane, dibromoethoxyphenylsilane, dichloroethoxyphenylsilane, iodomethoxyphenylsilane and iodoethoxyphenylsilane; dichloromethylphenoxysilane, dibromoethylphenoxysilane, dichloroethylphenoxysilane, Dihalogeno low such as iodomethylphenoxysilane, iodoethylphenoxysilane Alkyl aryloxy silanes or dichloro diphenoxy silane, dibromo diphenoxy silane, jaw mistakes phenoxy silane, di-halogeno diacetic aryloxy silanes such as jaw blunder naphthoxycarbonyl silane.

[Method] is a method for removing a protecting group for a hydroxyl group. The removal of the protecting group for the hydroxyl group varies depending on the type thereof, but is generally performed by a method well known in the art, for example, as follows.

When a tri-lower alkylsilyl group is used as a protecting group for a hydroxyl group, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or magnesium hydroxide, an alkaline earth hydroxide; sodium carbonate, sodium hydrogen carbonate Inorganic bases such as alkali metal carbonates and alkali metal bicarbonates; inorganic acids such as hydrochloric acid and hydrofluoric acid; Lewis acids such as trifluoroborane etherate; organic acids such as acetic acid and propionic acid; Organic amine salts such as butylammonium fluoride, pyridinium poly (hydrogenfluoride) and 2,4,6-trimethylpyridinium poly (hydrogenfluoride) are used. The solvent used is not particularly limited as long as it does not inhibit the reaction, and is preferably a nitrile such as acetonitrile, tetrahydrofuran, an ether such as dioxane, dimethylformamide, an amide such as dimethylacetamide, or dimethylsulfoxide. Such as sulfoxides, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform, methylene chloride, dichloroethane and tetrachloroethane, water, acetic acid, lower fatty acids such as propionic acid, or a mixed solvent thereof. is there. The reaction temperature and reaction time vary depending on the starting materials and the reagents to be used, but are usually from -20 to 60 ° C and from 10 minutes to 60 hours.

When the protecting group for a hydroxyl group is an aralkyloxycarbonyl group or an aralkyl group, it can be usually removed by contact with a reducing agent. For example, using a catalyst such as palladium carbon, platinum, Raney nickel,
This is achieved by performing catalytic reduction at room temperature. The reaction is performed in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in the reaction.
Alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; fatty acids such as acetic acid; and mixed solvents of these organic solvents and water are preferred. The reaction temperature and reaction time vary depending on the starting material, the reducing agent used, and the like, but are usually 0 ° C. to room temperature and 5 minutes to 12 hours.

In liquid ammonia or in alcohols such as methanol and ethanol, at -78 ° C to -20 ° C,
It can also be removed by the action of metallic lithium or sodium.

Furthermore, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in the reaction. Preferably, nitriles such as acetonitrile; methylene chloride,
Halogenated hydrocarbons such as chloroform or mixed solvents thereof are used. The reaction temperature varies depending on the starting materials and the like, but is usually 0 ° C to 50 ° C.

When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alcoholate such as sodium methoxide; aqueous ammonia;
It is carried out using an alkali metal carbonate such as sodium carbonate or potassium carbonate; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water, methanol, ethanol, alcohols such as n-propanol or tetrahydrofuran, ethers such as dioxane, etc. An organic solvent or a mixed solvent of water and an organic solvent is preferred. The reaction temperature and reaction time vary depending on the starting material, the base used, and the like, and are not particularly limited.
In order to suppress side reactions, the temperature is usually 1 to 0 ° C to 150 ° C.
Up to 10 hours.

When the protecting group of the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group or a substituted ethyl group, it can be usually removed by treating with an acid in a solvent. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, p-toluenesulfonic acid or acetic acid. The solvent to be used is not particularly limited as long as it does not participate in the present reaction, but includes alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water. It is suitable. The reaction temperature and the reaction time vary depending on the starting material and the kind of the acid used, but are usually from 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, it is usually treated with a base in the same manner as in the removal reaction when the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. Can be desorbed. In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

The removal of the protected mercapto group can also be achieved in the same manner as described above.

Furthermore, removal of the protecting group of the protected amino group is carried out in the same manner as described above, for example, as follows.

When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with an acid or a base in the presence of an aqueous solvent. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid is used, and the base is not particularly limited as long as it does not affect the other parts of the compound. It is carried out using an alkali metal carbonate such as potassium; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; concentrated ammonia-methanol or a carbonyl reagent such as hydrazine or hydroxylamine. The solvent used is not particularly limited as long as it is one used in a usual hydrolysis reaction.
Preferred is water or a mixed solvent of water and an organic solvent such as alcohols such as methanol, ethanol and n-propanol or ethers such as tetrahydrofuran and dioxane. The reaction temperature and reaction time vary depending on the starting material and the base used, and are not particularly limited. However, in order to suppress a side reaction, the reaction is usually performed at 0 ° C. to 150 ° C. for 30 minutes to 15 hours.

When the protecting group for the amino group is an aralkyl group or an aralkyloxycarbonyl group, a catalytic reduction such as platinum or palladium carbon is carried out at room temperature to remove and remove using an oxidizing agent. Is preferred.

The solvent used in the removal by reduction is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; toluene, Aromatic hydrocarbons such as benzene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; esters such as ethyl acetate and propyl acetate; fatty acids such as acetic acid; Mixed solvents are preferred.

The catalyst to be used is not particularly limited as long as it is usually used for a catalytic reduction reaction, but is preferably palladium carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-. Rhodium chloride and palladium-barium sulfate are used.

The pressure is not particularly limited, but it is usually 1 to 10 atm.

The reaction temperature and reaction time vary depending on the type of the starting material and the catalyst, etc., but are usually 0 ° C. to 100 ° C. and 5 minutes to
Implemented for hours.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the present reaction, but is preferably a water-containing organic solvent. Suitable examples of such an organic solvent include ketones such as acetone; nitriles such as acetonitrile; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide. be able to.

The oxidizing agent to be used is not particularly limited as long as it is a compound usually used for oxidation, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro- 5,6-dicyano-p-
Benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the type of the starting material and the catalyst, etc.
Implemented for hours.

When the protecting group for the amino group is an alkenyloxycarbonyl group, the base is usually used in the same manner as in the removal reaction when the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group or a lower alkoxycarbonyl group. Can be desorbed. In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

The above-mentioned operation of removing a protecting group for a hydroxyl group, a mercapto group or an amino group may simultaneously remove other protecting groups in the molecule.

Therefore, by selecting the protecting group, it becomes possible to selectively remove the protecting group at the 4-position or the 7-position (step 6, step 7, step 8, step 9), The protecting group at the 7-position can be removed at the same time (tenth step).

In the case where the diol is protected by a divalent protecting group, the protecting group of the diol can be removed according to the following conventional method, although it generally depends on the type of the protecting group.

When the protecting group of the diol is an oxomethylene, a thioxomethylene, a divalent sulfonyl group, a divalent phosphinyl group or a divalent thiophosphinyl group, the “protecting group for the hydroxyl group described in [Method] is An aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group "is used.

When the protecting group of the diol is a lower alkylidene group, an aralkylidene group or an alkoxymethylidene group,
The method is carried out in the same manner as described in [Method], wherein the protective group for the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group or a substituted ethyl group.

When the protecting group of the diol is a divalent silyl group, the “protecting group for the hydroxyl group described in [Method]
And a "tri-lower alkylsilyl group".

In the eleventh and subsequent steps, when R ³ ′ and / or R ⁶ ′ represent a hydroxyl group, a mercapto group or an amino group, after completion of each step, the 4-position and / or 7 Position can be protected, and R ³ ′ and / or
When R ⁶ ′ represents a protected hydroxyl group, a protected mercapto group or a protected amino group, after completion of each step, a hydroxyl group at the 4-position and / or 7-position may be optionally substituted according to [Method]. Can be deprotected.

[Method] is a method in which the acid anhydride in the molecule of the compound (VII) is ring-opened to form a half-acid amide (VIII) or (IX), or the ring is closed again without or without the imide compound (X) or ( X
I) is a method of manufacturing.

In the eleventh step, an acid anhydride in the molecule of the compound (VII) is
In this step, the ring is opened to produce half acid amides (VIII) and (IX).

The solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably an aromatic hydrocarbon such as benzene, toluene or xylene, or a halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane or tetrachloroethane. Hydrogens, nitriles such as acetonitrile, ethers, ethers such as tetrahydrophthalane and dioxane, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The amine used is ammonia; lower aliphatic amines such as methylamine, ethylamine, isopropylamine and t-butylamine; aralkylamines such as benzylamine, 4-methoxybenzylamine and 4-chlorobenzylamine; Hydroxy lower alkylamines such as hydroxypropylamine, 2-methyl-2-aminopropanol and ethanolamine; lower alkoxy lower alkylamines such as 2,2-dimethoxyethylamine; lower alkoxyamines such as methoxyamine; Aromatic amines such as aniline, 4-chloroaniline and 2,4-difluoroaniline and heteroaromatic amines such as 2-aminopyrimidine. The amount of amine used is from 1 to 5 equivalents, and when the amine is used in excess, the product can be a carboxylate of the amine used. When an amine having low nucleophilicity is used in the reaction, the reaction is preferably performed in the presence of a base such as triethylamine and triethylenediamine. The reaction is usually carried out at −20 to 50 ° C., and the reaction time varies depending on the solvent and temperature used.
Minutes to 24 hours.

In the twelfth step, the half acid amide (VIII) and / or (I
In this step, X) is dehydrated and reclosed to produce an imide compound (X) or compound (XI).

In this reaction, an isomer having a different cyclization direction may be produced as a by-product depending on the type of the amine of the half-acid amide used as the starting material or the type of the dehydrating agent. The reagent that can be used as a dehydrating agent is not limited as long as it is a general reagent used when generating an acid amide from a carboxylic acid and an amine.Examples of such a reagent, for example, other than DCC, Pyrophosphate derivatives such as tetraethyl pyrophosphate; 2-fluoro-1-methylpyridinium p-toluenesulfonate; The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably includes the solvent used in the eleventh step. When 2-fluoro-1-methylpyridinium p-toluenesulfonate is used,
The presence of two equivalents of a tertiary amine such as triethylamine is required. The reaction is usually performed at -20 to 120 ° C,
The reaction time varies depending on the reaction temperature and the solvent used, but is 30 minutes to 24 hours.

By using compound (VII) as a starting material and selecting reaction conditions, for example, an excess (4 equivalents) of aniline and DCC (2 equivalents) can be used, or a strong base DAB can be used.
By using CO with aniline, the above compound can be produced in one step without isolating the half-acid amide (step 13).

[Method] is a method for esterification of a carboxylic acid. For example, compound (VIII) can be converted to compound (XII), but the same can be carried out for other carboxylic acid compounds (eg, compound (IX)). (14th step).

The reaction conditions are the same as in [Method], or
Or, for example, as shown in the fifteenth step, diazomethane,
This can be achieved by an alkylating agent such as trimethylsilyldiazomethane.

[Method] is a separate production method of compound (XII).

The fifteenth step is a step of converting the acid anhydride portion of the compound (VII) to a diester, which is achieved by using a diazoalkylating agent such as diazomethane, trimethylsilyldiazomethane, diphenyldiazomethane, or by using dilute sodium hydroxide. Lyophilize the prepared sodium salt,
In this step, an amide such as dimethylformamide is used as a solvent and alkylated with an alkyl halide such as methyl iodide to obtain a diester.

In the reaction with the diazoalkylating agent, the solvent used is not particularly limited as long as it does not inhibit the reaction,
Preferably, methylene chloride, chloroform, halogenated hydrocarbons such as dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, methanol,
Alcohols such as ethanol, n-propanol,
Ethyl acetate, fatty acid esters such as ethyl propionate, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, ethers, tetrahydrofuran and ethers such as dioxane. it can. When using trimethylsilyldiazomethane, methanol is essential as a proton source, and the reaction is usually performed at -20 to 50 ° C. The reaction time varies depending on the solvent and the temperature used, but may be from 5 minutes to 5 minutes. 24 hours.

In the reaction using alkyl halides, the solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide,
Examples thereof include nitriles such as acetonitrile, and ethers such as ether, tetrahydrofuran and dioxane. The reaction temperature and time vary depending on the solvent and reagent used, but are usually 0 to 80 ° C and 1 to 30 hours.

The sixteenth step is a step of deprotecting the protected carboxylic acid.

The removal of the protecting group depends on its type, but is generally carried out by a method well known in the art as follows.

When a lower alkyl group or an aryl group is used as a protecting group for a carboxy group, it can be removed by treating with an acid or a base. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid is used, and the base is not particularly limited as long as it does not affect the other parts of the compound. It is carried out using an alkali metal carbonate such as potassium, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water or water and methanol, ethanol, n-
A mixed solvent with an organic solvent such as an alcohol such as propanol or an ether such as tetrahydrofuran or dioxane is preferable. The reaction temperature and the reaction time are different depending on the starting material and the base to be used and are not particularly limited.
And 1 to 10 hours.

When the protecting group for the carboxy group is a diaryl-substituted methyl group such as diphenylmethyl, it is usually removed under acidic conditions. The reaction solvent used is preferably an aromatic hydrocarbon such as anisole, and the acid is a fluorine-substituted organic acid such as trifluoroacetic acid. The reaction temperature and reaction time vary depending on the starting materials and the like, but are usually 30 minutes to 10 hours at room temperature.

When the protecting group of the carboxy group is an aralkyl group or a halogeno lower alkyl group, it can be usually removed by contact with a reducing agent. As the reducing agent, when the protective group of the carboxy group is a halogeno lower alkyl group, zinc-acetic acid is preferable, and when it is an aralkyl group, a catalyst such as palladium carbon or platinum is used,
It is carried out by catalytic reduction or by using an alkali metal sulfide such as potassium sulfide or sodium sulfide. The reaction is carried out in the presence of a solvent, and the solvent to be used is not particularly limited as long as it does not participate in the reaction. Alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; acetic acid And mixed solvents of these fatty acids or organic solvents with water are preferred. The reaction temperature and reaction time vary depending on the starting material, the reducing agent used, and the like.

When the protecting group of the carboxy group is an alkoxymethyl group, it can be usually removed by treating with an acid. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid or p-toluenesulfonic acid-acetic acid. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in the reaction. Alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; The mixed solvent of the organic solvent and water is preferable. The reaction temperature and the reaction time vary depending on the starting material and the kind of the acid used, but are usually 0 to 50 ° C. and 10 minutes to 18 hours.

Amidation can also be carried out by removing the protecting group for the carboxy group by treatment with ammonia according to a conventional method.

If desired, according to a conventional method, the carboxylic acid compound produced above is dissolved in a mixed solvent of water and an organic solvent immiscible with water such as ethyl acetate, and an alkali metal carbonate such as an aqueous sodium hydrogen carbonate solution or an aqueous potassium carbonate solution is dissolved. A salt or bicarbonate aqueous solution is added at 0 ° C.
The alkyl metal salt can be formed by filtering the vicinity and the precipitate deposited.

Further, the salt or carboxylic acid compound thus produced is converted into an ether such as tetrahydrofuran or N, N
Dissolved in polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide, triethylphosphate and 2 equivalents of an organic base such as triethylamine, dicyclohexylamine, alkali metal hydrides such as sodium hydride or carbonic acid A salt formed by reacting an alkali metal carbonate or bicarbonate such as sodium hydrogen, sodium carbonate or potassium carbonate is used, and an aliphatic acyloxymethyl halide such as acetoxymethyl chloride or propionyloxymethyl bromide is used. , 1-methoxycarbonyloxyethyl chloride, 1-ethoxycarbonyloxyethyl iodide, such as 1-lower alkoxycarbonyloxyethyl halides, phthalidyl halides or (2-O By reacting (so-5-methyl-1,3-dioxolen-4-yl) methyl halides, it is possible to produce an ester protected again with a carboxy-protecting group which is easily hydrolyzed in vivo. .
The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but the above-mentioned polar solvent is preferably used. The reaction temperature and reaction time vary depending on the types of starting materials, solvents and reaction reagents, but the reaction is usually carried out at 0 to 100 ° C for 0.5 to 10 hours.

The seventeenth step is a step of converting a carboxylic acid to an amide, and is performed according to the eleventh, twelfth, and thirteenth steps.

The reaction is carried out with activated acid residues (eg, acid halides,
Acid anhydride, etc.) and reacting with a corresponding amine (eg, ammonia gas).

As the activated acid residue, an acid anhydride obtained by treating with a chloroformate such as methyl chloroformate or ethyl chloroformate in the presence of a base such as triethylamine is particularly preferable.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Preferably, aromatic solvents such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane; and nitriles such as acetonitrile.
The reaction temperature is from −10 ° C. to 150 ° C., and the reaction time is
Although it depends mainly on the reaction temperature, the starting compound and the type of solvent used, it is usually from 10 minutes to 15 hours.

Incidentally, the amide group can be protected with a protecting group, if desired.

The eighteenth step is a step of selectively converting the ester at the 1-position of the compound (XIII) to an amide. The reagent to be used is preferably concentrated aqueous ammonia, ammonia gas, or an amine such as methylamine. And the like. The solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably water, methanol, ethanol, alcohols such as n-propanol, amides such as dimethylformamide, and dimethyl. Examples thereof include sulfoxides such as sulfoxide, nitriles such as acetonitrile, and ethers such as ether, tetrahydrofuran and dioxane. The reaction is preferably carried out under pressure using a Bomben roll or the like, if desired. The reaction is usually carried out at 0 to 50 ° C., and the reaction time is 1 to 24 hours, depending on the reaction temperature and the kind of the solvent used.

[Method], [Method] and [Method] describe, as an example, a reaction using compound (VII) as a starting compound.
Compounds (VIII), (IX), (X),
By using (XI), (XII), (XIII) or (XIV), the corresponding compounds can be obtained.

In a nineteenth step, the carbonyl group in the 9-membered ring of the compound (VII) is reacted with a hydrazine such as an arylsulfonylhydrazine such as phenylsulfonylhydrazine or an arylhydrazine such as phenylhydrazine to form a hydrazone such as phenylsulfonylhydrazone. This is the step of converting to. The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably includes ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide. . The reaction temperature is
Usually, it is -10 to 50 ° C, and the reaction time is 3 to 24 hours, depending on the reaction temperature and the kind of the solvent used.

The twentieth step is a step of epoxidizing the exo double bond of compound (VII) to produce compound (XVI).

The solvent used is preferably water; organic acids such as acetic acid; halogenated hydrocarbons such as dichloroethane, methylene chloride, chloroform; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile. An alcohol such as methanol, ethanol, n-propanol, isopronol, t-butanol, isobutanol, isoamyl alcohol or a mixed solvent of the above solvents.

The reagents used include inorganic peroxides such as hydrogen peroxide; organic peracids such as metachloroperbenzoic acid and peracetic acid; and organic compounds capable of forming an epoxy such as a peroxide alcohol such as t-butanol peroxide. It is a peroxide.

The reaction temperature is from -20 to 100 ° C, and the reaction time is
Although it depends mainly on the reaction temperature, the starting compound and the type of solvent used, it is usually from 10 minutes to 15 hours.

The twenty-first step is a step of converting a 9-membered ketone into a hydroxyl group. For example, a compound (XVII) having a hydroxyl group can be produced by using the compound (VII) as a starting compound.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Preferably alcohols such as methanol, ethanol, isopropanol; ethers, tetrahydrofuran,
Ethers such as dioxane and dimethoxyethane; amides such as dimethylformamide; sulfoxides such as dimethylsulfoxide and sulfolane; water; organic acids such as acetic acid; and mixed solvents thereof.

The reagent used is not particularly limited as long as it can reduce a ketone to a hydroxyl group, but is preferably sodium borohydride, sodium borohydride, lithium aluminum hydride, K-selectride, L-select. Alkali metal hydrides such as rides or transition metals such as zinc.

The reaction temperature is from -20 ° C to 120 ° C, and the reaction time is usually from 10 minutes to 10 hours, varying mainly depending on the reaction temperature, the type of the starting compound or the type of solvent used.

The twenty-second step is a step of stereoinverting a specific hydroxyl group.

Therefore, by carrying out this production method, it is possible to produce compounds having all steric coordination for all hydroxyl groups in the molecule.

The inversion of the hydroxyl group is carried out according to a conventional method by converting the hydroxyl group to be stereo-inverted into “aliphatic acylation”; “aromatic acylation”; “trihalogenomethylation”; “lower alkane sulfonylation” described in [Method]; "Halogeno lower alkane sulfonylation"; by "aryl sulfonylation", followed by reaction with sodium acetate and the like, and finally elimination of an acetyl group and the like.

In addition, a mercapto compound can be produced by reacting with sodium thioacetate or the like to remove an acetyl group or the like (step 23).

Furthermore, an amino compound can be produced by reacting with ammonia (24th step).

Further, it can also be carried out by oxidizing a hydroxyl group to be stereo-inverted to a corresponding ketone group according to a conventional method, and then reducing it.

The 25th step is a method for converting an unprotected hydroxyl group in a 9-membered ring into a halogen atom.

As the halogenating reagent, preferably, thionyl halides such as thionyl chloride, thionyl bromide and thionyl iodide; sulfonyl halides such as sulfonyl chloride, sulfonyl bromide and sulfonyl iodide; phosphorus trichloride, phosphorus tribromide Phosphorus trihalides such as phosphorus triiodide; phosphorus pentahalides such as phosphorus pentachloride, phosphorus pentabromide, and phosphorus pentaiodide; such as methyltriphenylphosphonium iodide and methyltriphenylphosphonium bromide Phosphonium halides; N-halogenosuccinimides such as N-bromosuccinimide or oxyhalogens such as phosphorus oxychloride, phosphorus oxybromide and phosphorus oxyiodide in the presence of phosphines such as triphenylphosphine Phosphorus halides, preferably phosphonium halides A.

The solvent used is preferably an aromatic hydrocarbon such as benzene or toluene; a halogenated hydrocarbon such as dichloroethane, methylene chloride or chloroform; an ether such as ether, tetrahydrofuran, dioxane or dimethoxyethane. Esters; esters such as ethyl acetate and methyl acetate; amides such as dimethylformamide, dimethylacetamide, and hexaphosphorotriamide; sulfoxides such as dimethylsulfoxide; and ketones such as acetone and methylethylketone.

The reaction is carried out at a temperature of 0 to 150 ° C., and the reaction time is usually 10 minutes to 20 hours, although it depends mainly on the reaction temperature, the kind of the starting compound and the kind of the solvent used.

In each of the above production methods, after completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Cornegistin (III) which is a starting compound of the present invention
Is manufactured as follows.

First, SANK, which produces the raw material compound Cornegistin,
21086 strain is a kind of incomplete fungi isolated from deer dung,
Its bacteriological properties are as follows.

The growth on the malt agar medium is good, and the colony diameter reaches 35 to 43 mm in 7 days at 24 ° C. The surface of the colony is initially light yellowish brown (Straw yellow 3B4), the center is raised, the surface is velvety, and eventually yellowish brown (Greyish yell
ow 3C4) and slightly powdery. The back of the colony is light brown (Greyish orange 5B3). The color display is “Th
e Methuen Handbook of Color "(A. Kornerup et al., London, UK, published by Eyre Methuen, 1978). Growth on Chapek agar is slower than on malt agar, at 24 ° C for 7 days. Colony diameter 18-22
Although it is mm, the shape and color of the colony are almost the same as those on a malt agar medium. At 37 ° C, growth is extremely poor, but conidium formation is observed.

As a result of observation with a microscope, the mycelium has partition walls, is almost colorless, has a smooth surface, and a diameter of 2 to 5 μm. The conidiophores are formed directly from the aerial or basal mycelium and are 20-
120 μm × 2.5 to 4.0 μm. The conidium may be formed from a phyllide on a conidium-forming structure in which a divergent branch is formed at the tip of the conidiophore, or a phyllide may be formed almost unbranched. The fluoride has a smooth surface of 10 to 40 μm × 2.5 to 4.0 μm, and its tip is an elongated tube. The conidium is light brown, long chain with smooth surface, and subglobular to oval, 3 to 5.5 × 2 to 4 μm.

When the various forms of the SANK 21086 strain as described above were compared with those of known strains, RASamson, Studies in Myc
ology No.6, 1974, CBS issued, page 14, and AHSBrow
n and G. Smith, Transactions British Mycological S
ociety, vol. 40, 1957, p. 40. Therefore, SANK 2
1086 shares of Pesilomyces barriot beinier (Paec
ilomyces variotii Bainier). SANK 21086
The strain was deposited on April 24, 1987, with the Ministry of International Trade and Industry, approved by the Budapest Treaty, by the Institute of Microbial Engineering, under the provisions of the treaty.
RM BP-1351.

Although the description of the SANK 21086 strain has been described above, it is well known that the properties of these fungi are not constant and are easily changed naturally and artificially, and the strains usable in the present invention belong to the genus Pesilomyces. It includes all strains of the genus belonging to Cornegistin.

The cultivation is carried out in accordance with the culturing method for general microorganisms, and is preferably performed by shaking culturing in a liquid medium or by aeration and stirring culturing. As the medium components, for example, glucose as a carbon source, glycerol, maltose, sucrose, mannitol, molasses, dextrin, starch, soybean oil,
Cottonseed oil, etc., as a nitrogen source, soybean flour, peanut flour, cottonseed flour, pharmamine, fish meal, corn steep liquor,
Peptone, meat extract, yeast, yeast extract, sodium nitrate, ammonium nitrate, ammonium sulfate, etc.
Salts, phosphates, calcium carbonate and the like are used as the inorganic salts. Also, a trace amount of a metal salt is appropriately added as needed. At the time of liquid culture, silicone oil, vegetable oil, surfactant and the like are used as an antifoaming agent.

The pH of the medium is slightly acidic to near neutral, and the culture temperature is 20 to 30.
° C, especially around 24 ° C. The time-dependent change in the titer of Cornegistin produced in the culture solution over the course of the culture is measured by the herbicidal activity of the foliage treatment of the rice plant. Usually, the cornegistin production reaches the highest value after culturing for 150 to 200 hours.

Cornegistin, which is mainly present in the liquid portion of the culture solution, is removed by filtration or centrifugation using diatomaceous earth as a filter aid after culturing, and is present in the filtrate or supernatant. Cornegistin can be extracted and purified by utilizing its physicochemical properties. As the adsorbent, for example, activated carbon,
Alternatively, Amberlite XAD-2, XAD-4,
XAD-7 (manufactured by Rohm and Haas) and Diaion HP10, HP20, CHP20P, HP50 (manufactured by Mitsubishi Kasei Kogyo KK) are used. To adsorb impurities contained therein and remove them, or after adsorbing Cornegistin, elute with methanol water, acetone water, n-butanol water or the like. It is also possible to neutrally and acidicly extract and purify from the culture filtrate or aqueous solution by using an organic solvent immiscible with water, for example, chloroform, ethyl acetate, n-butanol or the like alone or in combination.

In order to further purify Cornegistin, silica gel,
It can be purified by adsorption column chromatography using a carrier such as Furozil, distribution column chromatography using Sephadex LH-20 (manufactured by Pharmacia), etc., and liquid chromatography using normal-phase and reverse-phase columns. . Cornegistin can be purified by repeatedly using these purification means alone or in combination as appropriate.

[Effect] The novel Cornegistin derivative of the present invention exhibits herbicidal action on plants. The compound of the present invention exhibits an excellent herbicidal effect against various grasses and broadleaf weeds by both pre-emergence and post-emergence treatment methods, and is particularly useful as a foliar treatment herbicide. For example, Nobie, Tamayatsuri, Konagi,
Narrow leaf and broad leaf weeds of paddy fields such as Azena, Mizohakobe, Kikashigusa, Firefly, Matsubai, etc .; It can control narrow leaves and broad-leaved weeds in fields such as napsuna, tanecane, sendangusa, yaegura and buckwheat. Furthermore, it can be used not only in paddy fields and uplands, but also in orchards, mulberry fields, and non-cultivated lands.

In particular, the compounds of the present invention exhibit strong herbicidal activity against broadleaf weeds growing in the field. For example, in the foliage treatment in the field, Aobuyu, purslane, Onamomi, Sendangusa, Ragweed, Arechiuri, Koakazana, Sanaetade, Oinutade, Hakobe, Nazuna, Miminagusa, Shirobanachiyosenasaagao, Marubaasagao, Inuhobuzuoka, Inuhobazoi, Inouho-busa, Inuho-basu, Inuho-bazoi, Inuho-bazoi, Inuho-buki-o-buki, Inuho-bazoi, Inuho-bazoi, Inuho-bazoi, Insect, It shows an excellent herbicidal effect on weeds such as calf deer, oxalis, yamgra, buckwheat, Inoufuguri and poppy.

To prepare the herbicide of the present invention, the thus obtained conegistin derivative is diluted with a carrier, and if necessary, other adjuvants are added, so that powders, coarse powders, granules, fine granules,
It can be prepared into a wettable powder, a water solvent, a solvent and the like. Of course, the purification can be stopped at any stage of the purification, and the crude product can be used as the active ingredient. A carrier as used herein refers to a synthetic or natural inorganic or organic substance that is mixed with a herbicide to aid in the accessibility of the active ingredient to the plant or to facilitate storage, transport, or handling of the active ingredient. means.

Suitable solid carriers include clay, talc, diatomaceous earth, kaolin, bentonite, inorganic substances such as calcium carbonate,
Synthetic resins such as coumarone resin, alkyd resin and polyvinyl chloride; waxes such as carnauba wax and paraffin wax; or nut shells such as walnuts, nuts, and soybean flour.

Examples of suitable liquid carriers include, for example, water, alcohols such as methanol, ethanol, isopropanol, and ethylene glycol, and hydrocarbons such as xylene, methylnaphthalene, and solvent naphtha. dispersion,
Surfactants used for purposes such as wetting and spreading may be ionic or non-ionic. Suitable ionic surfactants include soaps such as higher fatty acid salts, higher alcohol sulfates, higher ester sulfates such as alkyl ether sulfates, sodium alkylbenzene sulfonates, and sodium salts of dialkyl sulfosuccinates. Anionic surfactants such as sulfonic acid salts, phosphoric acid ester salts, carboxylic acid and / or sulfonic acid-based polysoaps, amine salt type and quaternary ammonium salt type cationic surfactants, amino acid type And betaine-type amphoteric surfactants.

Suitable nonionic surfactants include, for example, glycerides of fatty acids, sucrose esters of fatty acids, ethylene oxide condensates of higher fatty alcohols, ethylene oxide condensates of higher fatty acids, ethylene oxide condensates of alkyl phenols or alkyl naphthols and oxidants. Copolymers of ethylene and propylene oxide can be exemplified.

The herbicides of the present invention may comprise other ingredients such as gelatin, acacia, casein, polyvinyl alcohol, protective colloids such as carboxymethylcellulose, dispersants such as sodium polyphosphate, inorganic dispersants such as bentonite, veegum, and stabilizing agents. It may also contain other ingredients generally acceptable for pesticides, such as agents, binders, and antifreezes.

The herbicide of the present invention can be mixed with other herbicides, plant growth regulators and the like to expand the range of application and save labor.

Next, the effect of the herbicide of the present invention will be described with reference to test examples.

Test example Foliage treatment Weeding test A soil is filled in a plastic pot of 7.5 cm in length, 20 cm in width, and 7 cm in height, and 5 kinds of grasses and 5 kinds of broadleaf weeds are sown, and a total of 10 kinds of plant seeds are sown, and about 1 cm is put on it. Covered soil. The pot is buried in vermiculite packed in a bench in a greenhouse, water is supplied indirectly through vermiculite, and the seeded plant is grown for about 2 weeks. Water containing 1000 ppm of each compound prepared according to Formulation Example 1 is prepared. The medicinal solution of the Japanese medicine was directly sprayed on the foliage of 10 ml of the plant per pot. The progress after spraying was observed, and a survey was performed on the 14th day. The result is
It is shown in the table. The determination of the herbicidal effect was obtained based on the following criteria.

Against untreated pot weeds And

 The weeds used in the test are as follows.

As is clear from the above results, the compound according to the present invention showed an excellent herbicidal effect on foliage in a wide range of grasses and broadleaf weeds by foliar treatment during the growing season.

Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples.

In addition, about the manufacturing method of Cornegistin, this invention
It is needless to say that the present invention is not limited to these methods, and that the type of culture medium, culture conditions, collection, purification methods, and the like can be greatly changed.

Example 1 One loopful of Pecillomyces varioti SANK 21086 strain was inoculated into a 500 ml Erlenmeyer flask containing 80 ml of a medium having the following composition, and cultured at 26 ° C. for 168 hours using a 2.0 rpm rotary shaking incubator.

Culture composition: glycerin 50 g raw potato 50 g yeast extract 5 g malt extract 5 g deionized water 1000 ml (pH 6.0) Inoculate 0.5 ml of this culture into 25 500 ml Erlenmeyer flasks containing 80 ml of the same medium and rotate at 200 rpm. The cells were cultured at 26 ° C. for 192 hours using a shaking incubator. 200 g of Celite 545 (manufactured by Johns Manville Product Corporation, USA) was added as a filter aid to 2 l of the obtained culture solution, followed by filtration to obtain a culture filtrate (1.7 l, pH 6.0). The culture filtrate is 300m from Diaion HP20 (Mitsubishi Chemical Industries, Ltd.)
The active substance was adsorbed through a column of l. After washing with 11 deionized water, elution was carried out with 1 liter of 80% acetone water, and 1 liter of the obtained eluate was concentrated under reduced pressure and lyophilized to obtain 3 g of a coarse powder which was an active class. 2.7 g of this coarse powder in 400 ml
Dissolve in deionized water and adjust to pH 2.5, then 400 ml of ethyl acetate
And extracted twice to obtain 800 ml of ethyl acetate containing Cornegistin. 800 ml of extract 300 ml of 0.1 M disodium phosphate solution
, Then twice with 300 ml of saturated saline, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 650 mg of an oil containing Cornegistin.

Further, this oily substance was mixed with ethyl acetate: chloroform (1: 1).
After dissolving and adsorbing on a 150 ml column of Sephadex LH-20 (manufactured by Pharmacia) packed and equilibrated in 1) with ethyl acetate: chloroform (1: 1), the mixture was developed and eluted with the same mixed solvent system. The eluate was fractionated in 10 ml portions, and fractions 22 to 28 containing Cornegistin were collected and concentrated under reduced pressure to a purity of about
100 mg of a 70% Cornegistin preparation was obtained.

Melting point: 100-103 ° C. Specific rotation: [α] _D ²³ + 168.3 ° (c = 1.0, CHCl ₃ ) Ultraviolet absorption spectrum: λmax nm (E _{1 cm} ^1% ) The ultraviolet absorption spectrum measured in methanol is 238n.
The maximum absorption is shown at m (131).

Infrared absorption spectrum: ν _max (KBr) cm-1: 3400, 3300, 2900, 1850 (W), 1820 (W), 1760, 1710, 1640, 1440, 1300, 1260, 1220, 1160, 1060, 1000, 920,800,760. Nuclear magnetic resonance spectrum: δ (ppm) ¹ H-nuclear magnetic resonance absorption spectrum (270 MHz) measured in deuterated chloroform using TMS (tetramethylsilane) as an internal standard is as follows.

0.93 (3H, t), 1.29 (2H, m), 1.70 (3H, d), 1.90-2.1
(2H, m), 2.57 (1H, dd), 3.15 (1H, d), 3.4 (3H, m), 4.
07 (1H, d), 5.12 (1H, dd), 5.85 (1H, dd).

Example 2 After culturing in the same manner as in Example 1, the obtained culture filtrate 1.81 was adjusted to pH 2.5, and then extracted twice with 1.5 l of ethyl acetate to obtain 3 l of an ethyl acetate extract containing conegistin. The extract was washed twice with 1 liter of a 0.1 M disodium phosphate solution and then twice with 1 liter of saturated saline, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 700 mg of an oily substance. A column of Sephadex LH-20 (manufactured by Pharmacia) which was preliminarily equilibrated and packed with ethyl acetate: chloroform (1: 1).
After dissolving and adsorbing in 80 ml with the same mixed solvent system, it was eluted with the same solvent. The eluate was fractionated by 10 ml, fractions Nos. 13 to 18 containing Cornegistin were collected, concentrated under reduced pressure, applied again to the same Sephadex LH-20 column, and concentrated to obtain 290 mg of an oil.

290 mg of this partially purified product was purified by high performance liquid chromatography using a reversed phase column. That is, after injecting a sample into a reverse phase column ((YMC; S-343 CI-15 ODS) manufactured by Yamamura Chemical Industry Co., Ltd.) previously equilibrated with a mixed solvent of 40% acetonitrile-water, the sample was monitored at UV absorption 240 nm. Elution was performed with the same mixed solvent at a flow rate of 5 ml / min. The same operation was performed three times to obtain 185 mg of Cornegistin having a purity of about 90%.

Example 3 One loopful of a Psillomyces varioti SANK 21086 strain was inoculated into a 500 ml Erlenmeyer flask containing 80 ml of a medium having the same composition as in Example 1, and incubated at 26 ° C. using a 200 rpm rotatory shaking incubator.
Incubated for 44 hours. 75 ml of this culture solution containing 15 l of the same medium
Two 0l jar fermenters were inoculated at 26 ° C,
The culture was carried out with aeration and agitation at a speed of 150 to 180 rotations / min and an aeration of 15 l / min for 192 hours. 1 kg of Celite 545 was added as a filter aid to 25 l of the obtained culture solution, followed by filtration to obtain 19 l of the filtrate. The culture filtrate was adjusted to pH 2.5, first 19 l, then 9.5 l
, And extracted once each with ethyl acetate to obtain a total of about 28 l of ethyl acetate extract. Then, the extract was mixed with 0.1 M phosphoric acid-2.
-Washed three times with 5 l of sodium solution and twice with 5 l of saturated saline, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 20.2 g of an oily substance. 20.2 g of the oily substance was equilibrated in advance with ethyl acetate: chloroform (1: 1), dissolved in the same mixed solvent and adsorbed on a packed Sephadex LH-20 500 ml column, and developed with the same mixed solvent system. Eluted. The eluate was fractionated in 20 ml portions, and fractions No. 35 to 52 containing Cornegistin were collected and concentrated under reduced pressure to obtain 7.56 g of an oily substance. The whole amount was dissolved in 10 ml of methylene chloride and left at room temperature to obtain 3.7 g of colorless needle crystals of Cornegistin.

Example 4 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,7-di-
(Isopropyldimethylsilyloxy) -5-oxo-
8 (Z) -ethylidene-1-cyclononene-1,2-dicarboxylic anhydride (compound 1); (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4-isopropyldimethylsilyloxy-5- Oxo-7-hydroxy-8 (Z) -ethylidene-1-cyclononene-1,2
Dicarboxylic anhydride (compound 2); and (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4-hydroxy-5-oxo-7-isopropyldimethylsilyloxy-8- (Z) -ethylidene -1-cyclononene-1,
2-Dicarboxylic anhydride (Compound 3) In a solution of Cornegistin (308 mg, 1 mmol) in dimethylformamide (DMF) (4 ml), dimethylisopropylsilyl chloride (328 mg, 2.4 mmol) in DMF (4 m
l) DMF in solution and imidazole (163 mg, 2.4 mmol)
(5 ml) The solution was sequentially added dropwise at room temperature and stirred for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and dried over sodium sulfate, and the solvent was distilled off to obtain 499 mg of a crude product. This was subjected to silica gel column chromatography to give n-
The compound 1 was eluted with hexane: ethyl acetate (15: 1).
5 mg (46% yield) was obtained. Then, elution was performed with n-hexane: ethyl acetate (5: 1), and Compounds 2 and 3 were each dissolved in 123 mg.
(Yield 30%), 10 mg (3%) were obtained.

[Compound 1] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.65 (d, J = 6.9 Hz, 1
H); 4.90 (b, 1H); 3.85 (d, J = 8.9 Hz, 1H); 3.42 (dt, J
= 10.5,4.8Hz); 3.5-3.3 (b, 1H); 3.22 (ABq, J = 13.7H
z, 2H); 2.38 (dd, J = 13.3, 5.6 Hz, 1H); 2.1 to 1.8 (b, 2
H); 1.73 (d, J = 7.2 Hz, 3H); 1.4-1.1 (m.2H); 1.0-0.
8 (m, 2H); 0.97 (d, J = 5.2 Hz, 6H); 0.95 (d, J = 4.8 Hz, 6
H); 0.89 (t, J = 4.8 Hz, 3H); 0.10 (s, 3H); 0.09 (s, 3
H); 0.08 (s, 3H); 0.04 (s, 3H). IR spectrum (nujol) νcm-1: 1860,1815,177
. 0,1700 mass spectrum (m / z): 508 ( M +); 465 (M-CO 2 +
¹⁺ ). Rf value: 0.43 (hexane / ethyl acetate = 10/1) [Compound 2] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.72 (q, J = 6.9 Hz, 1
H); 5.02 (dd, J = 5.6,4.4Hz, 1H); 4.01 (d, J = 8.5Hz, 1
H); 3.73 (d, J = 10.1Hz, 1H); 3.41 (dt, J = 8.5,4.4Hz, 1
H); 3.32 (dd, J = 13.3,5.6Hz, 1H); 3.22 (ABq, J = 13.7H
z, 2H); 2.41 (dd, J = 13.3,4.4Hz, 1H); 2.2-2.0 (m, 1
H); 2.0-1.9 (m, 1H); 1.67 (d, J = 7.3 Hz, 3H); 1.4-1.
2 (m, 2H); 1.01 (d, J = 4.8 Hz, 6H); 1.0 to 0.9 (m, 1H);
0.92 (t, J = 7.3 Hz, 3H); 0.16 (s, 3H); 0.14 (s, 3H). IR spectrum (nujol) νcm-1: 3500,1855,181
5,1760,1700. Mass spectrum (m / z): 408 (M ⁺ ); 365 (M + 1-C)
O ₂ ⁺ ). Rf value: 0.38 (hexane / ethyl acetate = 5/1) [Compound 3] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.90 (q, J = 6.9 Hz, 1
H); 5.04 (dd, J = 9.3,5.2Hz, 1H); 3.86 (d, J = 9.3Hz, 1
H); 3.42 (dd, J = 15.3,9.3Hz, 1H); 3.3-3.2 (m, 1H);
3.21 (ABq, J = 14.9Hz, 2H); 2.62 (dd, J = 15.3,5.2Hz, 1
H); 2.2-1.7 (m, 2H); 1.76 (d, J = 6.9, 3H); 1.6-1.5
(B, 1H); 1.4-1.1 (m, 2H); 1.0-0.9 (m, 1H); 0.97
(D, J = 2.8Hz, 6H); 0.91 (t, J = 7.2Hz, 3H); 0.12 (s, 3
H); 0.06 (s, 3H). IR spectrum (film) νcm-1: 3450, 1850, 1820, 1
. 760,1700 mass spectrum (m / z): 408 ( M +); 365 (M-CO 2 +
¹⁺ ). Rf value: 0.18 (hexane / ethyl acetate = 5/1) Example 5 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,7-di-
(Isopropyldimethylsilyloxy) -5-oxo-
8 (Z) -Ethylidene-1-cyclononene-1,2-dicarboxylic anhydride (Compound 1) Cornegistin (154 mg, 0.5 mmol) in DMF (7
The reaction and treatment were carried out in the same manner as in Example 4 except that dimethylisopropylsilyl chloride (274 mg, 2 mmol) and imidazole (136 mg, 2 mmol) were used in excess to the amount of Compound 1 to give 242 mg of Compound 1 (yield). 95%).

Example 6 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4-hydroxy-5-oxo-7-t-butyldimethylsilyloxy-8 (Z) -ethylidene-1-cyclononene-1, 2-Dicarboxylic anhydride (compound 4) A solution of Cornegistin (660 mg, 2.14 mmol) and imidazole (190 mg, 2.78 mmol) in DMF (10 ml) was t-
Butyldimethylsilyl chloride (420 mg, 2.78 mmol) was added at room temperature under a nitrogen atmosphere. After stirring overnight at room temperature, water (50 ml) was added, and the mixture was extracted with ethyl acetate, dried and concentrated, and then subjected to silica gel chromatography (hexane: ethyl acetate = 7: 1) to obtain 660 mg of compound 4 (yield 73%). Was.

[Compound 4] Oily substance.

NMR spectrum (CDCl ₃ ) δ ppm: 5.73 (q, J = 7.2 Hz, 1H);
5.04 (t, J = 5.2Hz, 1H); 4.02 (t, J = 8.4Hz, 1H); 3.59
(D, J = 8.4Hz, 1H); 3.45 (dt, J = 8.4,4.2Hz, 1H); 3.34
(Dd, J = 13.3,6.0Hz, 1H); 3.23 (ABq, J = 14.5Hz, 1H);
2.41 (dd, J = 13.3,4.4Hz, 1H); 2.2 ~ 2.0 (m, 1H); 2.0 ~
1.9 (m, 1H); 1.66 (d, J = 7.2Hz, 3H); 1.4 ~ 1.2 (m, 2
H); 0.97 (s, 9H); 0.92 (t, J = 7.2 Hz, 3H); 0.17 (s, 3H)
H); 0.14 (s, 3H). IR spectrum (CHCl ₃ ) νcm−1: 3600,3400,1830,1770,1
700. Mass spectrum (m / z): 423 (M + 1 ⁺ ); 365 (M-C
₄ H ₉ ^+). Rf value: 0.42 (hexane / ethyl acetate = 4/1). The following compounds were produced in the same manner as in Examples 4 to 6.

Compound 5 (R ³ ′ = R ⁶ ′ = compound of dimethyl t-butylsilyloxy group) Yield: 11%.

Oil.

Rf value: 0.73 (hexane / ethyl acetate = 5/1). Compound 6 (R ³ ′ = R ⁶ ′ = compound of triethylsilyloxy group) Yield: 69%.

Oil.

Rf value: 0.62 (hexane / ethyl acetate = 10/1). Compound 7 (R ³ ′ = hydroxyl group, R ⁶ ′ = triethylsilyloxy group compound) Yield: 23%.

Oil.

Rf value: 0.37 (hexane / ethyl acetate = 5/1). Compound 8 (R ³ ′ = R ⁶ ′ = compound of dimethylphenylsilyloxy group) Yield: 90%.

Oil.

Rf value: 0.20 (hexane / ethyl acetate = 10/1). Compound 9 (R ³ ′ = hydroxyl group, R ⁶ ′ = compound of dimethylphenylsilyloxy group) Yield: 31%.

Oil.

Rf value: 0.17 (hexane / ethyl acetate = 5/1). n _D ²³ 1.5291. Compound 10 (R ³ ′ = dimethylphenylsilyloxy group, R ⁶ ′ = hydroxyl compound) Yield: 12%.

Oil.

Rf value: 0.08 (hexane / ethyl acetate = 5/1). Compound 11 (R ³ ′ = R ⁶ ′ = compound of dimethylallylsilyloxy group) Yield: 63%.

Oil.

Rf value: 0.43 (hexane / ethyl acetate = 10/1). Compound 12 (R ³ ′ = hydroxyl group, R ⁶ ′ = compound of dimethylallyl thiolyloxy group) Yield: 11%.

Oil.

Rf value: 0.37 (hexane / ethyl acetate = 5/1). Compound 13 (R ³ ′ = dimethylallylsilyloxy group, R ⁶ ′ = hydroxyl compound) Yield: 5%.

Oil.

Rf value: 0.15 (hexane / ethyl acetate = 5/1). Compound 14 (R ³ ′ = R ⁶ ′ = compound of chloromethyldimethylsilyloxy group) Yield: 74%.

Oil.

Rf value: 0.32 (hexane / ethyl acetate = 10/1). Compound 15 (R ³ ′ = R ⁶ ′ = compound of trimethylsilyloxy group) Yield: 90%.

Oil.

Rf value: 0.63 (hexane / ethyl acetate = 10/1). Compound 16 (R ³ ′ = hydroxyl group, R ⁶ ′ = trimethylsilyloxy group compound) Yield: 16%.

Oil.

Rf value: 0.45 (hexane / ethyl acetate = 3/1). Compound 17 (R ³ ′ = trimethylsilyloxy group, R ⁶ ′ = hydroxyl compound) Yield: 11%.

Oil.

Rf value: 0.33 (hexane / ethyl acetate = 3/1). Example 7 (3S ^* , 4R ^* , 7R ^* ) isopropylamine 3-n-propyl-4,7-dihydroxy-5-oxo-8 (Z) -ethylidene-1-cyclononene-1- (N-isopropyl) carbamoyl -2-Carboxylate (compound 18) Isopropylamine (60 mg, 1 mmol) was added to a solution of conegistin (154 mg, 0.5 mmol) in chloroform (5 ml), and the mixture was stirred at room temperature for 2 hours. The generated white crystals were collected by filtration and washed with chloroform to give a white crystalline compound 18.
143 mg (82% yield) were obtained.

[Compound 18] Melting point: 127 ° C.

NMR spectrum _{(DMSO-d 6) δppm:} 6.02 (b, 1H); 5.34
(Q, J = 6.9Hz, 1H); 4.75 (dd, J = 5.6,4.8Hz, 1H); 4.6
(B, 1H); 3.94 (d, J = 9.7Hz, 1H); 3.76 (six, J = 6.4Hz,
1H); 3.6 (t, J = 6.5Hz, 1H); 3.4-3.2 (m, 1H); 3.22 (d
d, J = 13.3, 6.5Hz, 1H); 2.89 (ABq, J = 12.5Hz, 2H); 2.86
(S, 1H); 2.4 (dd, J = 16.1, 5.2Hz, 1H); 1.8 to 1.6 (m, 2
H); 1.57 (d, J = 6.9 Hz, 3H); 1.17 (d, J = 6.5 Hz, 6H); 1.
00 (d, J = 6.5Hz, 3H); 0.98 (d, J = 6.5Hz, 3H); 0.98 (d,
J = 6.5 Hz, 3H); 0.83 (t, J = 7.3 Hz, 3H). IR spectrum (nujol) νcm-1: 3370, 3150, 1690, 1
. 635,1610 mass spectrum (m / z): 349 ( M-H 2 O-NH 2 C 3 H 7 -
^{. i +); 331; 308} ; 290; 262; 246; 234; 219 Rf value: 0.06 (hexane / ethyl acetate = 1/2). The following compounds were produced in the same manner as in Example 7.

Compound 19 (R ¹ ′ = carbamoyl, R ² ′ = carboxylic acid ammonium salt, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: quantitative.

Melting point: 84-86 ° C.

Compound 20 (R ¹ ′ = methylcarbamoyl, R ² ′ = carboxylic acid / methylamine salt, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 97%.

Melting point: 110-111 ° C.

Compound 21 (R ¹ ′ = t-butylcarbamoyl, R ² ′ = carboxylic acid.
t-butylamine salt, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 69%.

Melting point: 116-118 ° C.

Compound 22 (R ¹ '= hydroxy t- butylcarbamoyl, R ^2' = carboxylic ^{acid, R 3 '= R 6'} = a compound of hydroxyl groups) Yield: 92%.

Melting point: 106-108 ° C.

Compound 23 (R ¹ ′ = 3-hydroxypropylcarbamoyl, R ² ′ =
(Carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 73%.

Melting point: 87-89C.

Compound 24 (R ¹ ′ = benzylcarbamoyl, R ² ′ = carboxylic acid,
R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 67%.

Melting point: 105-107 ° C.

Compound 25 (R ¹ ′ = 4-methoxybenzylcarbamoyl, R ² ′ = carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 75%.

Melting point: 102-103 ° C.

Compound 26 (R ¹ ′ = dimethoxymethylcarbamoyl, R ² ′ = carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 97%.

Melting point: 80-82 ° C.

Compound 27 (R ¹ ′ = phenylcarbamoyl, R ² ′ = carboxylic acid / triethylamine salt, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 53%.

Melting point: 114-115 [deg.] C.

Compound 28 (R ¹ ′ = methylcarbamoyl, R ² ′ = carboxylic acid, R ³ ′
= R ⁶ '= compound of acetoxy group) Yield: 99%.

Melting point: 97-98 ° C.

Compound 29 (R ¹ '= isopropylcarbamoyl, R ^2' = carboxylic acid isopropylamine ^{salt, R 3 '= R 6'} = a compound of dimethylisopropylsilyl group) Yield: 89%.

Melting point: 67-70 ° C.

Compound 30 (R ¹ ′ = isopropylcarbamoyl, R ² ′ = carboxylic acid / isopropylamine salt, R ³ ′ = R ⁶ ′ = dimethylphenylsilyloxy group) Yield: quantitative.

amorphous.

Compound 31 (R ¹ '= methylcarbamoyl, R ^2' = carboxylic acid methylamine salt, R ³ '= hydroxyl group, R ^6' = a compound of dimethyl t- butyl silyl group) Yield: 23%.

amorphous.

Compound 32 (R ¹ ′ = methylcarbamoyl, R ² ′ = carboxylic acid / methylamine salt, R ³ ′ = R ⁶ ′ = trimethylsilyloxy group) Yield: 42%.

Melting point: 71-76 ° C.

Compound 33 (R ¹ ′ = 2,4-difluorophenylcarbamoyl, R ² ′
= Carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 74%.

Melting point: 69-75C.

Compound 34 (R ¹ ′ = 2,6-difluorophenylcarbamoyl, R ² ′
= Carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 44%.

Melting point: 68-67 ° C.

Compound 35 (R ¹ ′ = 2,5-difluorophenylcarbamoyl, R ² ′
= Carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 78%.

Melting point: 63-73 ° C.

Compound 36 (R ¹ ′ = phenylcarbamoyl, R ² ′ = carboxylic acid / triethylenediamine salt, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 29%.

Oil.

Compound 37 (R ¹ ′ = 2-pyrimidylcarbamoyl, R ² ′ = carboxylic acid, R ³ ′ = R ⁶ ′ = hydroxyl compound) Yield: 50%.

Melting point: 110-112 ° C.

Example 8 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,7-diacetoxy-5-oxo-8 (Z) -ethylidene-1-cyclononene-1,2-dicarboxylic anhydride ( Compound 38) Cornegistin (66 mg, 0.21 mmol) and pyridine (0.2 ml) in methylene chloride (3 ml) were dissolved in acetic anhydride (0.2 m
l) was added, and the mixture was stirred at room temperature for 2 hours in the presence of a catalytic amount of 4-N, N-dimethylaminopyridine (DMAP) (10 mg). Water (15 ml) was added, the mixture was extracted with methylene chloride, dried and concentrated, and then subjected to silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain 85.2 mg (quantitative) of compound 38.

[Compound 38] Melting point: 134-136 ° C NMR spectrum (CDCl ₃ ) δ ppm: 5.9-5.8 (m, 2H); 4.90
(D, J = 9.0Hz, 1H); 3.51 (ddd, J = 9.0,4.4,3.6Hz, 1H);
3.41 (d, J = 16.5Hz, 1H); 3.25 (d, J = 16.5Hz, 1H); 3.12
(Dd, J = 14.5,9.0Hz, 1H); 2.70 (dd, J = 14.5,5.0Hz, 1
H); 2.15 (s, 3H); 2.07 (s, 3H); 2.0-1.9 (m, 1H); 1.8
1 (d, J = 7.2 Hz, 3H); 1.8 to 1.6 (m, 1H); 1.4 to 1.2 (m, 2
H); 0.93 (t, J = 7.2 Hz, 3H). IR spectrum (CHCl ₃ ) νcm−1: 1830, 1770, 1740. Mass spectrum (m / z): 392 (M ⁺ ); 332; 290; 262; 244. Rf value: 0.72 (hexane / ethyl acetate = 1 / 2). The following compounds were produced in the same manner as in Example 8.

Compound 39 (compound in which R ³ ′ = R ⁶ ′ = methoxymethylcarbonyloxy group) Yield: 91%.

Oil Rf value: 0.40 (hexane / ethyl acetate = 1/1).

Compound 40 (compound in which R ³ ′ = R ⁶ ′ = 2,4-dichlorophenyloxymethylcarbonyloxy group) Yield: 75%.

Melting point: 64-65 [deg.] C.

Rf value: 0.30 (hexane / ethyl acetate = 3/1).

Compound 41 (a compound in which R ³ ′ = R ⁶ ′ = phenyloxymethylcarbonyloxy group) Yield: 76%.

Oil.

Rf value: 0.39 (hexane / ethyl acetate = 3/1).

Compound 42 (compound in which R ³ ′ = R ⁶ ′ = 2,4-dichlorophenylcarbonyloxy group) Yield: 19%.

Melting point: 66-67 [deg.] C.

Rf value: 0.61 (hexane / ethyl acetate = 3/1).

Compound 43 (a compound in which R ³ ′ = hydroxyl group and R ⁶ ′ = 2,4-dichlorophenylcarbonyloxy group) Yield: 56%.

Melting point: 60-61 ° C.

Rf value: 0.31 (hexane / ethyl acetate = 3/1).

Compound 44 (a compound in which R ³ ′ = acetoxy group and R ⁶ ′ = dimethyl t-butylsilyloxy group) Yield: 87%.

Oil.

Rf value: 0.51 (hexane / ethyl acetate = 4/1).

Compound 45 (a compound in which R ³ ′ is a hydroxyl group and R ⁶ ′ is an ethoxycarbonyloxy group) Yield: 11%.

Oil.

Rf value: 0.62 (hexane / ethyl acetate = 1/1).

Compound 46 (a compound in which R ³ ′ = hydroxyl group and R ⁶ ′ = dimethylcarbamoyloxy group) Yield: 15%.

Oil.

Rf value: 0.26 (hexane / ethyl acetate = 1/1).

Compound 47 (a compound in which R ³ ′ is a hydroxyl group and R ⁶ ′ is a benzoyloxy group) Yield: 56%.

Melting point: 59-60 [deg.] C.

Rf value: 0.49 (hexane / ethyl acetate = 2/1).

Example 9 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4-methanesulfonyloxy-5-oxo-7-hydroxy-8
(Z) -Ethylidene-1-cyclononene-1,2-dicarboxylic anhydride (Compound 48) Chlorination of Cornegistin (155 mg, 0.5 mmol), diazabicyclo [2,2,2] octane (DBU) (124 mg, 1.11 mmol) To a methylene (5 ml) solution was added methanesulfonyl chloride (86 μl, 1.11 mmol) at 0 ° C. under a nitrogen atmosphere. After stirring at 0 ° C. for 2 hours and room temperature for 2 days,
After adding water (20 ml), extracting with methylene chloride, drying and concentrating, silica gel column chromatography (hexane / hexane).
(Ethyl acetate = 1/1) to give 33 mg of a colorless oily compound 38.
(17% yield). In addition, 65 mg of Cornegistin (recovery rate
42%).

NMR spectrum (CDCl ₃ ) δ ppm: 5.87 (q, J = 7.0 Hz, 1H);
5.08 (dd, J = 7.6, 5.2 Hz, 1H); 4.68 (d, J = 10.4 Hz, 1H);
3.66 (ddd, J = 10.4,4.0,3.2Hz, 1H); 3.41 (d, J = 15.1H
z, 1H); 3.31 (dd, J = 14.9,7.6Hz, 1H); 3.16 (d, J = 15.1
Hz, 1H); 3.12 (s, 3H); 2.84 (dd, J = 14.9, 5.2Hz, 1H);
2.2-2.0 (m, 1H); 1.98 (b, 1H); 1.9-1.8 (m, 1H); 1.7
6 (d, J = 7.0 Hz, 3H); 1.4 to 1.1 (m, 2H); 0.94 (t, J = 7.3
Hz, 3H). IR spectrum (CHCl ₃ ) νcm−1: 3550,3400,1830,1765,1
710. Mass Spectrum (m / z): 386 ( M +); 368 (M-H 2 O +); 29
0; 248; 219. Rf value: 0.29 (hexane / ethyl acetate = 1/1). The following compounds were produced in the same manner as in Example 9.

Compound 49 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4-p-toluenesulfonyloxy-5-oxo-7-hydroxy-
8 (Z) -ethylidene-1-cyclononene-1,2-dicarboxylic anhydride Melting point: 54-55 ° C.

NMR spectrum (CDCl ₃ ) δ ppm: 7.89 (d, J = 8.1 Hz, 2H);
7.40 (d, J = 8.1Hz, 2H); 5.85 (q, J = 7.0Hz, 1H); 5.00
(Dd, J = 8.0, 4.8Hz, 1H); 4.32 (d, J = 10.1Hz, 1H); 3.58
(Ddd, J = 10.1,6.8,4.0Hz, 1H); 3.36 (dd, J = 14.5,8.0H
z, 1H); 3.22 (ABq, J = 14.7 Hz, 2H); 2.66 (dd, J = 14.5, 4.8 Hz, 1H); 2.49 (s, 3H); 1.96 (s, 1)
H); 1.9-1.7 (m, 1H); 1.74 (d, J = 7.0 Hz, 3H); 1.7-1.
5 (m, 1H); 1.2 to 1.0 (m, 2H); 0.81 (t, J = 7.2 Hz, 3H). IR spectrum (CDCl ₃ ) νcm−1: 3600,3370,1835,1770,1
720. Mass spectrum (m / z): 462 (M ⁺ ); 444; 290; 244; 219; 15.
5. Rf value: 0.49 (hexane / ethyl acetate = 1/1). Example 10 3-n-propyl-4,7-dibromo-5-oxo-8
(Z) -Ethylidene-1-cyclononene-1,2-dicarboxylic anhydride (compound 50) Cornegistin (275 mg, 0.89 mmol), triphenylphosphine (583 mg, 2.22 mmol) in DMF (10 ml)
N-bromosuccinimide (NBS) (396 mg, 2.22
Mmol). Heated at 60 ° C. for 3 hours in a nitrogen atmosphere. After cooling, saturated sodium sulfite (20 ml) was added and 5
Stir vigorously for minutes. After ether extraction, drying and concentration, the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 50 mg of Compound 50 (13% yield).

Colorless oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.68 (q, J = 7.0 Hz, 1H);
4.98 (d, J = 9.3Hz, 1H); 4.41 (d, J = 6.8Hz, 1H,); 3.64
(D, J = 14.5Hz, 1H); 3.4 to 3.3 (m, 1H); 3.07 (ddd, J = 1
8.3,9.5,1.2Hz, 1H); 2.80 (d, J = 14.5Hz, 1H); 2.35 (d,
J = 18.3Hz, 1H); 2.1-1.9 (m, 1H); 1.9-1.7 (m, 1H);
1.81 (d, J = 7.0Hz, 3H); 1.7-1.5 (m, 1H); 1.5-1.3
(M, 1H); 0.99 (t, J = 7.2 Hz, 3H). IR spectrum (CHCl ₃ ) νcm−1: 1850, 1830, 1765. Mass spectrum (m / z): 434 (M ⁺ ). Rf value: 0.28 (hexane / ethyl acetate = 3/1). Example 11 (3S ^* , 4R ^* , 7R ^* )-N-isopropyl 3-n-propyl-4,7-dihydroxy-5-oxo-8 (Z) -ethylidene-1-cyclononene-1,2-dicarboxy Imide (Compound 51) Compound 18 (60 mg, 0.14 mmol) was treated with methylene chloride (2m
l), and N, N'-dicyclohexylcarbodiimide (DCC) (58 mg, 0.28 mmol) was added. After stirring at room temperature for 3 hours, the solvent was distilled off and silica gel column chromatography (hexane / ethyl acetate = 5/1). And then 1/1) to obtain 36 mg of compound 51 (yield 53%).

Melting point: 125-127 ° C NMR spectrum (CDCl ₃ ) δ ppm: 5.88 (q, J = 7.3 Hz, 1H);
5.02 (dd, J = 7.7,4.4Hz, 1H); 4.12 (quint, J = 6.4Hz, 1
H); 4.02 (d, J = 8.9Hz, 1H); 3.65 (b, 1H); 3.40 (dd, J
= 14.1, 7.7 Hz, 1H); 3.30 (ABq, J = 14.9 Hz, 2H); 3.4 to 3.
3 (m, 1H); 2.78 (b, 1H); 2.56 (dd, J = 14.1,4.4Hz, 1
H); 2.2-2.1 (m, 1H); 2.0-1.8 (m, 1H); 1.70 (d, J =
7.3Hz, 3H); 1.4 ~ 1.1 (m, 2H); 1.19 (d, J = 6.4Hz, 3H);
1.17 (d, J = 6.4H.3H); 0.92 (t, J = 7.3Hz, 3H). IR spectrum (nujol) vcm-1: 3470, 3310, 1770, 1
680. Mass Spectrum (m / z): 349 ( M +); 320; 306 (M-CO 2 +
¹⁺ ). Rf value: 0.17 (hexane / ethyl acetate = 1/1). Example 12 (3S ^* , 4R ^* , 7R ^* )-N- (4-chlorophenyl) 3-
n-propyl-4,7-dihydroxy-5-oxo-8
(Z) -ethylidene-1-cyclononene-1,2-dicarboximide (compound 66) and (3S ^* , 4R ^* , 7R ^* )-9 (Z) -ethylidene-5,8-dihydroxy-1- (N -4-chlorophenyl) imide-
3,6-dioxo-4-n-propyl-cyclononeno [2,1
-C] Oxolene (Compound 67) In a solution of conegistin (82.1 mg, 0.266 mmol) in ether (1 ml), 4-chloroaniline (136 mg, 1.06 mmol), dicyclohexylcarbodiimide (DCC) (110
mg, 0.534 mmol), and the mixture was stirred at room temperature for 15 hours, and further heated under reflux for 2 hours and 30 minutes. The reaction solution is filtered, and the filtrate is directly applied to a thin-layer silica gel chromatography plate (manufactured by Merck, Art.5744, 20 × 20 cm, thickness 0.5 mm), 4
Adsorbed on a sheet and developed (hexane / ethyl acetate = 1/1)
92 mg of a mixture of compound 66 and compound 67 was obtained. This was used as a thin-layer silica gel chromatography plate (Merck,
Art.5715, 20 × 20cm, thickness 0.25mm)
Developed 5 times with (hexane / ethyl acetate = 3: 1), developed 3 times with (hexane / ethyl acetate = 2: 1), developed twice with (hexane / ethyl acetate = 3: 2), purified, and purified the compound. 67 to 24.
13.6 mg (yield: 21%) of a mixture of compounds 66 and 67 was obtained. This mixture was separated by silica gel for preparative chromatography (manufactured by Fujigel Sales Co., Ltd., ODSQ3,
/ 0 → 2/1 → 1/1 → 3/4. ) To obtain 17.5 mg (yield 15%) of compound 66.

[Compound 66] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 7.40 (dt, J = 8.9, 2.4 Hz,
2H); 7.35 (dt, J = 8.9,2.4Hz, 2H); 5.80 (q, J = 6.9Hz, 1
H); 5.08 (dd, J = 6.8, 4.4 Hz, 1H); 4.1-4.0 (b, 2H); 3.
5 to 3.4 (m, 4H); 3.19 (d, J = 14.5 Hz, 1H); 2.50 (dd, J =
14.1,4.4Hz, 1H); 2.20 (m, 1H); 1.94 (m, 1H); 1.68 (d,
J = 6.9 Hz, 3H); 1.29 (m, 2H); 0.93 (t, J = 6.8 Hz, 3H). IR spectrum (KBr) νcm-1: 3440, 2950, 2925, 2870, 170
0. Mass spectrum (m / z): 417 (M ⁺ ); 399; 374; 356; 345. ¹³ C-NMR (ppm): 212.3, 169.3, 142.5, 139.0, 135.0, 133.
1,130.4,129.4,129.0,127.0,81.1,68.4,45.3,41.6,30.
9,26.3,21.6,13.9,13.4. Rf value: 0.33 (hexane / ethyl acetate = 1/1). [Compound 67] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 7.3 (s, 4H); 5.96 (q, J
= 6.5Hz, 1H); 5.10 (b, 1H); 4.08 (m, 1H); 3.5-3.3
(M, 5H); 2.56 (dd, J = 14.1,4.4Hz, 1H); 2.44 (b, 1H);
2.20 (m, 1H); 1.95 (m, 1H); 1.71 (d, J = 6.5 Hz, 3H); 1.
27 (m, 2H); 0.93 (t, J = 7.3 Hz, 3H). IR spectrum (KBr) νcm-1: 3400, 2920, 2870, 1775, 167
5. Mass spectrum (m / z): 417 (M ⁺ ); 399; 388; 374; 344; 32
^{8. 13 C-NMR (ppm)} : 211.6,116.3,151.7,150.1,142.2,134.
9,134.2,132.5,130.1,129.9,126.6,80.6,68.4,44.8,40.
9,30.4,27.0,21.3,13.8,13.5. Rf value: 0.37 (hexane / ethyl acetate = 1/1). The following compounds were produced in the same manner as in Examples 11 and 12.

Compound 52 (a compound wherein R ³ ′ = R ⁶ ′ = hydroxyl group and R ⁷ ′ = t-butyl group) Yield: 29%.

Melting point: 87-91C.

Rf value: 0.40 (hexane / ethyl acetate = 1/2). Compound 53 (compound in which R ³ ′ = R ⁶ ′ = acetoxy group, R ⁷ ′ = isopropyl group) Yield: 44%.

Melting point: 119-121 ° C.

Rf value: 0.49 (hexane / ethyl acetate = 1/1). Compound 54 (a compound wherein R ³ ′ = R ⁶ ′ = hydroxyl group and R ⁷ ′ = 2,2-dimethoxyethyl group) Yield: 45%.

Oil.

Rf value: 0.24 (hexane / ethyl acetate = 1/2). Compound 55 (R ³ ′ = R ⁶ ′ = dimethylisopropylsilyloxy group,
Compound in which R ⁷ ′ = methoxy group) Yield: 40%.

Oil.

Rf value: 0.47 (hexane / ethyl acetate = 5/1). Compound 57 (R ³ ′ = R ⁶ ′ = dimethylisopropylsilyloxy group,
Compound in which R ⁷ ′ = isopropyl group) Yield: quantitative.

Oil.

Rf value = 0.59 (hexane / ethyl acetate = 10/1). Compound 58 (R ³ ′ = R ⁶ ′ = dimethylphenylsilyloxy group, R ⁷ ′
= Compound having an isopropyl group) Yield: 48%.

Oil.

Rf value: 0.52 (hexane / ethyl acetate = 10/1). Compound 59 (a compound wherein R ³ ′ = R ⁶ ′ = hydroxyl group and R ⁷ ′ = 3-hydroxypropyl group) Yield: 3%.

Oil.

Rf value: 0.48 (ethyl acetate). Compound 61 (a compound in which R ³ ′ = R ⁶ ′ = hydroxyl group and R ⁷ ′ = hydrogen atom) Yield: 3%.

Oil.

Rf value: 0.16 (hexane / ethyl acetate = 1/2). Compound 62 (R ³ ′ = R ⁶ ′ = hydroxyl group, R ⁷ ′ = methyl group) Yield: 8%.

Oil.

Rf value: 0.30 (hexane / ethyl acetate = 1/2). Compound 63 (compound in which R ³ ′ = R ⁶ ′ = acetoxy group, R ⁷ ′ = methyl group) Yield: 8%.

Oil.

Rf value: 0.52 (hexane / ethyl acetate = 1/1). Compound 64 (a compound in which R ³ ′ is a hydroxyl group, R ⁶ ′ is a dimethyl tert-butylsilyloxy group, and R ⁷ ′ is a methyl group) Yield: 12%.

Oil.

Rf value: 0.35 (hexane / ethyl acetate = 5/1). Compound 68 (a compound in which R ⁷ ′ is a phenyl group) Yield: 43%.

Oil.

Rf value [mixture containing 1/4 of compound 69]: 0.45 (hexane / ethyl acetate = 1/2). Compound 70 (R ⁷ ′ = compound having 2,4-difluorophenyl group) Yield: 54%.

Oil.

Rf value: 0.48 (hexane / ethyl acetate = 1/2). Compound 71 (compound in which R ⁷ ′ = 4-fluorophenyl group) Yield: 38%.

Oil.

Rf value: 0.45 (hexane / ethyl acetate = 1/2). Compound 72 (compound in which R ⁷ ′ = 2-fluoro-4-chlorophenyl group) Yield: 22%.

Oil.

Rf value: 0.43 (hexane / ethyl acetate = 2/3). Compound 73 (R ⁷ ′ = compound having 2,4-dichlorophenyl group) Yield: 14%.

Oil.

Rf value: 0.43 (hexane / ethyl acetate = 2/3). Compound 74 (a compound wherein R ⁷ ′ = benzyl group) Yield: 49%.

Oil.

Rf value: 0.55 (hexane / ethyl acetate = 1/2). Compound 75 (a compound wherein R ⁷ ′ = 4-methoxybenzyl group) Yield: 42%.

Oil.

Rf value: 0.48 (hexane / ethyl acetate = 1/2). Compound 76 (compound in which R ⁷ ′ = methylamino group) Yield: 36%.

Melting point: 60-62 [deg.] C.

Compound 56 (R ³ ′ = R ⁶ ′ = dimethylisopropylsilyloxy group,
Compound in which R ⁷ ′ = methoxy group) Yield: 17%.

Oil.

Rf value: 0.56 (hexane / ethyl acetate = 5/1). Compound 60 (a compound in which R ³ ′ = R ⁶ ′ = hydroxyl group and R ⁷ ′ = 3-hydroxypropyl group) Yield: 10%.

Oil.

Rf value: 0.35 (ethyl acetate). Compound 65 (a compound in which R ³ ′ is a hydroxyl group, R ⁶ ′ is a dimethyl tert-butylsilyloxy group, and R ⁷ ′ is a methyl group) Yield: 17%.

Oil.

Rf value: 0.28 (hexane / ethyl acetate = 5/1). Compound 67 (R ⁷ ′ = compound having 4-chlorophenyl group) Yield: 21%.

Oil.

Rf value: 0.37 (hexane / ethyl acetate = 1/1). Compound 69 (compound in which R ⁷ ′ = phenyl group) Yield: 43%.

Oil.

Rf value [mixture containing 3/4 of compound 68]: 0.45 (hexane / ethyl acetate = 1/2). Example 13 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4-acetoxy-5-oxo-7-hydroxy-8 (Z) -ethylidene-1-cyclononene-1,2-dicarnbonic anhydride Compound (Compound 77) To a solution of compound 44 (213 mg, 0.46 mmol) in acetonitrile (6 ml) was added an Olar reagent (68% HF, 0.6 ml), and the mixture was stirred at room temperature for 8 hours. Water (15 ml) was added, and the mixture was extracted with ethyl acetate, dried, concentrated, and then subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1) to give Compound 77.
Was obtained in a yield of 129 mg (81%).

Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.85 (q, J = 6.9 Hz, 1H);
5.06 (dd, J = 8.5, 5.2 Hz, 1H); 4.84 (d, J = 9.3 Hz, 1H);
3.49 (ddd, J = 9.3,5.6,4.0Hz, 1H); 3.45 (d, J = 15.7Hz,
1H); 3.14 (d, J = 15.7Hz, 1H); 3.02 (dd, J = 14.9,8.5H
z, 1H); 2.72 (dd, J = 14.9, 5.2 Hz, 1H); 2.16 (s, 3H); 2.
1 ~ 1.9 (m, 1H); 1.79 (d, J = 6.9Hz, 3H); 1.8 ~ 1.7 (m, 2
H); 1.4-1.1 (m, 2H); 0.92 (t, J = 7.2 Hz, 3H). IR spectrum (CHCl ₃ ) νcm−1: 3600,3400,2970,1830,1
770, 1370. Mass spectrum (m / z): 351 (M + 1 ⁺ ); 333; 290; 219; 17
5; 91. Rf value: 0.46 (hexane / ethyl acetate = 1/1) Example 14 (3S ^* , 4R ^* , 7R ^* )-1,2-dimethoxycarbonyl-3
-N-propyl-4,7-dihydroxy-5-oxo-8
(Z) -Ethylidene-1-cyclononene (Compound 78) To a solution of conegistin (308 mg, 1 mmol) in methanol (2 ml) was added trimethylsilyldiazomethane (10% hexane solution, 4 ml, 3.5 mmol) at room temperature for 3 hours at room temperature. Stirred. The reaction solution was concentrated, and the obtained crude target product was recrystallized from a mixed solution of ethyl acetate-hexane to give Compound 78.
Was obtained in an amount of 354 mg (quantitative).

Melting point: 132-134.5C.

NMR spectrum (CDCl ₃ ) δ ppm: 5.62 (q, J = 7.0 Hz, 1H);
4.82 (b, 1H); 4.51 (t, J = 8.7Hz, 1H); 4.17 (d, J = 7.6H
z, 1H); 3.76 (s, 3H); 3.70 (s, 3H); 3.4-3.0 (m, 3H);
3.0-2.6 (m, 2H); 2.1-1.9 (m, 1H); 1.7 (d, J = 7.3 Hz,
3H); 1.5-1.3 (m, 2H); 1.3-1.1 (m, 1H); 0.86 (t, J =
7.3Hz, 3H). IR spectrum (nujol) vcm-1: 3370, 3300, 1720, 1
460. Mass Spectrum (m / z): 354 (M ⁺ ); 336; 323; 304; 275; 24.
7; 217. Rf value: 0.44 (hexane / ethyl acetate = 1/2) Example 15 (3S ^* , 4R ^* , 7R ^* )-1- (N-isopropyl) carbamoyl-2-methoxycarbonyl-3-n- Propyl
4,7-dihydroxy-5-oxo-8 (Z) -ethylidene-1-cyclononene (compound 79) and (3S ^* , 4R ^* , 7R ^* )-1- (N-isopropyl) carbamoyl-2-trimethylsilylmethoxycarbonyl -3
-N-propyl-4,7-dihydroxy-5-oxo-8
(Z) -ethylidene-1-cyclononene (Compound 80) Compound 18 (55 mg, 0.13 mmol) in methylene chloride (2 m
l) Trimethylsilyldiazomethane (10
% Hexane solution, 50 mg, 0.39 mmol) was added dropwise at room temperature, and 1 ml of methanol was further added, followed by reaction at room temperature for 3 hours and 30 minutes. The oily substance obtained by concentration was subjected to silica gel column chromatography (eluted with ethyl acetate),
11 mg (yield 19%) of 80, then 20 mg of compound 79 (40% yield)
%)Obtained.

[Compound 79] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.75 (d, J = 8.1 Hz, 1H);
5.39 (q, J = 14.1,7.2Hz, 1H); 5.07 (b, 1H); 4.18 (d, J
= 8.9Hz, 1H); 3.96 (six, J = 6.9Hz, 1H); 3.67 (s, 3H);
3.49 (dd, J = 13.7,6.1Hz, 1H); 3.43 (d, J = 14.9Hz, 1
H); 3.32 (m, 1H); 2.9 (d, J = 13.3Hz, 1H); 2.39 (dd, J
= 13.7,3.6Hz, 1H); 2.0-1.8 (m, 1H); 1.6-1.4 (m, 1
H); 1.58 (d, J = 6.9Hz, 3H); 1.4 ~ 1.0 (m, 2H); 1.11
(D, J = 6.0Hz, 3H); 1.09 (d, J = 6.0Hz, 3H); 0.86 (t, J
= 6.9Hz, 3H). IR spectrum (liquid film) vcm-1: 3360, 1712, 1640, 1520. Mass spectrum (m / z): 381 (M ⁺ ); 363; 353; 338; 320; 30
8. ¹³ C-NMR spectrum (ppm): 216.8,169.5,167.4,146.9,
135.5,133.1,127.3,81.8,68.5,51.7,46.3,44.0,41.6,3
2.5, 30.8, 22.5, 22.4, 14.0, 13.0. Rf value: 0.5 (ethyl acetate). [Compound 80] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.6 (m, 1H); 5.46 (q, J
= 6.9Hz, 1H); 5.1 (t, J = 4.8Hz, 1H); 4.24 (dd, J = 9.3H
z, 1H); 4.00 (m, 1H); 4.0-3.4 (m, 2H); 3.47 (m, 1H);
3.38 (d, J = 14.1 Hz, 1H); 3.4 to 3.2 (m, 1H); 2.49 (dd, J
= 14.5,4.4Hz, 1H); 1.64 (d, J = 7.3Hz, 1H); 1.6 ~ 1.4
(M, 1H); 1.4 to 1.21 (m, 2H); 1.14 (d, J = 6.9Hz, 3H);
1.10 (d, J = 6.9Hz, 3H); 0.88 (t, J = 7.3Hz); 0.09 (s, 9
H). IR spectrum (liquid film) νcm-1: 3350, 1710, 1640, 1250. Mass spectrum (m / z): 453 (M ⁺ ); 438; 410; 381; 354; 33
6; 324. Rf value: 0.64 (ethyl acetate). Example 16 (3S ^* , 4R ^* , 7R ^* )-1,2-dimethoxycarbonyl-3
-N-propyl-4,7-dihydroxy-5-oxo-8
(Z) -Ethylidene-1-cyclononene (compound 78) Cornegistin (308 mg, 1 mmol) was dissolved in water, adjusted to pH 8 with 1N aqueous sodium hydroxide, and lyophilized to obtain 368 mg of white crystals. The crystals were dissolved in DMF (5 ml), methyl iodide (426 mg, 3 mmol) was added, the mixture was stirred at room temperature for 6 hours, poured into water (10 ml), and ethyl acetate (50 ml).
, And washed with saturated aqueous sodium chloride solution (10 ml x 3 times)
The residue was purified by drying, concentration, and silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1/2) in order to obtain 158 mg (45%) of Compound 78.

Melting point: 90-91C.

Example 17 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,7-dihydroxy-5-phenylsulfonylhydrazono-8 (Z)
-Ethylidene-1,2-dicarboxylic anhydride (Compound 81) To a solution of Cornegistin (308 mg, 1 mmol) in dioxane (5 ml) was added phenylsulfonylhydrazine (175 mg,
1 mmol) and stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried and concentrated to give Compound 81.
Was obtained as a white powder (462 mg, quantitative).

Melting point: 88-91C.

NMR spectrum (CDCl ₃ ) δ ppm: 10.3 (s, 1H); 7.8 to 7.5
(M, 5H); 5.8 (d, J = 5.2Hz, 1H); 5.62 (q, 1H, J = 7.0Hz,
1H); 5.20 (d, J = 3.5Hz, 1H); 4.38 (bs, 1H); 3.89 (dd,
J = 10.5,5.2Hz, 1H); 3.4-3.2 (m, 1H); 3.15 (ABq, J = 1
6.9Hz, 2H); 2.80 (dd, J = 14.0,9.3Hz, 1H); 2.71 (dd, J
= 14.5,4.1Hz, 1H); 1.9-1.6 (m, 2H); 1.82 (d, J = 7.0H
z, 3H); 1.4-1.0 (m, 2H); 0.81 (t, J = 7.0 Hz, 3H). IR spectrum (nujol) νcm-1: 3300,3302,2907,1
. 860,1820,1760,1700,1450 mass spectrum (m / z): 444 ( M-H 2 O +); 426; 303 Rf value:. 0.16 (hexane / ethyl acetate = 1/1). Example 18 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,7-dihydroxy-5-phenylhydrazono-8 (Z) -ethylidene-1-cyclononene-1,2-dicarboxylic anhydride Compound (Compound 82) Cornegistin (154 mg, 0.5 mmol) was dissolved in chloroform (5 ml), phenylhydrazine (54 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The oily substance obtained by concentration was subjected to silica gel chromatography (hexane /
Ethyl acetate was changed sequentially from 1/1 to 1/2. ) To give 138 mg (69%) of compound 82 as white crystals.

Melting point: 76-80 ° C.

NMR spectrum _{(CDCl 3) δppm: 7.26~7.17 (} m, 2H); 6.9
6 to 6.80 (m, 3H); 5.71 (q, J = 7.3 Hz, 1H); 4.78 (d, J =
4.0 Hz, 1H); 4.5 (d, J = 9.3 Hz, 1H); 3.45 (dt, J = 9.3, 5.
6 Hz, 1H); 3.27 (ABq, J = 16.5 Hz, 2H); 3.06 (dd, J = 14.
9,7.3Hz, 1H); 2.65 (dd, J = 14.9,2.8Hz, 1H); 2.1 ~ 1.9
(M, 2H); 1.87 (d, J = 7.3 Hz, 3H); 1.3-1.2 (m, 2H);
92 (t, J = 7.3 Hz, 3H). Mass spectrum (m / z): 398 (M ⁺ ); 380; 362; 336; 305; 29
0. IR spectrum (nujol) νcm-1: 3400,3350,1850,1
825,1760,1720,1600,1500. Rf value: 0.58 (benzene / methanol / acetic acid = 8/1/1). Example 19 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,7-dihydroxy-5-oxo-8- (1,2-epoxy) propyl-1-cyclononene-1,2-dicarboxylic Acid Anhydride (Compound 83) To a solution of Cornegistine (152 mg, 0.49 mmol) in methylene chloride was added metachloroperbenzoic acid (130 mg, 0.74 mmol) at 0 ° C. under a nitrogen atmosphere. 4.5 hours, 0 ° C
After stirring with, an aqueous solution of sodium hydrogen carbonate (10 ml) was added,
After extraction with methylene chloride, drying and concentration, silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1
Changed to / 2. ) By purification, 19 mg of compound 83 as a colorless solid
(12%) obtained.

Melting point: 122-125 ° C.

NMR spectrum (CDCl ₃ ) δ ppm: 4.2 to 4.1 (m, 2H);
4.0 (m, 1H); 3.73 (s, 1H); 3.44 (dd, J = 14.9,7.0Hz);
3.42 (t, J = 7.6Hz, 1H); 3.29 (q, J = 5.6Hz, 1H); 2.95
(D, J = 14.5Hz, 1H); 2.62 (d, J = 14.5Hz, 1H); 2.59 (d
d, J = 14.5, 2.4Hz, 1H); 1.97 (q, J = 7.6Hz, 2H); 1.38
(D, J = 5.6Hz, 3H); 1.3-1.2 (m, 2H); 0.94 (t, J = 7.2H
z, 3H). IR spectrum (KBr) νcm-1: 3400, 2980, 1835, 1770, 172
0,1450. Mass spectrum (m / z): 324 (M ⁺ ); 306; 277; 221; 206; 16
7. Rf value: 0.41 (hexane / ethyl acetate = 1/2). Example 20 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,5,7-trihydroxy-8 (Z) -ethylidene-1,2-dicarboxylic anhydride [small polar isomer] (Compound 84) and Highly Polar Isomer (Compound 85)] To a solution of conegistin (308 mg, 1 mmol) in dioxane (10 ml) was added sodium borohydride at room temperature, and after 3 hours at room temperature, the mixture was further heated under reflux for 2 hours. . After completion of the reaction, the reaction product was poured into ice water, and extracted with ethyl acetate.
After drying and concentrating, 190 mg of the crude product obtained was subjected to silica gel column chromatography (hexane / ethyl acetate = 1 /
Appended to 2). First, 34 mg (10%) of compound 84 and then 44 mg (14%) of compound 85 were obtained.

[Compound 84] Melting point: 130-136 ° C.

NMR spectrum (deuterized acetone + deuterated water) δ ppm: 5.66 (q, J =
6.9Hz, 1H); 4.67 (d, J = 7.7Hz, 1H); 4.22 (dd, J = 5.6,
1.66, 1H); 4.06 (dd, J = 10.1, 5.6Hz, 1H); 3.77 (d, J =
5.2Hz, 1H); 3.38 (ABq, J = 17.7Hz, 2H); 3.09 (dt, J = 1
0.1,3.6Hz, 1H); 2.4-2.2 (m, 1H); 1.9-1.7 (m, 1H);
1.83 (d, J = 7.3 Hz, 3H); 1.5 to 1.2 (m, 1H); 1.3 to 1.1
(M, 2H); 0.88 (t, J = 7.3 Hz, 3H). IR spectrum (KBr) νcm-1: 3400, 1830, 1760, 1630. Mass spectrum (m / z): 310; 292; 274; 246; 233; 217; 205. Rf value: 0.28 (hexane / ethyl acetate = 1 / 2). [Compound 85] Amorphous.

NMR spectrum (CDCl ₃ ) δ ppm: 5.98 (q, J = 7.3 Hz, 1H);
4.93 (dd, J = 10.5,5.2Hz, 1H); 3.91 (d, J = 10.9Hz, 1
H); 3.76 (dd, J = 10.5, 2.0 Hz, 1H); 3.24 (s, 2H);
3.1 (m, 1H); 3.04 (dt, J = 10.9, 4.0 Hz, 1H); 2.32 (m, 1
H); 2.0-1.7 (m, 2H); 1.75 (d, J = 7.3 Hz, 3H); 1.4-1.
1 (m, 2H); 0.91 (t, J = 6.9 Hz, 3H). IR spectrum (KBr) νcm-1: 3400, 1820, 1750, 1630. Mass spectrum (m / z): 310; 292; 274; 256; 246; 231; 217. Rf value: 0.18 (hexane / ethyl acetate = 1 / 2). Example 21 (3S ^* , 4R ^* , 7R ^* )-3-n-propyl-4,5-dihydroxy-7-dimethyl-t-butylsilyloxy-8
(Z) -Ethylidene-1-cyclononene-1,2-dicarboxylic anhydride (Compound 86) In the same manner as in Example 18 except that Compound 4 (127 mg, 0.3 mmol) was used as a raw material, 21.5 mg of Compound 86 was used. (17
%)Obtained.

Melting point: 75-80C.

NMR spectrum (CDCl ₃ ) δ ppm: 5.53 (q, J = 6.8 Hz, 1H);
4.90 (dd, J = 8.9, 4.8 Hz, 1H); 4.27 (dd, J = 10.1, 6.9 Hz,
1H); 3.82 (d, J = 17.3Hz, 1H); 3.62 (dt, J = 6.9,2.4Hz,
1H); 3.0 ~ 2.9 (m, 1H); 2.93 (d, J = 17.3Hz, 1H); 2.1 ~
1.6 (m, 4H); 1.76 (dd, J = 6.9, 2.0 Hz, 3H); 1.3 to 1.1
(M, 2H); 0.90 (t, J = 7.3 Hz, 3H); 0.86 (s, 9H); 0.04
(D, J = 2.0Hz, 6H). IR spectrum (KBr) νcm−1: 3450, 1820, 1760, 1620. Mass spectrum (m / z): 423 (M−1 ⁺ ); 409; 390; 381; 36
7; 349; 331; 321; 303; 275. Rf value: 0.2 (hexane / ethyl acetate = 3/1). Example 22 (3S ^* , 4R ^* , 7R ^* )-1,2-dimethoxycarbonyl-3
-N-propyl-4,7-diacetoxy-5-oxo-8
(Z) -Ethylidene-1-cyclononene (Compound 87) Compound 78 (60 mg, 0.17 mmol) was treated with acetic anhydride (1 ml).
And pyridine (13.4 mg, 0.17 mmol) was added.
After stirring at room temperature for 1 hour, the mixture was concentrated and subjected to silica gel column chromatography (hexane / ethyl acetate = 5/1 to 2/1).
Changed to ) To give 73.8 mg (99.4%) of compound 87.

Melting point: 147-148 [deg.] C.

NMR spectrum (CDCl ₃ ) δ ppm: 5.85 (dd, J = 9.7, 4.4 Hz,
1H); 5.65 (q, J = 7.3Hz, 1H); 5.04 (d, J = 10.9Hz, 1H);
3.74 (s, 3H); 3.70 (s, 3H); 3.35 (dd, J = 15.7,9.7Hz, 1
H); 3.26 (ABq, J = 14.9Hz, 2H); 3.3-3.2 (m, 1H); 2.63
(Dd, J = 15.7,4.4Hz, 1H); 2.16 (s, 3H); 2.05 (s, 3H);
1.8-1.5 (m, 1H); 1.5-1.3 (m, 1H); 1.63 (d, J = 6.9H
z, 3H); 1.3-1.1 (m, 2H); 0.89 (t, J = 6.9 Hz, 3H). IR spectrum (nujol) νcm−1: 1740, 1730, 1460. Mass spectrum (m / z): 438 (M ⁺ ); 407; 378; 364; 346; 33
6; 319; 304; 286; 297; 257; 247; 217. Rf value: 0.35 (hexane / ethyl acetate = 1/1). Example 23 (3S ^* , 4R ^* , 7R ^* )-1- (N-isopropyl) carbamoyl-2-methoxycarbonyl-3-n-propyl-
4,7-Diacetoxy-5-oxo-8 (Z) -ethylidene-1-cyclononene (Compound 88) Compound 79 (26 mg, 0.068 mmol) was treated with methylene chloride (1
acetic anhydride (0.5 ml), pyridine (1 drop)
After reacting at room temperature for 12 hours, the mixture was concentrated, and the obtained oil was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give 25 mg of compound 88 (79
%)Obtained.

Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.96 (dd, J = 8.9, 5.2 Hz,
1H); 5.71 (q, J = 6.9Hz.1H); 5.52 (d, J = 8.1Hz, 1H);
5.02 (d, J = 10.9Hz, 1H); 4.1-3.9 (m, 1H); 3.7 (s, 3
H); 3.33 (dd, J = 16.1, 8.9 Hz, 1H); 3.4-3.3 (m, 2H);
3.18 (d, J = 13.7Hz, 2H); 2.55 (dd, J = 15.7,5.2Hz, 1
H); 2.18 (s, 3H); 2.09 (s, 3H); 1.8-1.6 (m, 1H); 1.6
~ 1.4 (m, 1H); 1.62 (d, J = 6.9Hz, 3H); 1.4 ~ 1.2 (m, 2
H); 1.12 (d, J = 6.5 Hz, 3H); 1.09 (d, J = 6.5 Hz, 3H);
89 (t, J = 7.3Hz, 3H) IR spectrum (liquid film) νcm-1: 3400,1740,1720,1662,15
15,1370. Mass spectrum (m / z): 465 (M ⁺ ); 450; 437; 422; 406; 39
0; 378; 362; 351; 304; 277; 260; 217. Rf value: 0.43 (hexane / ethyl acetate = 1/2). Example 24 (3S ^* , 4R ^* , 7R ^* )-1,2-dimethoxycarbonyl-3
-N-propyl-4,7-di (trimethylsilyloxy)
-8 (Z) -ethylidene-1-cyclononene (compound 8
9) To a solution of compound 78 (276 mg, 0.78 mmol) in DMF (5 ml) was added imidazole (159 mg, 2.34 mmol) and trimethylsilyl chloride (254 mg, 2.34 mmol) at room temperature and stirred for 2 hours. The reaction product was poured into ice water, extracted with ethyl acetate, dried, concentrated, and purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain 311 mg (80%) of compound 89.

Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.38 (q, J = 7.3 Hz, 1H);
5.02 (dd, J = 8.5,6.5HZ, 1H); 4.11 (d, J = 4.4Hz, 1H);
3.70 (s, 6H); 3.42 (dd, J = 15.3,8.9Hz, 1H); 3.19 (dd,
J = 9.7,4.0Hz, 1H); 3.15 (ABq, J = 14.5Hz, 2H); 2.49 (d
d, J = 15.3, 6.5Hz, 1H); 1.8 to 1.7 (m, 1H); 1.67 (d, J =
7.3Hz, 3H); 1.4 ~ 1.2 (m, 1H); 0.87 (t, J = 6.8Hz, 3H);
0.12 (s, 9H); 0.11 (s, 9H). IR spectrum (Nujol) vcm-1: 1720, 1460. Mass spectrum (m / z): 498 (M ⁺ ); 408; 259. Rf value: 0.53 (hexane / ethyl acetate = 3/1). Example 25 (3S ^* , 4R ^* , 7R ^* )-1,2-dimethoxycarbonyl-3
-N-propyl-4,7-di (dimethylisopropylsilyloxy) -5-oxo-8 (Z) -ethylidene-1-
Cyclononene (compound 90) and (3S ^* , 4R ^* , 7R ^* )-1,2-dimethoxycarbonyl-3
-N-propyl-4-hydroxy-5-oxo-7-dimethylisopropylsilyloxy-8 (Z) -ethylidene (compound 91) A solution of compound 78 (87.4 mg, 0.25 mmol) in DMF (3 ml) was first added with dimethylisopropyl. Silyl chloride (109m
g, 0.86 mmol) and then imidazole (58.7m
g, 0.86 mmol) and stirred overnight at room temperature. Thereafter, the same treatment as in Example 21 was performed, and the mixture was subjected to silica gel column chromatography (elution with hexane / ethyl acetate = 10/1).
10 mg (5%) of compound 90 was obtained as the first eluate, and 99 mg (86%) of compound 91 was obtained as the second eluate.

[Compound 90] Oily substance.

NMR spectrum (CDCl ₃ ) δ ppm: 5.36 (q, J = 7.3 Hz, 1H);
4.98 (dd, J = 7.7, 6.9 Hz, 1H); 4.13 (d, J = 10.1 Hz, 1H);
3.70 (s, 6H); 3.42 (dd, J = 14.9,8.0Hz, 1H); 3.24 (dt,
J = 10.1,3.2Hz, 1H); 3.16 (s, 2H); 2.47 (dd, J = 14.9,
6.5Hz, 1H); 1.8-1.7 (m, 1H); 1.66 (d, J = 7.3Hz, 3H);
1.4-1.3 (m, 1H); 1.4-1.1 (m, 2H); 0.97 (d, J = 6.8H
z); 0.95 (d, J = 6.9 Hz, 3H); 1.0-0.7 (m, 2H); 0.87
(D, J = 6.4Hz, 3H); 0.75 (s, 6H); 0.05 (s, 3H); 0.02
(S, 3H). IR spectrum (nujol) νcm−1: 1720, 1460. Mass spectrum (m / z): 554 (M−1 ⁺ ); 511; 436; 259; 10
1. Rf value: 0.73 (hexane / ethyl acetate = 3/1). [Compound 91] Oil.

NMR spectrum (CDCl ₃ ) δ ppm: 5.57 (q, J = 6.9 Hz, 1H);
5.06 (dd, J = 10.1,5.6Hz, 1H); 4.22 (d, J = 10.1Hz, 1H
H); 3.70 (s, 3H); 3.68 (s, 3H); 3.32 (dd, J = 16.5, 10.
1 Hz, 1H); 3.19 (ABq, J = 13.7 Hz, 2H); 3.05 (dt, J = 10.
1,3.2Hz, 1H); 2.67 (dd, J = 16.5,4.8Hz, 1H); 1.9 ~ 1.7
(M, 1H); 1.71 (d, J = 5.6Hz, 6H); 0.87 (t, J = 6.9Hz, 3
H); 1.1-0.8 (m, 1H); 0.09 (s, 3H); 0.05 (s, 3H). IR spectrum (nujol) vcm-1: 3370, 3300, 1720, 1
460. Mass spectrum (m / z): 454 (M ⁺ ); 257; 101. Rf value: 0.63 (hexane / ethyl acetate = 3/1). Formulation Example 1 wettable powder compound 18, 25 parts by weight, dodecylbenzene sulfonate
2.5 parts by weight, 2.5 parts by weight of lignin sulfonate and 70 parts by weight of diatomaceous earth were thoroughly pulverized and mixed to obtain a wettable powder.

Formulation Example 2 wettable powder Compound 19, 10 parts by weight, dodecylbenzenesulfonate 3 parts by weight, polyvinyl alcohol 2 parts by weight, diatomaceous earth 20 parts by weight, and clay 65 parts by weight are uniformly mixed and pulverized to obtain a wettable powder. Formulation Example 3 obtained Wettable powder 20, 20 parts by weight of compound, 2 parts by weight of polyoxyethylene nonylphenyl ether, 10 parts by weight of synthetic silicic acid and 38 parts by weight of ammonium sulfate were uniformly mixed to obtain a wettable powder. Emulsion Emulsion was obtained by thoroughly mixing 39 parts by weight of Compound 39, 10 parts by weight of emulsifier Solpol SM100 (trade name of Toho Chemical) and 60 parts by weight of xylene.

Formulation Example 5 Emulsion 10 parts by weight of Compound 51 were dissolved in 75 parts by weight of xylene, and 15 parts by weight of Parachol KRS (manufactured by Nippon Emulsifier Co., Ltd.) were uniformly mixed to obtain an emulsion.

Formulation Example 6 Granules Compound 77, 5 parts by weight, 1 part by weight of white carbon, 5 parts by weight of lignin sulfonate and 89 parts by weight of clay are thoroughly pulverized and mixed, kneaded well with water, and granulated and dried. Granules were obtained.

Formulation Example 7 Granules Compound 77, 1 part by weight, was dissolved in 10 parts by weight of methanol, and this was absorbed into 99 parts by weight of pumice particles sieved to 10 to 48 mesh. After drying, methanol was volatilized to obtain granules containing 1% of the compound.

Formulation Example 8 Liquid Preparation A liquid preparation was obtained by dissolving 22, 10 parts of compound, 2 parts by weight of sodium dodecylbenzenesulfonate and 88 parts by weight of water.

Formulation Example 9 Solution 24, 10 parts of compound, sodium lauryl sulfate 2
A solution was obtained by dissolving parts by weight and 88 parts by weight of methanol.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 237/24 C07C 237/24 323/61 323/61 C07D 209/52 C07D 209/52 307/93 307/93 C07F 7/18 C07F 7/18 A // A01N 37/08 A01N 37/08 37/36 37/36 37/42 37/42 37/44 37/44 37/50 37/50 (72) Inventor Makoto Ozasa Yasu-gun, Shiga Prefecture 1041, Yasu, Yasumachi Sankyo Co., Ltd. (72) Inventor Mutsumi Nakajima 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References Patent 2644818 (JP, B2) (58) Fields investigated ( Int.Cl. ⁶ , DB name) C07C 1/00-409/44 C07D 209 / 52,307 / 93 C07F 7/18 A01N 37/00-37/52 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula [Wherein, R ¹ and R ² are the same or different and represent a carboxy group or a carbamoyl group, or together form a general formula (Wherein X, Y and Z are the same or different and each represent an oxygen atom or an imino group), and R ³ and R ⁶ are the same or different and are a hydroxyl group, a mercapto group, or an amino group. Or a halogen atom, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a hydroxyl group, or R ⁴ and R ⁵ together represent an oxo group or an imino group, and A represents an oxygen atom Or a single bond. Or a hydroxyl group, a mercapto group in the compound molecule,
A compound in which an amino group, a carboxy group, a carbamoyl group or / and an imino group is protected and a salt thereof; provided that 3-n-propyl-4,7-dihydroxy-5-oxo-8-ethylidene-1-cyclononene-1 , 2-Dicarboxylic anhydride and 3-n-propyl-4,7-dihydroxy-5-oxo-8-ethylidene-1-cyclononene-
Except for 1,2-dicarboxylic acid and salts thereof, wherein the protecting group for the hydroxyl group and / or the mercapto group is a protecting group selected from the following group A, group B and group C; A protecting group for a carboxy group, a carbamoyl group and / or an imino group is a protecting group selected from the following group A; group A is a lower alkyl group; a silyl lower alkyl group; an aliphatic acyl group; A lower alkoxyaliphatic acyl group;
Aryloxy aliphatic acyl group; aralkyl group; aralkylcarbonyl group; aromatic acyl lower alkyl group; di-substituted lower alkoxythiophosphinyl group; di-substituted lower alkoxyphosphinyl group; di-substituted lower alkoxyphosphinyl lower alkyl group. Disubstituted lower alkoxythiophosphinyl lower alkyl group; lower alkane sulfonyl group; fluorinated lower alkane sulfonyl group; aryl sulfonyl group; lower alkane sulfonyl lower alkyl group; fluorinated lower alkane sulfonyl lower alkyl group; Sulfonyl lower alkyl group; alkoxycarbonyl group; alkenyloxycarbonyl group; aryloxycarbonyl group; aralkyloxycarbonyl group; lower alkenyl group; lower alkynyl group; lower alkoxy lower alkyl group; A carbamoyl group which may be substituted; an aminosulfonyl lower alkyl group which may be substituted; a sulfonamide group which may be substituted; a carboxy lower alkyl group; and a protected carboxy lower alkyl group; The protecting group for the carboxy group of the carboxy lower alkyl group is a lower alkyl group, a halogeno lower alkyl group, an aralkyl group, a lower alkoxy lower alkyl group, an aliphatic acyloxymethyl group or a 1-lower alkoxycarbonyloxyethyl group. Group B is a heteroarylcarbonyl group; a heteroarylthiocarbonyl group; and a silyl group; group C is an oxomethylene; thioxomethylene; a lower alkylidene group; an aralkylidene group; an alkoxyethylidene group as a divalent protecting group. ; Divalent sulfonyl group; 2 A divalent phosphinyl group; a divalent thiophosphinyl group; and a divalent silyl group.