JP2007254406A - Milbemycin derivative having oxime group at 13 site, and insecticidal, miticidal or anthelmintic agent containing the derivative as active component - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new milbemycin derivative having excellent insecticidal, miticidal and/or anthelmintic activity. <P>SOLUTION: The milbemycin derivative having oxime group at 13 site is expressed by formula (I) (the geometrical isomeric structure of the oxime group is E or Z; R is a 1-6C alkyl group; and A is a structural unit expressed by A1 to A10). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a milbemycin derivative having an oxime group at the 13-position and an insecticidal, acaricidal or anthelmintic agent containing it as an active ingredient.

  A group of macrolide compounds isolated from the B-41-146 strain belonging to the genus Streptomyces is referred to as B-41 in JP-A-50-29742, and nine types of compounds are disclosed ( Patent Document 1). Thereafter, B-41 is also called milbemycin, and related compounds have been discovered one after another (see Patent Documents 2 to 4 and Non-Patent Document 1).

  Further, compounds that are 16-membered macrolide compounds and are similar to milbemycins have also been found (see Patent Documents 5 to 11).

  Furthermore, the bacteriological properties of the B-41-146 strain belonging to the genus Streptomyces are described in detail in Patent Document 1, and the B-41-146 strain belonging to the genus Streptomyces has been deposited with the Institute of Microbial Industries, Institute of Industrial Science and Technology. The microorganism accession number is Mikkenkenmyoji No. 1438.

Furthermore, milbemycin derivatives having an oxime group at the 13-position are also known (see Patent Documents 12 to 14), but the structures containing the 2-position carbon atom and the 10-position carbon atom are all natural products. is identical to that of such is milbemycin a _3.
Japanese Unexamined Patent Publication No. 50-29742 JP 56-32461 JP-A-57-77686 JP 57-136585 A JP 52-151197 A JP 57-59892 JP-A-57-150699 JP 58-52300 A JP-A 61-10589 JP 61-118387 A British Patent Publication No. 2170499 JP-A-8-259570 JP-A-9-143183 JP 2000-44751 J. Antibiotics vol.36, 980-990 (1983)

  The object of the invention is to provide a novel milbemycin derivative having an oxime group at the 13-position and an insecticide, acaricide or anthelmintic containing the same as an active ingredient.

  As a result of diligent efforts to synthesize a milbemycin derivative and study its biological activity in order to develop an excellent insecticidal, acaricidal or anthelmintic agent, the present inventors have obtained a novel milbemycin derivative having an oxime group at the 13-position. It has been found that it has excellent insecticidal, acaricidal and / or anthelmintic activity and has led to the completion of the present invention.

  That is, the present invention provides a milbemycin derivative having an oxime group at the 13-position represented by the formula (I) and an insecticide, acaricide or anthelmintic containing the same as an active ingredient.

  The novel milbemycin derivative having an oxime group at position 13 of the present invention has excellent insecticidal, acaricidal and / or anthelmintic activity and is useful as an insecticidal, acaricidal or anthelmintic agent.

  The novel milbemycin derivative having an oxime group at the 13-position of the present invention has the formula (I)

(Wherein the geometric isomerism of the oxime group represents E or Z;
R represents a C ₁ -C ₆ alkyl group,
A has a structure containing a carbon atom at the 2-position and a carbon atom at the 10-position to which the bond is bonded, and the following formulas A1 to A10

Any structural unit represented by
It is represented by

In the compound represented by formula (I), the C ₁ -C ₆ alkyl group of R is, for example, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, pentyl, 1-methylbutyl, It can be 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably methyl , Ethyl, isopropyl or s-butyl group, more preferably methyl or ethyl, and most preferably ethyl group.

A is preferably any structural unit represented by formula A1, A2, A3, A8 or A10, more preferably any structural unit represented by formula A1, A2 or A3. And is most preferably a structural unit represented by Formula A2.
The geometric isomerism of the oxime group can be Z or E, both of which are encompassed by the present invention, but is preferably Z.

  Illustrative compounds are shown in Table 1 as specific examples of compound (I).

  In Table 1, “Me” represents a methyl group, “Et” represents an ethyl group, and “iPr” represents an isopropyl group.

Among the above exemplified compounds,
Suitably, compound numbers 1, 2, 3, 7, 8, 9, 13, 14, 15, 19, 20, 21, 25, 26, 27, 31, 32, 33, 37, 38, 39, 40, 41, 42, 43, 44, 45, 49, 50, 51, 55, 56 or 57,
More preferably, it is a compound of Compound No. 1, 2, 8, 14, 44 or 56,
Even more preferred is the compound of Compound No. 1, 2, 8, or 14.
Most preferred is the compound of Compound No. 8.

  The compound of the general formula (I) of the present invention can be produced by Method A to Method G described below.

  Method A is a method for producing compound (Ia) in which compound A is a structural unit represented by formula A1 in compound (I) of the present invention.

  In the above formula, the geometric isomerism and R of oxime have the same meaning as described above.

  In the step A-1, in the presence or absence of a solvent (preferably in the presence of a solvent), a milbemycin derivative having an oxime group at the 13-position represented by the general formula (II) is reacted with an oxidizing agent. This is a process for producing a 26-hydroxymilbemycin derivative represented by (Ia).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene and toluene; aliphatic such as hexane and pentane. Hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; esters such as ethyl acetate and butyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dimethyl sulfoxide Sulfoxides such as: ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl isobutyl ketone; or a mixed solvent thereof Preferably, aromatic carbonization Motorui, aliphatic hydrocarbons, halogenated hydrocarbons or a mixture of these solvents, more preferably a halogenated hydrocarbon, and most preferably is dichloromethane.

  The oxidizing agent used can be, for example, selenium dioxide or a combination of selenium dioxide and t-butyl hydroperoxide, preferably a combination of selenium dioxide and t-butyl hydroperoxide.

  The amount of selenium dioxide used is usually a catalytic amount to 5 equivalents, preferably 0.1 equivalents to 2 equivalents, more preferably 0.2 equivalents, relative to compound (II). -0.5 equivalent.

  The reaction temperature is -78 ° C to 100 ° C, preferably -20 ° C to 50 ° C, and more preferably 0 ° C to room temperature.

  The reaction time can vary greatly depending on the reaction temperature, the raw material compound and / or the type of the reaction solvent, but is usually 15 minutes to 3 days and nights, preferably 2 hours to 1 day and night.

  After completion of the reaction in this step, the target compound (Ia) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  The starting compound (II) of this reaction is known or can be easily produced by a known method (for example, JP-A-8-259570, JP-A-9-143183 or JP-A-2000-44751).

  Method B is a method for producing compounds (Ib) and (Ic) in which A is a structural unit represented by formula A2 or A3 in compound (I) of the present invention.

  In the above formula, the geometric isomerism and R of oxime have the same meaning as described above.

  In step B-1, compound (Ia) is converted to 3,3-dimethyl represented by the general formula (III) in the presence or absence of a solvent (preferably in the presence of a solvent) and in the presence of a condensing agent. This is a step of producing compound (Ib) or (Ic) by reacting with acrylic acid or pyrrole-2-carboxylic acid represented by formula (IV).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene and toluene; aliphatic such as hexane and pentane. Hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; esters such as ethyl acetate and butyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dimethyl sulfoxide Sulfoxides such as: ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl isobutyl ketone; or a mixed solvent thereof Preferably, aromatic carbonization Motorui, aliphatic hydrocarbons, halogenated hydrocarbons, or a mixed solvent thereof, more preferably an aromatic hydrocarbon (particularly benzene or toluene).

  The condensing agent to be used is not particularly limited as long as it condenses a carboxylic acid and an alcohol to produce an ester. For example, a combination of diethyl azodicarboxylate and triphenylphosphine, N, N -Dicyclohexylcarbodiimide or 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, preferably a combination of diethyl azodicarboxylate and triphenylphosphine.

  The amount of the condensing agent to be used is usually a catalytic amount to a large excess with respect to compound (Ia), preferably 0.1 equivalents to 10 equivalents, more preferably 1 equivalents to 2 equivalents. is there.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and more preferably 0 ° C. to room temperature.

  The reaction time can vary greatly depending on the reaction temperature, the raw material compound and / or the type of reaction solvent, but is usually 1 minute to 6 hours, and preferably 15 minutes to 1 hour.

  After completion of the reaction in this step, the target compounds (Ib) and (Ic) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Method C is a method for producing compound (Id) in which compound A is a structural unit represented by formula A4 in compound (I) of the present invention.

In the above formula, R ^{2 s} are the same or different and each represents a C _{1 to} C ₆ alkyl group or a phenyl group, and the geometric isomerism and R of oxime have the same meaning as described above.

  Step C-1 is a step of producing a compound having the general formula (V) by simultaneously protecting the hydroxyl groups at the 5-position and the 26-position with a silyl group, and in the presence or absence of a solvent (preferably, It is achieved by reacting compound (Ia) with a silylating agent in the presence of a base) in the presence of a base.

  The silylating agent used is not particularly limited as long as it is a silylating agent used for alkyl or / and phenylsilylation. For example, trimethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, It can be t-butyldimethylsilyl triflate, triethylsilyl chloride or triisopropylsilyl chloride, preferably t-butyldimethylsilyl chloride.

  The amount of the silylating agent to be used is generally 2 to 10 equivalents, preferably 2 to 5 equivalents, relative to compound (Ia).

  The base used can be, for example, an organic base such as triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole, preferably imidazole.

  The amount of the base to be used is generally 1.5 equivalents to 10 equivalents, preferably 2 equivalents to 5 equivalents, relative to compound (Ia).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated carbons such as carbon tetrachloride, chloroform and dichloromethane; N, N- Amides such as dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; or mixtures of these solvents, preferably amides (particularly N , N-dimethylformamide).

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, the reaction reagent, and / or the type of solvent used in the reaction, but is usually 15 minutes to 3 days and nights, and preferably 30 minutes to 1 day and nights.

  After completion of the reaction in this step, the target compound (V) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step C-2 is a step for producing a compound having the general formula (VI) by deprotecting only the silyloxy group at position 26 of the compound (V), and in the presence or absence of a solvent (preferably, This is achieved by reacting compound (V) with an acid in the presence of a solvent.

  The acids used can be, for example, organic acids such as formic acid, acetic acid and propionic acid; mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, preferably organic acids, most preferably acetic acid. is there.

  The amount of acid used is usually used in a large excess relative to compound (V).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; carbon tetrachloride, Halogenated carbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; water; It may be a mixture of solvents, preferably ethers, amides, sulfoxides, nitriles, water or a mixture of these solvents, more preferably a mixed solvent of ethers and water, most preferred Is a mixed solvent of tetrahydrofuran and water.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, the reaction reagent, and / or the type of solvent used in the reaction, but is usually 30 minutes to 2 days and nights, and preferably 1 hour to 1 day and nights.

  After completion of the reaction in this step, the target compound (VI) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step C-3 is a step of producing a compound having the general formula (VII) by methanesulfonylating the hydroxyl group at the 26th position of the compound (VI), in the presence or absence of a solvent (preferably a solvent In the presence of a base) by reacting compound (VI) with a methanesulfonylating agent.

  The methanesulfonylating agent used can be, for example, methanesulfonyl halide, preferably methanesulfonyl chloride.

  The amount of the methanesulfonylating agent to be used is generally 1 equivalent to 10 equivalents, preferably 1.5 equivalents to 3 equivalents, relative to compound (VI).

  The base used can be, for example, an organic base such as triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole, preferably triethylamine.

  The amount of the base to be used is generally 2 equivalents to 10 equivalents, preferably 2 equivalents to 5 equivalents, relative to compound (VI).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; carbon tetrachloride, Halogenated carbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; or of these solvents It can be a mixture, preferably a halogenated carbon, most preferably dichloromethane.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, the reaction reagent, and / or the type of solvent used in the reaction, but is usually 15 minutes to 1 day and night, and preferably 30 minutes to 2 hours.

  After completion of the reaction in this step, the target compound (VII) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step C-4 is a step of subjecting compound (VII) to an elimination reaction to produce a compound having the general formula (VIII), in the presence or absence of a solvent (preferably in the presence of a solvent). ), Which is accomplished by reacting compound (VII) with a base.

  Bases used are, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; lithium hydroxide, sodium hydroxide and water Alkali metal hydroxides such as potassium oxide; can be organic bases such as triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole, preferably alkali metal carbonates, most preferably Is lithium carbonate.

  The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (VII).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; carbon tetrachloride, Halogenated carbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; or their solvents And is preferably an amide, and more preferably N, N-dimethylformamide.

  The reaction temperature is usually −78 ° C. to 200 ° C., preferably room temperature to 180 ° C., and more preferably 70 ° C. to 150 ° C.

  The reaction time varies depending on the reaction temperature, the reaction reagent, and / or the type of solvent used in the reaction, but is usually from 1 minute to 2 hours, and preferably from 5 minutes to 1 hour.

  After completion of the reaction in this step, the target compound (VIII) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step C-5 is a step of producing compound (Id) by desilylating the silyloxy group at the 5-position of compound (VIII), and in the presence or absence of a solvent (preferably, In the presence) compound (VIII) is achieved by reacting with an acid or fluoride ion source.

  The acids used are, for example, dilute acids such as dilute hydrochloric acid and dilute sulfuric acid, organic acids such as formic acid, acetic acid and trifluoroacetic acid, sulfonic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid or acidic ion exchange It can be a resin and is preferably a sulfonic acid (especially p-toluenesulfonic acid).

  The amount of the acid to be used is generally 1 equivalent to 20 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (VIII).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, alcohols such as methanol and ethanol; hexane, cyclohexane, methylcyclohexane, petroleum ether, benzene And hydrocarbons such as toluene; halogenated carbons such as carbon tetrachloride, chloroform and dichloromethane; ethers such as ethyl ether, tetrahydrofuran and 1,4-dioxane; N, N-dimethylformamide and N, N Amides such as dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; water; or mixtures of these solvents, preferably alcohols, ethers, water or these A mixture of solvents, more preferably Alcohols (particularly, methanol) are.

  The reaction temperature is usually −20 ° C. to 70 ° C., preferably 0 ° C. to 50 ° C.

  The reaction time varies depending on the reaction temperature, reaction reagent, type of solvent used in the reaction, etc., but is usually 15 minutes to 3 days and nights, and preferably 30 minutes to 1 day and nights.

  The fluoride ion source used can be, for example, a hydrogen fluoride pyridine complex or tetrabutylammonium fluoride, preferably a hydrogen fluoride pyridine complex.

  The amount of the fluoride ion source to be used is generally 1 equivalent to large excess, preferably 3 equivalent to large excess, relative to compound (VIII).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated carbons such as carbon tetrachloride, chloroform and dichloromethane; N, N-dimethyl Amides such as formamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Nitriles such as acetonitrile; Alcohols such as methanol and ethanol; Like diethyl ether, tetrahydrofuran and 1,4-dioxane Ethers; water; or mixtures of these solvents, preferably nitriles (especially acetonitrile).

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  While the reaction time varies depending on the reaction temperature, the reaction reagent, and / or the type of solvent used in the reaction, it is usually 15 minutes to 1 day and night, and preferably 30 minutes to 3 hours.

  After completion of the reaction in this step, the target compound (Id) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Method D is a method for producing compound (Ie) in which compound A is a structural unit represented by formula A5 in compound (I) of the present invention.

In the above formula, oxime geometric isomerism, R and R ² are as defined above.

  Step D-1 is a step of producing a compound having the general formula (IX) by protecting the hydroxyl group at the 5-position of the compound (II) with a silyl group. The amount of the silylating agent and the amount of the base used are reduced. Except for the above, it is performed in the same manner as in the above-mentioned method C, C-1.

  The amount of the silylating agent to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to compound (II).

  The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to compound (II).

  The step D-2 is a step of producing a compound having the general formula (X) by isomerizing the 3,4-position double bond of the compound (IX) to the 2,3-position double bond. And is achieved by reacting compound (IX) with a base in the presence or absence of a solvent (preferably in the presence of a solvent).

  Bases used are, for example, organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole; lithium carbonate Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; or alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide Preferred are organic bases (particularly 1,8-diazabicyclo [5.4.0] undec-7-ene).

  The amount of the base to be used is generally catalytic amount to 10 equivalents, preferably 1 equivalent to 3 equivalents, more preferably 1 equivalent to 2 equivalents, relative to compound (IX).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene and toluene; hexane, heptane and octane, etc. Aliphatic hydrocarbons; ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; halogenated carbons such as carbon tetrachloride, chloroform and dichloromethane; N, N-dimethylformamide and N, N-dimethylacetamide Amides such as: sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; water; or mixtures of these solvents, preferably aromatic hydrocarbons, most preferably Toluene.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, the reaction reagent, and / or the type of the solvent used in the reaction, but is usually 5 hours to 1 week, preferably 10 hours to 2 days and nights.

  After completion of the reaction in this step, the target compound (X) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step D-3 is a step of producing compound (Ie) by desilylation (deprotection) of the 5-position silyloxy group of compound (X), and is carried out in the same manner as in the above-mentioned Method C, Step C-5 Is done.

  Method E is a method for producing compound (If) in which compound A is a structural unit represented by formula A6 in compound (I) of the present invention.

In the above formula, oxime geometric isomerism, R and R ² are as defined above.

  In step E-1, the 2,3-position double bond of compound (X) is isomerized to the 3,4-position double bond, and at the same time the steric structure at the 2-position is reversed, A step of producing a compound having (XI) by reacting compound (X) with a base in the presence or absence of a solvent (preferably in the presence of a solvent) and then reacting with an acid. Achieved.

  Bases used are, for example, alkali metal amides such as lithium diisopropylamide, lithium hexamethyldisilazane and sodium hexamethyldisilazane; alkyllithiums such as butyllithium and hexyllithium; 1,8-diazabicyclo [5 4.0] undec-7-ene, triethylamine, 2,6-lutidine, organic bases such as pyridine, dimethylaminopyridine and imidazole; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen and potassium hydrogen carbonate; or alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably alkali metal amides or alkyls Lithium There, more preferably, an alkali metal amide, and most preferably lithium diisopropylamide.

  The amount of the base to be used is 1 equivalent to 50 equivalents, preferably 2 equivalents to 20 equivalents, more preferably 3 equivalents to 10 equivalents, relative to compound (X).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene and toluene; hexane, heptane, octane, etc. Aliphatic hydrocarbons; ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; halogenated carbons such as carbon tetrachloride, chloroform and dichloromethane; N, N-dimethylformamide and N, N-dimethyl Amides such as acetamide; Sulfoxides such as dimethyl sulfoxide; Nitriles such as acetonitrile; Water; or a mixture of these solvents, preferably ethers, most preferably tetrahydrofuran. .

  The reaction temperature with the base is usually −100 ° C. to 0 ° C., preferably −78 ° C. to −40 ° C.

  The reaction time with the base varies depending on the reaction temperature, the reaction reagent or / and the type of the solvent used in the reaction, but is usually 1 minute to 1 hour, preferably 5 minutes to 15 minutes.

  The acid used for the reaction after the reaction with the base can be, for example, organic acids such as formic acid, acetic acid and propionic acid; mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, preferably organic acids Most preferably, it is acetic acid.

  The usage-amount of an acid is 1 equivalent-50 equivalent with respect to compound (X), Preferably it is 2 equivalent-30 equivalent, More preferably, it is 5 equivalent-20 equivalent.

  The reaction temperature with the acid is usually −100 ° C. to 0 ° C., preferably −78 ° C. to −40 ° C.

  Although the reaction time with an acid changes with reaction temperature, a reaction reagent, or / and the kind of solvent used for reaction, it is 5 minutes-3 hours normally, Preferably it is 10 minutes-1 hour.

  After completion of the reaction in this step, the target compound (XI) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step E-2 is a step of producing compound (If) by desilylating (deprotecting) the 5-position silyloxy group of compound (XI), and is carried out in the same manner as in the above-mentioned Method C-5. The

  Method F is a method for producing compound (Ig) in which A is a structural unit represented by formula A7 in compound (I) of the present invention.

  In the above formula, the geometric isomerism and R of oxime have the same meaning as described above.

  Step F-1 is a step of producing a compound having the general formula (XII) by methanesulfonylating the hydroxyl group at the 5-position of the compound (II), and in the presence or absence of a solvent (preferably In the presence of a base) in the presence of a base by reacting compound (II) with a methanesulfonylating agent.

  The methanesulfonylating agent used is, for example, methanesulfonyl halide, and preferably methanesulfonyl chloride.

  The amount of the methanesulfonylating agent to be used is generally 1 equivalent to 10 equivalents, preferably 1.5 equivalents to 3 equivalents, relative to compound (II).

  The base used can be, for example, an organic base such as triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole, preferably triethylamine.

  The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 1.5 equivalents to 3 equivalents, relative to compound (II).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; carbon tetrachloride, Halogenated carbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; or of these solvents It can be a mixture, preferably a halogenated carbon, most preferably dichloromethane.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, reaction reagent or / and the type of solvent used in the reaction, but is usually 15 minutes to 1 day and night, and preferably 30 minutes to 2 hours.

  After completion of the reaction in this step, the target compound (XII) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step F-2 is a step of producing a compound having the general formula (XIII) by substituting the methanesulfonyloxy group at the 5-position of the compound (XII) with formic acid, and in the presence or absence of a solvent ( Suitably, this is achieved by reacting compound (XII) with formic acid in the presence of a base) in the presence of a base.

  The amount of formic acid to be used is generally 1 equivalent to large excess, preferably 3 equivalents to 20 equivalents, relative to compound (XII).

  The base used can be, for example, an organic base such as triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole, preferably triethylamine.

  The amount of the base to be used is generally 1 equivalent to large excess, preferably 3 equivalents to 20 equivalents, relative to compound (XII).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; carbon tetrachloride, Halogenated carbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; or of these solvents It can be a mixture, preferably a halogenated carbon, most preferably dichloromethane.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, the reaction reagent or / and the type of solvent used in the reaction, but is usually 6 hours to 1 week, preferably 1 day to 5 days.

  After completion of the reaction in this step, the target compound (XIII) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Step F-3 is a step of producing compound (Ig) by deformylation of the 5-position formyloxy group of compound (XIII), in the presence or absence of a solvent (preferably a solvent In the presence of a compound) by reacting compound (XIII) with a base.

  Bases used are, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate; lithium hydroxide, sodium hydroxide and hydroxide. Alkali metal hydroxides such as potassium; or organic bases such as triethylamine, 2,6-lutidine, pyridine, dimethylaminopyridine and imidazole, preferably alkali metal bicarbonates, most preferred Is sodium bicarbonate.

  The amount of the base to be used is generally 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, relative to compound (XIII).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol and ethanol; tetrahydrofuran, diethyl ether and 1,4-dioxane Ethers such as: carbon tetrachloride, halogenated carbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; Nitriles; water; or a mixture of these solvents, preferably a mixed solvent of alcohols and water, and most preferably a mixed solvent of methanol and water.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably 0 ° C. to room temperature.

  The reaction time varies depending on the reaction temperature, the reaction reagent and / or the type of solvent used in the reaction, but is usually 10 minutes to 1 day and night, and preferably 30 minutes to 2 hours.

  After completion of the reaction in this step, the target compound (Ig) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  Method G is a method for producing compounds (Ih) to (Ij) wherein A is a structural unit represented by formulas A8 to A10 in compound (I) of the present invention.

  In the above formula, the geometric isomerism and R of oxime have the same meaning as described above.

  Step G-1 is a step of producing compounds (Ih) to (Ij) by reacting compound (II) with an oxidizing agent in the presence or absence of a solvent (preferably in the presence of a solvent). It is.

  The oxidizing agents used are, for example, peracids such as metachloroperbenzoic acid, peracetic acid, performic acid and perbenzoic acid; peroxides such as hydrogen peroxide and t-butyl hydroperoxide; or persulfuric acid and It can be a persulfonic acid such as oxone, preferably a peracid, and most preferably a metachloroperbenzoic acid.

  The usage-amount of an oxidizing agent is 1 equivalent-10 equivalent normally with respect to compound (II), Preferably it is 1 equivalent-3 equivalent, More preferably, it is 1 equivalent-2 equivalent.

  The reaction temperature is usually −78 ° C. to 100 ° C., preferably −20 ° C. to 50 ° C., and more preferably 0 ° C. to room temperature.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aromatic hydrocarbons such as benzene and toluene; aliphatic such as hexane and pentane. Hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; esters such as ethyl acetate and butyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dimethyl sulfoxide Sulfoxides such as: ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl isobutyl ketone; or a mixed solvent thereof Preferably aromatic hydrocarbons S, aliphatic hydrocarbons, halogenated hydrocarbons or a mixture of these solvents, more preferably a halogenated hydrocarbon (particularly dichloromethane).

  The reaction time may vary depending on the reaction temperature, the raw material compound and / or the type of the reaction solvent, but is usually 15 minutes to 3 days and nights, and preferably 2 hours to 1 day and nights.

  After completion of the reaction in this step, the target compounds (Ih) to (Ij) can be collected from the reaction mixture according to a known method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, followed by adding a water-immiscible organic solvent such as ethyl acetate, washing with water, and then containing the target compound. Is separated and dried with a desiccant such as anhydrous magnesium sulfate, and then the solvent is distilled off. Furthermore, if necessary, it can be further purified by a known means such as column chromatography, preparative thin layer chromatography and / or high performance liquid chromatography.

  The compound (I) of the present invention is a compound of the spider mite (Tetranychus), apple spider mite, Panonychus, and adult mite, and eggs, and the parasitic tick (Ixodidae), spider (Dermanysside) ) And Scaroptidae (excellent acaricidal activity against Sarcoptidae. In addition, animals such as Oestrus, Lucilia, Hypoderma, Gautrophilus, honey and white spot And avian ectoparasites; sanitary pests such as cockroaches and house flies; and / or various agro-horticultural pests such as aphids, diamondback moths and lepidopterous pests.

  The compound (I) of the present invention is also active against Meloidogyne, Bursaphelenchus and Tizoglyphus.

  The compound (I) of the present invention also has excellent activity against animal and human endoparasites. In particular, nematodes that infect livestock and pets, such as pigs, sheep, goats, horses, dogs, cats and chickens, parasites of the Filariidae and Setariidae, and the human digestive tract, It is also effective against parasites found in blood or other tissues and organs.

  When the compound (I) of the present invention is used for agriculture and horticulture (agricultural chemicals), the compound (I) of the present invention is usually used as an agricultural chemical by mixing with a carrier and other auxiliary agents as required. It is prepared and used in a pharmaceutical form such as a composition such as powder, wettable powder, emulsion, water or oily suspension, aerosol.

  When the composition of the present invention prepared in various dosage forms is sprayed on crops or livestock infested with harmful insects and spider mites in, for example, orchards or upland fields, the active ingredient concentration is 0.5 to 100 ppm. Can be effectively controlled by treating the crops with foliage, soil or livestock.

  When the compound (I) of the present invention is used as an anthelmintic agent in animals and humans, it can be administered orally as a liquid beverage. Beverages are usually solutions, suspensions or dispersions in suitable non-toxic solvents or water, together with suspending and wetting agents such as bentonite, or excipients thereof. In general, beverages contain an antifoaming agent. Beverage formulations generally contain from 0.01 to 0.5% by weight of active compound, preferably from 0.01 to 0.1% by weight.

  When the compound (I) of the present invention is administered by animal feed, it is uniformly dispersed in the feed, used as a top dressing, or used in the form of pellets. In order to achieve the normally desired antiparasitic effect, the final feed contains 0.0001-0.02% by weight of active compound.

  In addition, the compound (I) of the present invention dissolved or dispersed in a liquid carrier vehicle can be administered parenterally to animals by injection into the stomach, intramuscular, intratracheal or subcutaneous. Can do. For parenteral administration, the active compound is preferably mixed with a suitable vegetable oil, such as peanut oil or cottonseed oil. Such formulations generally contain 0.05 to 50% by weight of active compound.

  Furthermore, the compound (I) of the present invention may be administered topically by mixing with a suitable carrier such as dimethyl sulfoxide or a hydrocarbon solvent. This formulation is applied directly to the external surface of the animal by spraying or direct injection. The optimum amount of active compound used to achieve the best results depends on the type of animal being cured and the type and extent of parasitic infection, but is generally about 0.01-100 mg / kg animal body weight, suitable Is 0.5 to 50 mg (for oral administration). Such usage is given over a relatively short period of time, such as 1 to 5 days, at a time or in portions.

  EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated concretely, this invention is not limited to these.

Example 1
26-hydroxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of Exemplified Compound No. 2)
77.2 mg (0.70 mmol) of selenium dioxide was added to 50 ml of dichloromethane and stirred at room temperature. To this was added t-butyl hydroperoxide (concentration 80%, 0.78 ml, 6.95 mmol) and then 13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ 1.00 g (1. 39 mmol) was added and stirred overnight at room temperature. To this, an aqueous sodium thiosulfate solution and Celite were added, stirred, and then filtered. The obtained organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate, gradient) to obtain 0.51 g of the title compound (yield 50%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.54 (2H, m), 7.38 (3H, m), 5.87 (2H, m), 5.72 (1H, br), 5.30-5.61 (3H, m), 5.21 (1H, d, J = 10.6Hz), 4.71 (2H, br), 4.58 (1H, m), 4.29 (2H, br), 4.21 (1H, s), 3.99 (3H, s), 3.97 (1H, d, J = 4.0Hz), 3.62 (1H, m), 3.33 (1H, t, J = 1.8Hz), 3.07 (1H, m), 2.75 (1H, br), 2.61 (1H, m), 2.28- 2.49 (3H, m), 2.03 (1H, m), 1.56 (3H, br), 1.10 (3H, d, J = 6.2Hz), 1.00 (3H, t, J = 7.1Hz), 0.83 (3H, d , J = 6.2Hz).
EI-MS (m / z): 735 (M ⁺ ), 717, 556, 538, 510, 412, 195, 167.

Example 2
26- (3,3-dimethylacryloxy) -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of Exemplified Compound No. 8)
26-Hydroxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ 100 mg (0.14 mmol), 3,3-dimethylacrylic acid 20.5 mg (0.20 mmol) and triphenylphosphine 53 0.5 mg (0.20 mmol) was dissolved in 2 ml of toluene and stirred at room temperature under a nitrogen stream. To this was added 89 μl (0.20 mmol) of diethyl azodicarboxylate (40% toluene solution), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/2) to give 100.2 mg of the title compound (yield 90%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.50 (2H, m), 7.38 (3H, m), 5.83 (2H, m), 5.73 (2H, m), 5.36-5.57 (3H, m), 5.20 (1H, d, J = 10.3Hz), 4.82 (1H, d, J = 13.6Hz), 4.70 (2H, br), 4.68 (1H, d, J = 13.6Hz), 4.49 (1H, m), 4.14 (1H, s), 4.01 (1H, d, J = 4.4Hz), 3.99 (3H, s), 3.62 (1H, m), 3.33 (1H, br), 3.06 (1H, m), 2.77 (1H, d, J = 7.3Hz), 2.62 (1H, m), 2.21-2.49 (2H, m), 2.18 (3H, s), 1.90 (3H, s), 1.56 (3H, br), 1.10 (3H, d , J = 6.6Hz), 1.00 (3H, t, J = 7.1Hz), 0.83 (3H, d, J = 6.2Hz).
EI-MS (m / z): 817 (M ⁺ ), 717, 699, 538, 520, 195, 167.

Example 3
26- (pyrrole-2-carbonyloxy) -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of Exemplified Compound No. 14)
26-hydroxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ 100 mg (0.14 mmol), pyrrole-2-carboxylic acid 22.7 mg (0.20 mmol) and triphenylphosphine 53. 5 mg (0.20 mmol) was dissolved in 2 ml of toluene and stirred at room temperature under a nitrogen stream. To this was added 89 μl (0.20 mmol) of diethyl azodicarboxylate (40% toluene solution), and the mixture was stirred at room temperature for 35 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain 99.4 mg of the title compound (yield 88%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.72 (1H, br), 7.51 (2H, m), 7.38 (3H, m), 6.97 (2H, m), 6.25 (1H, m), 5.84 (3H , M), 5.25-5.55 (3H, m), 5.20 (1H, d, J = 10.6Hz), 4.98 (1H, d, J = 13.5Hz), 4.85 (1H, d, J = 13.5Hz), 4.71 (2H, br), 4.55 (1H, m), 4.17 (1H, s), 4.01 (1H, d, J = 5.9Hz), 3.99 (3H, s), 3.63 (1H, m), 3.34 (1H, br), 3.07 (1H, m), 2.62 (1H, m), 2.15-2.50 (3H, m), 1.56 (3H, br), 1.10 (3H, d, J = 6.2Hz), 0.99 (3H, t , J = 7.3Hz), 0.83 (3H, d, J = 6.2Hz).
EI-MS (m / z): 828 (M ⁺ ), 717, 699, 649, 195, 167.

Example 4
^{Δ 2,3, Δ 4,26 -13β - [} (2Z) - methoxyimino-2- phenyl-acetoxy] - (compound of Exemplary compound No. 20) milbemycin A ₄
(1) 5-O, 26-O-di (t-butyldimethylsilyl) -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (Step C-1)
119 mg (0.16 mmol) of 26-hydroxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A _{4 was} dissolved in N, N-dimethylformamide (2 ml) and stirred at room temperature under a nitrogen stream. . To this, 73.2 mg (0.49 mmol) of t-butyldimethylsilyl chloride and 33.1 mg (0.49 mmol) of imidazole were added and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 5/1) to give 145.9 mg of the title compound (yield 94%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.51 (2H, m), 7.38 (3H, m), 5.75-5.93 (2H, m), 5.62 (1H, br), 5.27-5.61 (3H, m) , 5.20 (1H, d, J = 10.6Hz), 4.52-4.75 (3H, m), 4.21 (2H, m), 4.17 (1H, s), 3.99 (3H, s), 3.82 (1H, d, J = 5.5Hz), 3.62 (1H, m), 3.38 (1H, m), 3.06 (1H, m), 2.62 (1H, m), 2.40 (2H, m), 2.08 (1H, m), 1.57 (3H , Br), 1.09 (3H, d, J = 6.6Hz), 1.00 (3H, t, J = 7.3Hz), 0.91 (9H, s), 0.90 (9H, s), 0.82 (3H, d, J = 6.2Hz), 0.12 (3H, s), 0.10 (3H, s), 0.06 (3H, s), 0.05 (3H, s).
EI-MS (m / z): 963 (M ⁺ ), 906, 831, 195, 167.

(2) 5-Ot-butyldimethylsilyl-26-hydroxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (step C-2)
5-O, 26-O-di-t-butyldimethylsilyl-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ 145 mg (0.15 mmol) was dissolved in tetrahydrofuran (1.5 ml). And stirred at room temperature. Water (3.5 ml) and acetic acid (6.5 ml) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water, saturated aqueous sodium bicarbonate, water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 82.6 mg of the title compound (yield 65%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.52 (2H, m), 7.38 (3H, m), 5.83 (2H, m), 5.67 (1H, br), 5.51 (1H, m), 5.25-5.46 (2H, m), 5.21 (1H, d, J = 10.3Hz), 4.55-4.75 (3H, m), 4.12-4.33 (3H, m), 3.99 (3H, s), 3.83 (1H, d, J = 5.5Hz), 3.62 (1H, m), 3.40 (1H, br), 3.08 (1H, m), 2.62 (1H, m), 2.20-2.50 (2H, m), 2.08 (1H, m), 1.57 (3H, br), 1.10 (3H, d, J = 6.6Hz), 1.00 (3H, t, J = 7.3Hz), 0.93 (9H, s), 0.82 (3H, d, J = 6.6Hz), 0.15 (6H, s).
EI-MS (m / z) : 849 (M +), 831,792,652,595,195,167.

(3) 5-Ot-butyldimethylsilyl-26-methanesulfonyloxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (step C-3)
200 mg (0.24 mmol) of 5-Ot-butyldimethylsilyl-26-hydroxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ was dissolved in 8 ml of dichloromethane, Stir at room temperature. To this, 46 μl (0.59 mmol) of methanesulfonyl chloride and 66 μl (0.47 mmol) of triethylamine were added and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 188 mg of the title compound (yield 86%).
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 7.52 (2H, m), 7.38 (3H, m), 5.82 (3H, m), 5.52 (1H, m), 5.30-5.48 (2H, m), 5.20 (1H, d, J = 10.5Hz), 4.86 (1H, m), 4.74 (1H, d, J = 11.3Hz), 3.63 (3H, m, H-5), 4.18 (1H, s), 3.99 ( 3H, s), 3.86 (1H, d, J = 5.5Hz), 3.62 (1H, m), 3.40 (1H, m), 3.08 (1H, m), 3.02 (3H, s), 2.62 (1H, m ), 2.23-2.47 (2H, m), 2.05 (1H, m), 1.57 (3H, br), 1.09 (3H, d, J = 6.4Hz), 0.99 (3H, t, J = 7.3Hz), 0.93 (9H, s), 0.83 (3H, d, J = 6.4Hz), 0.16 (3H, s), 0.15 (3H, s).
EI-MS (m / z): 870 (M ⁺ -57), 831, 800, 195.

(4) 5- ^Ot- butyldimethylsilyl-Δ ^2,3 , Δ ^4,26 -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (step C-4)
5-O-t-butyldimethylsilyl -26- methanesulfonyloxy -13β - [(2Z) - methoxyimino-2- phenylacetoxy] - milbemycin _A 4 180 mg of (0.19 mmol) was dissolved in dimethylformamide 4 ml, room temperature And stirred. To this was added 43 mg (0.58 mmol) of lithium carbonate, and the mixture was heated at 120 ° C. for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain 12 mg of the title compound (yield 7%).
^{1 H-NMR (270MHz, CDCl} 3) δ: 7.50 (2H, m), 7.38 (3H, m), 6.68 (1H, br), 6.16 (1H, d, J = 11.9Hz), 5.79 (1H, m ), 5.70 (1H, m), 5.32-5.58 (4H, m), 5.20 (1H, d, J = 10.7Hz), 4.76 (1H, s), 4.61 (1H, m), 4.58 (1H, m) , 4.45 (1H, m), 4.02 (1H, m), 3.98 (3H, s), 3.68 (1H, m), 3.08 (1H, m), 2.60 (1H, m), 2.21-2.56 (2H, m ), 1.95 (1H, m), 1.51 (3H, br), 1.09 (3H, d, J = 6.4Hz), 1.01 (3H, t, J = 7.3Hz), 0.96 (9H, s), 0.83 (3H , D, J = 6.4Hz), 0.16 (3H, s), 0.15 (3H, s).
EI-MS (m / z): 831 (M ⁺ ), 813, 774, 756, 652, 195, 167.

^{(5) Δ 2,3, Δ 4,26} -13β - [(2Z) - methoxyimino-2- phenylacetoxy] - milbemycin A ₄ (compound of Exemplary compound No. 20, C-5 step)
5- ^Ot- butyldimethylsilyl-Δ ^2,3 , Δ ^4,26 -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ 12 mg (0.014 mmol) is dissolved in 1 ml of acetonitrile. And stirred under ice cooling. 0.4 ml of hydrogen fluoride pyridine complex (concentration: about 70%) was added thereto, and stirred for 1 hour and 30 minutes. The reaction mixture was carefully poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 6.3 mg of the title compound (yield 61%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.51 (2H, m), 7.37 (3H, m), 6.68 (1H, s), 6.19 (1H, m), 5.80 (2H, m), 5.32-5.58 (4H, m), 5.20 (1H, d, J = 10.5Hz), 4.76 (1H, s), 4.40-4.62 (3H, m), 4.14 (1H, d, J = 2.6Hz), 3.98 (3H, s), 3.68 (1H, m), 3.08 (1H, m), 2.60 (1H, m), 2.42 (1H, m), 2.30 (1H, m), 2.15 (1H, br), 1.99 (1H, m ), 1.50 (3H, br), 1.09 (3H, d, J = 6.4Hz), 1.01 (3H, t, J = 7.2Hz), 0.84 (3H, d, J = 6.4Hz).
EI-MS (m / z): 717 (M ⁺ ), 699, 668, 538, 520, 195, 167.

Example 5
^{Δ 2,3 -13β - [(2Z)} - methoxyimino-2- phenylacetoxy] - milbemycin A ₄ (Compound No. 26)
(1) 5-Ot-butyldimethylsilyl-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (step D-1)
13β-[(2Z) -Methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (10.0 g, 13.9 mmol) was dissolved in N, N-dimethylformamide (100 ml) and stirred at room temperature under a nitrogen stream. . To this, t-butyldimethylsilyl chloride (6.29 g, 41.7 mmol) and imidazole (2.84 g, 41.7 mmol) were added and stirred at room temperature for 1 hour 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed twice with water and once with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate, gradient) to obtain 11.31 g of the title compound (yield 97.6%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.52 (2H, m), 7.39 (3H, m), 5.72-5.95 (2H, m), 5,55 (1H, m), 5.25-5.45 (3H, m), 5.20 (1H, d, J = 10.6Hz), 4.64 (2H, m), 4.42 (1H, m), 4.12 (1H, s), 3.99 (3H, s), 3.82 (1H, d, J = 5.5Hz), 3.62 (1H, m), 3.37 (1H, m), 3.07 (1H, m), 2.62 (1H, m), 2.25-2.48 (2H, m), 2.05 (1H, m), 1.80 (3H, br), 1.56 (3H, br), 1.08 (3H, d, J = 6.6Hz), 1.00 (3H, t, J = 7.3Hz), 0.93 (9H, s), 0.82 (3H, d, J = 6.2Hz), 0.13 (6H, s).
EI-MS (m / z): 833 (M ⁺ ), 815, 776, 758.

(2) 5-Ot-butyldimethylsilyl-Δ ^2,3 -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (step D-2)
5-O-t-butyldimethylsilyl -13β - [(2Z) - methoxyimino-2- phenylacetoxy] - milbemycin _A 4 1.00 g of (1.20 mmol) was dissolved in toluene 20 ml, under a nitrogen stream, at room temperature Stir. To this was added dropwise 0.18 ml (1.20 mol) of 1,8-diazabicyclo [5.4.0] undec-7-ene, and the mixture was stirred at room temperature for 2 days. The reaction solution was poured into 1N hydrochloric acid and extracted with toluene. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate, gradient) to obtain 0.98 g of the title compound (yield 98%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.52 (2H, m), 7.38 (3H, m), 6.19 (2H, m), 5.81 (1H, dd, J = 14.7 Hz, 11.0 Hz), 5.35 5.60 (3H, m), 5.20 (1H, m, J = 10.3Hz), 4.85 (1H, s), 4.53 (2H, m), 3.98 (3H, s), 3.95 (1H, d, J = 2.2Hz ), 3.70 (2H, m), 3.08 (1H, m), 1.51 (3H, br), 1.14 (3H, d, J = 7.3Hz), 1.08 (3H, d, J = 6.6Hz), 0.93 (9H , S), 0.88 (3H, t, J = 6.6Hz), 0.83 (3H, d, J = 5.9Hz), 0.13 (6H, s).
EI-MS (m / z): 833 (M ⁺ ), 815, 776, 636, 579, 504, 195, 167.

(3) Δ ^2,3 -13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of exemplified compound number 26, step D-3)
5-O-t-butyldimethylsilyl ^{-Δ 2,3 -13β - [(2Z)} - methoxyimino-2- phenylacetoxy] - milbemycin _A 4 100 mg of (0.12 mmol) was dissolved in methanol 2 ml, stirred at room temperature did. To this was added 68.5 mg (0.36 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 2/1) to give 66.4 mg of the title compound (yield 77%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.50 (2H, m), 7.38 (3H, m), 6.10-6.23 (2H, m), 5.81 (1H, dd, J = 14.5 Hz, 11.4 Hz), 5.35-5.60 (3H, m), 5.20 (1H, d, J = 10.6Hz), 4.88 (1H, s), 4.55 (2H, m), 4.04 (1H, d, J = 2.6Hz), 3.98 (3H , S), 3.50-3.75 (2H, m), 3.05 (1H, m), 1.50 (3H, br), 1.22 (3H, d, J = 7.3Hz), 1.09 (3H, d, J = 6.2Hz) , 1.01 (3H, t, J = 7.3Hz), 0.84 (3H, d, J = 6.2Hz).
EI-MS (m / z): 719 (M ⁺ ), 701, 683, 540, 522, 195, 167.

Example 6
2-epi-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound No. 32)
(1) 5-Ot-butyldimethylsilyl-2-epi-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (step E-1)
1.2 ml (2.40 mol) of lithium diisopropylamide as a 2N solution was dissolved in 5 ml of tetrahydrofuran and stirred at -78 ° C. under a nitrogen stream. This 5-O-t-butyldimethylsilyl ^{-Δ 2,3 -13β - [(2Z)} - methoxyimino-2- phenylacetoxy] - milbemycin _A 4 200 mg solution of (0.24 mmol) in tetrahydrofuran 2ml It was dripped. After stirring at −78 ° C. for 10 minutes, a solution of 0.21 ml (3.60 mmol) of acetic acid in 1 ml of tetrahydrofuran was added dropwise, and the mixture was further stirred at −78 ° C. for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 4/1) to give 93.5 mg of the title compound (yield 47%).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.52 (2H, m), 7.40 (3H, m), 5.72-5.98 (2H, m), 5.67 (1H, br), 5.32-5.66 (3H, m) , 5.18 (1H, d, J = 10.9Hz), 4.60 (1H, d, J = 13.9Hz), 4.34 (1H, br), 4.21 (1H, s), 4.07-4.18 (2H, m), 3.98 ( 3H, s), 3.65 (1H, m), 3.16 (1H, m), 3.07 (1H, m), 2.60 (1H, m), 2.18-2.52 (2H, m), 1.85 (3H, br), 1.52 (3H, br), 1.07 (3H, d, J = 6.6Hz), 1.01 (3H, t, J = 7.3Hz), 0.94 (9H, s), 0.83 (3H, d, J = 6.6Hz), 0.14 (6H, s).
EI-MS (m / z): 833 (M ⁺ ), 815, 195, 167.

(2) 2-epi-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of exemplified compound number 32, step E-2)
5-O-t-butyldimethylsilyl-2-epi -13β - [(2Z) - methoxyimino-2- phenylacetoxy] - milbemycin _A 4 90 mg of (0.11 mmol) was dissolved in methanol 4 ml, and stirred at room temperature . To this was added 61.7 mg (0.32 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 62.0 mg of the title compound (yield 80%).
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 7.51 (2H, m), 7.38 (3H, m), 5.92 (1H, d, J = 11.2 Hz), 5.79 (1H, dd, J = 14.5 Hz, 11.2 Hz), 5.71 (1H, m), 5.38-5.62 (3H, m), 5.18 (1H, d, J = 10.6Hz), 4.62 (1H, d, J = 13.5Hz), 4.53 (1H, s), 4.33 (1H, d, J = 3.0Hz), 4.23 (1H, m), 4.13 (1H, d, J = 13.5Hz), 3.98 (3H, s), 3.68 (1H, m), 3.20 (1H, m ), 3.05 (1H, m), 2.60 (1H, m), 1.88 (3H, br), 1.52 (3H, br), 1.09 (3H, d, J = 6.6Hz), 1.01 (3H, t, J = 7.3Hz), 0.83 (3H, d, J = 6.3Hz).
EI-MS (m / z): 719 (M ⁺ ), 683, 591, 540, 522, 504, 412, 195, 167, 151.

Example 7
5-epi-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound No. 38)
(1) 5-Methanesulfonyloxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (Step F-1)
13β - [(2Z) - methoxyimino-2- phenylacetoxy] - milbemycin _A 4 1.00 g of (1.39 mmol) was dissolved in dichloromethane (20 ml), and the mixture was stirred under nitrogen stream while cooling with ice. To this were added 0.27 ml (3.48 mmol) of methanesulfonyl chloride and 0.48 ml (3.48 ml) of triethylamine, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate, gradient) to obtain 1.00 g of the title compound (yield 90%).
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 7.52 (2H, m), 7.38 (3H, m), 5.85 (2H, m), 5.62 (1H, br), 5.52 (1H, m), 5.41 (2H , M), 5.33 (1H, m), 5.20 (1H, d, J = 10.5Hz), 4.70 (2H, m), 4.15 (1H, s), 4.12 (1H, d, J = 7.0Hz), 3.99 (3H, s), 3.63 (1H, m), 3.36 (1H, m), 3.11 (3H, s), 3.08 (1H, m), 2.62 (1H, m), 2.23-2.50 (2H, m), 2.03 (1H, m), 1.88 (3H, br), 1.56 (3H, br), 1.10 (3H, d, J = 6.4Hz), 0.99 (3H, t, J = 7.3Hz), 0.83 (3H, d , J = 6.4Hz).
EI-MS (m / z): 504 (M ⁺ -293), 279, 195, 167.

(2) 5-epi-5-formyloxy -13β - [(2Z) - methoxyimino-2- phenylacetoxy] - milbemycin A ₄ (F-2 step)
Triethylamine (1.54 ml, 11.06 mmol) was dissolved in dichloromethane (10 ml), and the mixture was stirred while cooling with ice in a nitrogen stream. To this was added 0.42 ml (11.06 mmol) of formic acid, and then 897 mg (1.11 mmol) of 5-methanesulfonyloxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A _{4 was} added to dichloromethane. A solution dissolved in 10 ml was added dropwise. Thereafter, the mixture was stirred at room temperature for 4 days and nights. The reaction mixture was poured into water and extracted twice with dichloromethane. The obtained organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate, gradient) to obtain 0.33 g of the title compound (yield 40%). In addition, 0.41 g of the raw material compound was recovered.
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 8.18 (1H, s), 7.52 (2H, m), 7.39 (3H, m), 5.88 (2H, m), 5.61 (1H, br), 5.35-5.58 (4H, m), 5.18 (1H, d, J = 10.5Hz), 4.61 (2H, br), 3.99 (4H, s), 3.75 (1H, s), 3.63 (1H, m), 3.09 (2H, m), 2.63 (1H, m), 2.23-2.50 (2H, m), 2.05 (1H, m), 1.79 (3H, br), 1.55 (3H, br), 1.09 (3H, d, J = 6.4Hz ), 1.00 (3H, t, J = 7.1Hz), 0.83 (3H, d, J = 6.4Hz).
EI-MS (m / z): 747 (M ⁺ ), 568, 522, 279, 195, 167.

(3) 5-epi-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (Exemplary Compound No. 38, Step F-3)
377 mg (0.50 mmol) of 5-epi-5-formyloxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ was dissolved in 15 ml of methanol and stirred at room temperature. To this, 1.5 ml of water and 105.8 mg (1.26 mmol) of sodium bicarbonate were sequentially added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 235.7 mg of the title compound (yield 65%).
^{1 H-NMR (270MHz, CDCl} 3) δ: 7.53 (2H, m), 7.38 (3H, m), 5.84 (2H, m), 5.31-5.57 (4H, m), 5.20 (1H, d, J = 10.5Hz), 4.60 (2H, br), 4.13 (1H, s), 4.01 (1H, m), 3.99 (3H, s), 3.84 (1H, d, J = 1.4Hz), 3.63 (1H, m) , 3.08 (2H, m), 2.61 (1H, m), 2.21-2.48 (3H, m), 2.02 (1H, m), 1.91 (3H, br), 1.55 (3H, br), 1.10 (3H, d , J = 6.7Hz), 1.00 (3H, t, J = 7.3Hz), 0.83 (3H, d, J = 6.7Hz).
EI-MS (m / z): 719 (M ⁺ ), 591, 412, 279, 195, 167.

Example 8
3,4β-epoxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of exemplary compound number 44), 3,4β-8,9α-diepoxy-13β-[(2Z) -Methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (compound of Exemplified Compound No. 50) and 8,9α-epoxy-13β-[(2Z) -methoxyimino-2-phenylacetoxy] -milbemycin A ₄ (Exemplary Compound Compound No. 56, step G-1)
13β-[(2Z) -Methoxyimino-2-phenylacetoxy] -milbemycin A ₄ 500 mg, 0.70 mmol) was dissolved in dichloromethane (40 ml) and stirred at room temperature under a nitrogen stream. To this, 150 mg (0.70 mmol) of metachloroperbenzoic acid (purity 80%) was added and stirred at room temperature overnight. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with sodium bicarbonate water and water in that order, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative high performance liquid chromatography (column: ODS-Pack S-365-10, φ30 × 500 mm, eluent: acetonitrile / water = 3/1), and 3,4β-epoxy compound (exemplary compound) Compound No. 44) 86.4 mg (yield 17%), 3,4β-8,9α-diepoxy compound (Exemplary Compound No. 50 compound) 110.5 mg (yield 21%) and 8,9α-epoxy compound ( Compound of Exemplified Compound No. 56) was obtained in an amount of 75.9 mg (yield 15%).

3,4β-epoxy compound (compound No. 44)
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.51 (2H, m), 7.35 (3H, m), 5.80 (2H, m), 5.32-5.58 (3H, m), 5.19 (1H, d, J = 10.6Hz), 4.61 (2H, m), 4.31 (1H, s), 4.22 (1H, m), 3.99 (3H, s), 3.91 (1H, d, J = 6.6Hz), 3.62 (1H, m) , 3.30 (1H, d, J = 2.2Hz), 3.08 (1H, dt, Jt = 9.1Hz, Jd = 2.2Hz), 2.82 (1H, d, J = 2.2Hz), 2.62 (1H, m), 2.25 -2.50 (3H, m), 2.00 (1H, m), 1.55 (3H, s), 1.51 (3H, br), 1.09 (3H, d, J = 6.6Hz), 1.01 (3H, t, J = 7.3 Hz), 0.82 (3H, d, J = 6.2Hz).
EI-MS (m / z): 735 (M ⁺ ), 677, 556, 538, 195, 167.

3,4β-8,9α-diepoxy compound (Compound No. 50)
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.51 (2H, m), 7.38 (3H, m), 5.87 (1H, dd, J = 15.4 Hz, 9.5 Hz), 5.65 (1H, dd, J = 11.4 Hz, 4.0Hz), 5.30 (1H, m), 5.25 (1H, d, J = 10.6Hz), 5.05 (1H, dd, J = 15.4Hz, 9.5Hz), 4.32 (1H, d, J = 11.4Hz) ), 4.12 (1H, m), 4.02 (1H, d, J = 6.2Hz), 3.99 (3H, s), 3.86 (1H, d, J = 11.4Hz), 3.68 (1H, m), 3.61 (1H , S), 3.55 (1H, d, J = 9.5Hz), 3.33 (1H, s), 3.08 (1H, m), 2.97 (1H, s), 2.70 (1H, m), 2.27-2.55 (3H, m), 2.18 (1H, m), 1.57 (3H, s), 1.51 (3H, br), 1.12 (3H, d, J = 6.6Hz), 0.99 (3H, t, J = 7.7Hz), 0.84 ( 3H, d, J = 6.2Hz).
EI-MS (m / z): 751 (M ⁺ ), 720, 572, 554, 536, 195, 167.

8,9α-epoxy compound (Compound No. 56)
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.51 (2H, m), 7.38 (3H, m), 5.65 (1H, dd, J = 11.2 Hz, 3.8 Hz), 5.35 (2H, m), 5.25 ( 1H, d, J = 10.9Hz), 5.03 (1H, dd, J = 15.0Hz, 9.5Hz), 4.38 (1H, d, J = 11.4Hz), 4.30 (1H, br), 4.15 (1H, d, J = 5.1Hz), 3.99 (3H, s), 3.95 (1H, s), 3.94 (1H, d, J = 11.4Hz), 3.68 (1H, m), 3.58 (1H, d, J = 9.5Hz) , 3.30 (1H, dd, J = 4.8Hz, 2.6Hz), 3.08 (1H, dt, Jt = 9.2Hz, Jd = 2.6Hz), 2.73 (1H, m), 2.05-2.55 (4H, m), 1.86 (3H, br), 1.56 (3H, br), 1.12 (3H, d, J = 6.6Hz), 0.99 (3H, t, J = 7.0Hz), 0.84 (3H, d, J = 6.2Hz).
EI-MS (m / z): 735 (M ⁺ ), 556, 538, 195, 167.

Test example 1
Effectiveness of acaricide against resistant spider mite A spider mite (Tetranychus urticae) was inoculated on the primary leaves of cowpea (Vigna sinensis Savi). One day after inoculation, a solution containing 10 ppm and 1 ppm of the test compound in the inoculated leaves [10 ppm solution: 0.004% spreading agent (Nikkor 710F), 0.01% spreading agent (Gramin S), dispersing agent (polyvinyl Alcohol) 100 mg of an aqueous solution containing 0.06% and acetone 0.2% contains 1 mg of the test compound. 1 ppm solution: a solution obtained by diluting the above 10 ppm solution 10 times with water] was sprayed in a Mizuho rotary spray tower so that the sprayed liquid amount was 3.5 mg / cm ² leaf area. Three days later, the life and death of adults (reaction rate: including bitter worms) were examined with a binocular microscope. Each compound was tested in duplicate, and the chemical-treated leaves were stored in a constant temperature room at 25 ° C. during the test. The results are shown in Table 2.

  From the results in Table 2, the compounds of the present invention in Table 2 show high acaricidal activity against resistant spider mites in trace amounts.

  The milbemycin derivative (I) having an oxime group at position 13 of the present invention has excellent insecticidal, acaricidal and / or anthelmintic activity and is useful as an insecticidal, acaricidal or anthelmintic agent.

Claims (9)

Formula (I)

(Wherein the geometric isomerism of the oxime group represents E or Z;
R represents a C ₁ -C ₆ alkyl group,
A has a structure containing a carbon atom at the 2-position and a carbon atom at the 10-position to which the bond is bonded, and the following formulas A1 to A10

Any structural unit represented by
A milbemycin derivative having an oxime group at the 13-position.   The milbemycin derivative according to claim 1, wherein R is a methyl, ethyl, isopropyl or s-butyl group.   The milbemycin derivative according to claim 1, wherein R is a methyl or ethyl group.   The milbemycin derivative according to claim 1, wherein R is an ethyl group.   The milbemycin derivative according to claim 1, wherein the geometric isomerism of the oxime group is Z.   The milbemycin derivative according to claim 1, wherein A is any structural unit represented by the formulas A1, A2, A3, A8 or A10.   The milbemycin derivative according to claim 1, wherein A is any structural unit represented by formula A1, A2 or A3.   The milbemycin derivative according to claim 1, wherein A is a structural unit represented by formula A2.   An insecticide, acaricide or an anthelmintic containing the milbemycin derivative according to claim 1 as an active ingredient.