JPH08134071A - New 13-site-substituted milbemycin derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new compound having insecticidal, miticidal or insect-repelling activity. CONSTITUTION: This new compound, a milbemycin derivative, is expressed by formula I [R<1> is methyl, ethyl, isopropyl or sec-butyl; A is a group of formula II (X<1> is a 1-6C alkoxyl, a di-1-6C alkylamino, etc.; R<2> is H or a 1-3C alkyl), a group of formula III (X<2> is H; R<3> is a 1-3C alkyl), etc.], e.g. 13-(dimethylaminocarbonylmethyl)-5-O-(t-butyldimethylsilyl)-7-O-(trime thylsilyl) milbemycin A4 . The compound is obtained by the following process: a toluene solution containing 13-dehydro-15-hydro-15-hydroxy-5-O-(t-butyldimethylsilyl)-7- O-(trimethylsilyl)milbemycin A4 and N,N-dimethylacetamide-dimethylacetal is heated at 80-90 deg.C for 11hr followed by adding water to the system and the resultant organic layer is put to extraction with ethyl acetate followed by purifying the extract.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a milbemycin derivative having a substituent at the 13-position, which has insecticidal, acaricidal or anthelmintic activity.

[0002]

2. Description of the Related Art Milbemycins and avermectins are a series of macrolide compounds, and are disclosed in, for example, Japanese Patent Application Laid-Open No. Sho 5 (1993) -58.
0-29742, 56-32481 and 54-6.
Known formula (A) described in Japanese Patent No. 1198, etc.
Compound.

[0003]

[Chemical 7]

The above-mentioned milbemycins and avermectins are known to have insecticidal, acaricidal and anthelmintic activities, and other semi-synthetic milbemycins having various substituents at the 13-position have been reported. .

Among the semisynthetic milbemycins having various substituents at the 13-position, milbemycins having a substituent by a carbon-carbon bond at the 13-position of milbemycin which is particularly related to the present invention are disclosed in JP-A-63-014.
No. 784 discloses a 13-alkyl milbemycin derivative, and EP 332580 (1989) discloses a 13- (substitutable) aryl milbemycin derivative.
JP-A-38082 discloses a 13-vinyl milbemycin derivative. In addition, 13-hydroxy-13-allyl milbemycin derivative or 13-hydroxy-1
The 3-alkyl milbemycin derivative is EP351923.
(1990), 13-hydroxy-13- {2-
The (2,3-dioxan-2-yl)} ethyl milbemycin derivative is described in EP284563 (1988).

[0006]

The object of the present invention is to develop new milbemycin derivatives having excellent acaricidal, insecticidal or anthelmintic activity.

[0007]

Means for Solving the Problems As a result of intensive investigations by the present inventors to develop a 13-position substituted milbemycin derivative having a novel excellent acaricidal, insecticidal or anthelmintic activity, the novel carbon-carbon at the 13-position has been found. The present invention was completed by finding excellent acaricidal, insecticidal or anthelmintic activity in a 13-position substituted milbemycin derivative having a substituent by bonding.

That is, the present invention has the general formula (I)

[0009]

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[Wherein R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and A represents a compound represented by the general formula (II)

[0011]

[Chemical 9]

A group represented by the formula (wherein X ¹ is C ₁ -C ₆
Alkoxy group; di-C ₁ -C ₆ alkylamino group; C ₂ -
A C ₆ alkylene group is a cyclic amino group in which both ends are bonded to one nitrogen atom, and R ² is a C ₁ -C ₃ alkyl group. ), General formula (III)

[0013]

[Chemical 10]

A group represented by the formula (wherein X ² represents a hydrogen atom and R ³ represents C ₁ -C ₃ alkyl), the general formula (IV)

[0015]

[Chemical 11]

A group represented by the formula (wherein X ² represents a hydrogen atom), the general formula (V)

[0017]

[Chemical 12]

{In the formula, X ³ is a C ₁ -C ₆ alkyl group;
C ₂ -C optionally substituted by a C ₆ -C ₁₀ aryl group
₉ Alkenyl group; C ₆ -C ₁₀ aryl group which may be substituted with a group selected from the following (substituent group A); which may be substituted with a group selected from the following (substituent group A) C ₆ -C ₁₀ aryloxy group; C ₇ -C ₁₂ aralkyl group optionally substituted with a group selected from the following (substituent group A); substituted with a group selected from the following (substituent group A) It is shown also good C ₆ -C ₁₂ aralkyloxy group optionally.

(Substituent group A) Halogen atom; Hydroxyl group; C
₁ -C ₆ alkyl group; C ₁ -C ₃ alkoxy group}, the formula (VI)

[0020]

[Chemical 13]

[Wherein, X ⁴ is a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₂ -C ₉ alkenyl group optionally substituted by a C ₆ -C ₁₀ aryl group; the above (substituent group A selected good C ₆ -C ₁₀ aryl group optionally substituted with a group from); the (optionally substituted by selected from substituent group A) radicals C ₆ -C ₁₀ aryloxy group; the C _7- which may be substituted with a group selected from (Substituent group A)
C ₁₂ aralkyl group; represents a C ₆ -C ₁₂ aralkyloxy group which may be substituted with a group selected from the above (Substituent group A). }] The milbemycin derivative having a substituent at the 13-position represented by a carbon-carbon bond.

The details will be described below.

In the general formula (I), "a cyclic amino group in which both ends of a C ₂ -C ₆ alkylene group are bonded to one nitrogen atom" in the definition of X ¹ is, for example, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, cyclic amino group at both ends is attached to one nitrogen atom of the "C ₂ -C ₆ alkylene group" such as hexamethylene, for example, aziridinyl, pyrrolidyl, Examples thereof include groups such as piperidyl group, and preferably pyrrolidyl group.

In the definition of X ¹ and X ³ , "di C ₁ -C ₆
Alkylamino group ", the" C ₁ -C ₆ alkyl group "and" C ₁ -C ₆ alkyl group (substituent group A) in "" C ₁
The "-C ₆ alkyl group" is, for example, a straight chain or branched chain such as methyl, ethyl, propyl, isopropyl, butyl group, isobutyl, sec-butyl, ter-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl group. Is an alkyl group, preferably a C ₁ -C ₃ alkyl group, and more preferably a methyl group.

The "C ₁ -C ₆ alkoxy group" in the definition of X ¹ is, for example, methoxy, ethoxy, propoxy,
The above-mentioned "C such as butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy and isohexyloxy groups.
A ₁ -C ₆ alkyl group "to an oxygen atom is bonded group, preferably a C ₁ -C ₃ alkoxy group, more preferably a methoxy group.

In the definition of X ³ and X ⁴ , "C ₆ -C ₁₀
Good C ₂ -C ₉ alkenyl group optionally substituted with an aryl group "and" lower (upper) Symbol optionally substituted by is selected from (substituent group A) based on C ₆ -C ₁₀ aryl group ""C ₆ -C ₁₀ aryl group" is, for example, an aromatic group having 6 or 10 carbon atoms such as phenyl or naphthyl group,
A phenyl group is preferred.

"C ₂ -C ₉ alkenyl group optionally substituted by C ₆ -C ₁₀ aryl group" in the definition of X ³
Is, for example, cinnamyl, vinyl, 1-propenyl, allyl (2-propenyl), 2-methyl-1-propenyl, 1,2-dimethyl-1-propenyl, crotyl (2
-Butenyl), 2,4-butane-dienyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl group such as "C ₂ -C ₉ alkenyl group" and the above "C _6- ". A “C ₁₀ aryl group” may be bonded, and is preferably a vinyl, 2-methyl-1-propenyl or cinnamyl group.

In the definition of X ³ and X ⁴ , "C ₆ -C ₁₀ " of "C ₆ -C ₁₀ aryloxy group optionally substituted by a group selected from the following (substituent group A)" _{The “10} aryloxy group” is a group in which an oxygen atom is bonded to the above “C ₆ -C ₁₀ aryl group”, and for example, a phenoxy group,
It is a 1-naphthyloxy group or a 2-naphthyloxy group, and preferably a phenoxy group.

The "C ₇ -C ₁₂ the" bottom (top) Symbol optionally substituted by selected from (Substituent group A) radicals C ₇ -C ₁₂ aralkyl group "in the definition of X ³ and X ⁴ The "aralkyl group" is an aralkyl group having a carbon number of 7 to 12, such as benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl and 2-naphthylethyl groups.

The "halogen atom in (substituent group A)" in the definitions of X ³ and X ⁴ is a fluorine, chlorine, bromine or iodine atom, and preferably a chlorine atom.

The "C ₁ -C ₃ alkoxy group in (substituent group A)" in the definition of X ³ and X ⁴ has 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and isopropoxy groups. It is an alkoxy group, preferably a methoxy group.

Next, suitable compounds in the general formula (I) are mentioned.

(1) A compound in which R ¹ is a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and (2) A is
General formula (III) (wherein X ² and R ³ are the same as above. }, The formula (V) {wherein, X ³ is as defined above. } Or general formula (VI) {wherein X ⁴ is as defined above. }, A more preferred compound is (3) R ¹ is a methyl group,
A compound which is an ethyl group, (4) A has the general formula (III)
{In the formula, X ² is a hydrogen atom, R ³ is a hydrogen atom; C ₁ -C ₂
Indicates an alkyl group. }, General formula (V) {wherein X ³
Is a C ₁ -C ₄ alkyl group; a styryl group; a C ₃ -C ₆ alkenyl group; a phenyl group which may be substituted with a group selected from the following (substituent group A ₁ );
₁ ) C ₇ -C which may be substituted with a group selected from
₉ Indicates an aralkyl group.

(Substituent group A ₁ ) Halogen atom; Hydroxyl group;
C ₁ -C ₂ alkyl group; C ₁ -C ₂ alkoxy group} or general formula (VI) {wherein X ⁴ is a hydrogen atom; C ₁ -C ₄ alkyl group; C ₃ -C ₆ alkenyl group; Substituent group A
₁ ) A phenyl group which may be substituted with a group selected from: a C ₇ -C ₉ aralkyl group which may be substituted with a group selected from the above (Substituent group A ₁ ). }, A particularly preferred compound is (5) a compound in which R ¹ is an ethyl group, (6) A is a compound represented by the general formula (III) {in the formula, X:
² represents a hydrogen atom, and R ³ represents a C ₁ -C ₃ alkyl group. }, General formula (V) {In the formula, X ³ is a C ₁ -C ₂ alkyl group, a C ₃ -C ₄ alkenyl group, the following (substituent group A
₂ ) C ₇ -C which may be substituted with a group selected from
₉ Indicates an aralkyl group.

(Substituent group A ₂ ) Fluorine atom; Chlorine atom;
A compound having a hydroxyl group; a methyl group; a methoxy group}.

Next, Table 1 shows specific examples of the compound of the present invention.

[0037]

[Table 1]

[0038]

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In the table below, the abbreviations represent groups or symbols.

Bu ・ ・ ・ ・ ・ ・ Butyl Bz ・ ・ ・ ・ ・ ・ Benzyl Crt ・ ・ ・ ・ ・ Crotyl Cin ・ ・ ・ ・ ・ ・ Cinnamyl Et ・ ・ ・ ・・ Ethyl Me ・ ・ ・ ・ ・ ・ Methyl Ph ・ ・ ・ ・ ・ ・ Phenyl Pip ・ ・ ・ ・ ・ ・ ・ Piperidinyl Pr ・ ・ ・ ・ ・ ・ Propyl Pre ・ ・ ・ ・ ・ ・ ・ Propenyl Pyrd ・ ・ ・ ・ ・ ・ ・ Pyrrolidinyl Vin ・ ・ ・ ・ ・ ・ Vinyl i ・ ・ ・ ・ ・ ・ Iso s ・ ・ ・ ・ ・ ・ Secondary t ・ ・ ・ ・ ・ ・ Tertiary ────────────────────────────────── Compound number R ¹ A ──────────── ─────────────────────── 1 Me MeOCOCH ₂ 2 Et MeOCOCH ₂ 3 Me EtOCOCH ₂ 4 Et EtOCOCH ₂ 5 Me BuOCOCH ₂ 6 Et BuOCOCH ₂ 7 Et BuOCO (Pr) CH 8 Et BuOCO (Pr) CH 9 Me Me ₂ NCOCH ₂ 10 Et M e ₂ NCOCH ₂ 11 Me Et ₂ NCOCH ₂ 12 Et Et ₂ NCOCH ₂ 13 Me 1-PipCOCH ₂ 14 Et 1-PipCOCH ₂ 15 Me 1-PyrdCOCH ₂ 16 Et 1-PyrdCOCH ₂ 17 Me (MeO) ₂ CHCH ₂ 18 Et (MeO) ₂ CHCH ₂ 19 Me (EtO) ₂ CHCH ₂ 20 Et (EtO) ₂ CHCH ₂ 21 Me (MeO) ₂ CMeCH ₂ 22 Et (MeO) ₂ CMeCH ₂ 23 Me OHCCH ₂ 24 Et OHCCH ₂ 25 i-Pr OHCCH ₂ 26 s-Bu OHCCH ₂ 27 Me MeCOCH ₂ 28 Et MeCOCH ₂ 29 i-Pr MeCOCH ₂ 30 s-Bu MeCOCH ₂ 31 Me EtCOCH ₂ 32 Et EtCOCH ₂ 33 Me BuCOCH ₂ 34 Et BuCOCH ₂ 35 Me t-BuCOCH ₂ 36 Et t-BuCOCH ₂ 37 Me VinCOCH ₂ 38 Et VinCOCH ₂ 39 Me CrtCOCH ₂ 40 Et CrtCOCH ₂ 41 Me 2-Me-1-PreCOCH ₂ 42 Et 2-Me-1-PreCOCH ₂ 43 Me 1,2- (Me ) ₂ -1-PreCOCH ₂ 44 Et 1,2- (Me) ₂ -1-PreCOCH ₂ 45 Me CinCOCH ₂ 46 Et CinCOCH ₂ 47 Me PhCOCH ₂ 48 Et PhCOCH ₂ 49 Me 4-Cl-PhCOCH ₂ 50 Et 4- Cl-PhCOCH ₂ 51 Me 4-F-PhCOCH ₂ 52 Et 4-F-PhCOCH ₂ 53 Me 4-MeO-PhCOCH ₂ 54 Et 4-MeO-PhCOCH ₂ 55 Me 4-OH-PhCOCH ₂ 56 Et 4-OH- PhCOCH ₂ 57 Me 4-Me-PhCOCH ₂ 58 Et 4-Me-PhCOCH ₂ 59 Me BzCOCH ₂ 60 Et BzCOCH ₂ 61 Me 4-Cl-BzCOCH ₂ 62 Et 4-Cl-BzCOCH ₂ 63 Me 4-F-BzCOCH ₂ 64 Et 4-F -BzCOCH ₂ 65 Me 4-MeO-BzCOCH ₂ 66 Et 4-MeO-BzCOCH ₂ 67 Me 4-OH-BzCOCH ₂ 68 Et 4-OH-BzCOCH ₂ 69 Me 4-Me-BzCOCH ₂ 70 Et 4-Me-BzCOCH ₂ 71 Me PhC ₂ H ₄ COCH ₂ 72 Et PhC ₂ H ₄ COCH ₂ 73 Me PhC ₃ H ₆ COCH ₂ 74 Et PhC ₃ H ₆ COCH ₂ 75 Me HOCH ₂ CH ₂ 76 Et HOCH ₂ CH ₂ 77 Me HOCHMeCH ₂ 78 Et HOCHMeCH ₂ ─────────────────────────────────── In the above table, preferably, compound number 17, 18, 1
9, 20, 21, 22, 23, 24, 25, 26, 2
7, 28, 29, 32, 34, 41, 42, 45, 4
6, 4748, 50, 52, 54, 56, 58, 59,
60, 62, 64, 66, 68, 70, 72, 75, 7
6 or 78, and more preferably 17, 18, 1
9, 20, 22, 23, 24, 27, 28, 32, 3
4, 42, 46, 48, or 59.

The compounds of general formula (I) of the present invention are
It is manufactured according to the following method.

[0042]

[Chemical 15]

[0043]

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[0044]

[Chemical 17]

[0045]

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In the above formula, R ¹ and R ² , R ³ , X ¹ , X
² , X ³ and X ⁴ have the same meanings as described above. R ⁴
Represents a tri-C ₁ -C ₄ alkylsilyl group, for example,
Trimethylsilyl, methyldiethylsilyl, triethylsilyl, methyldiisopropylsilyl, triisopropylsilyl group or tert-butyldimethylsilyl group,
Preferred is a trimethylsilyl group. R ⁵ is a bird C ₁
-C shows a ₄ alkylsilyl group or a di C ₆ -C ₁₀ aryl mono C ₁ -C ₄ alkylsilyl group. The tri-C ₁ -C ₄ alkylsilyl group, has the same meaning as R ^4,
It is preferably a trimethylsilyl group or a tert-butyldimethylsilyl group. Di C ₆ -C ₁₀ aryl mono C ₁ -C
_{The 4-} alkylsilyl group is, for example, a group such as diphenylmethylsilyl, diphenylethylsilyl, dinaphthylmethylsilyl, tert-butyldiphenylsilyl group, preferably diphenylmethylsilyl, tert-butyldiphenylsilyl group. .

The 15-hydroxymilbemycin derivative represented by the general formula (VII) in the above reaction scheme, which is the starting material of this production method, is produced according to the method described in JP-A-5-97863. Further, the starting material milbemycin and its analog compounds are fermentation products,
It can be either single or a mixture thereof. Therefore, the compound of general formula (VI) can also be prepared as a single compound or a mixture. Method A is a formula (I), wherein A is a group represented by the formula (II), and R ¹ is a methyl, ethyl, isopropyl or sec-butyl group. Is the way.

The step A1 (represented by A-1 in the reaction formula. The same applies hereinafter) is a process for producing the compound (IX) represented by the general formula, which is represented by the general formula (VII) in an inert solvent. It can be achieved by reacting the milbemycin derivative described with a reagent represented by the following general formula (VIII).

[0049]

[Chemical 19]

(In the formula, R ⁶ represents a C ₁ -C ₃ alkyl group, X ¹ has the same meaning as described above, and Y and Z
Represents a C ₁ -C ₃ alkoxy group. ) When using dialkyl acetamide dialkyl acetals as reagent (VIII), the reaction conditions are
Liebigs Annalen Hemmy or Helvetica Kimika The method described in Acta (Justus Liebigs Ann.
m. 1961, 641, 1. Helv. Chim. Acta 1964, 47, 2425.
Helv. Chim. Acta 1969, 52, 1030.).

When the reagent (VIII) is an orthoalkanoic acid ester, it is described in Journal of American Chemical Society (J. Am. Chem. Soc. 1970, 92, 74).
1.) It can be performed according to the described method.

The step A2 (A-2) is a step for producing the compound (IX), and the compound (VIII) obtained in the previous step is used.
Is heated without isolation to cause so-called Claisen rearrangement.

Steps A1 and A2 are reactions usually called Claisen rearrangement. When the above-mentioned two kinds of reagents are used, the above-mentioned two steps are continuously carried out and the compound (VII
I) cannot be isolated.

The dialkyl acetamide dialkyl acetals used are dimethyl acetamide dimethyl acetal, diethyl acetamide dimethyl acetal, diethyl acetamide diethyl acetal, diethyl acetamide dipropyl acetal, preferably dimethyl acetamide. It is cetamide dimethyl acetal.

The solvent used is benzene, toluene,
It is an aromatic hydrocarbon such as xylene, preferably toluene.

The reaction temperature is 50 to 200 ° C, preferably 60 to 150 ° C.

The reaction time is 2 to 24 hours, preferably 5 to 15 hours. The orthoacetates used are methyl orthoacetate, ethyl orthoacetate and propyl orthoacetate, preferably ethyl orthoacetate.

The solvent is generally not used, and the reagent is used in excess to substitute for the solvent. Since the reaction proceeds in the presence of a catalyst, as the catalyst, an organic acid such as acetic acid, propionic acid, butyric acid or a sulfuric acid, a mineral acid such as hydrochloric acid is used, and preferably an organic acid, particularly Preferred is propionic acid.

The reaction temperature is 100 to 200 ° C, preferably 120 to 150 ° C.

The reaction time is 1 to 10 hours, preferably 2 to 5 hours.

The step A3 (A-3) is a step for producing the compound (Ia), and is accomplished by deprotecting the compound obtained in the previous step in an inert solvent in the presence of a catalyst.

The catalyst used for deprotection (desilylation) is, for example, a fluoride such as tributylammonium fluoride or an organic acid or an inorganic acid such as p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, Organic acids are preferable, and p-toluenesulfonic acid is particularly preferable.

As the solvent, for example, tetrahydrofuran, methanol, ethanol, or a hydrate of these solvents can be used, but preferably methanol,
It is hydrous methanol.

The reaction temperature is 15 ° C to 100 ° C,
It is preferably 20 ° C to 50 ° C. The reaction time varies depending on the compound, the reaction temperature, etc., but it is usually 1 hour to 1 hour.
It is 0 hour, preferably 1 hour to 3 hours.

After completion of the reaction, the desired compound can be prepared by a conventional method,
For example, it is obtained by pouring the reaction solution into water and extracting it with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and distilling off the solvent from the extract solution, or by concentrating the reaction solution after the reaction. . Further, if desired, it can be purified by various kinds of chromatography.

In method B, in the general formula (I), A is the formula:
(III) is a group represented by R ¹ is methyl, ethyl,
In the method for producing general formula (Ib1) which is an isopropyl or sec-butyl group and in general formula (I), A is a group represented by formula: (IV), R ¹ is methyl, ethyl, isopropyl, This is a method for producing the general formula (Ib2) which is a sec-butyl group. This method is also a method for producing a target compound using Claisen rearrangement.

The step B1 (B-1) comprises the compound (XII)
In the presence of a catalyst in an inert solvent,
A compound represented by the general formula (VII) and the following general formula (XI)

[0068]

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(Wherein X ² represents a hydrogen atom and R ⁷ represents a C ₁ -C ₃ alkyl group or a C ₂ -C ₃ alkanoyl group). To be achieved.

The catalyst used is, for example, mercuric acetate or mercuric trifluoroacetate, preferably mercuric trifluoroacetate.

As the reagent, for example, an alkyl vinyl ether such as methyl vinyl ether, ethyl vinyl ether or a vinyl alkanoate such as vinyl acetate can be used, but an alkyl vinyl ether is preferable, and an alkyl vinyl ether is particularly preferable. , Ethyl vinyl ether.

The reaction solvent may be used without any particular limitation as long as it does not participate in the reaction, but it is preferably carried out in the absence of a solvent using an excess of the reagent.

The reaction temperature is usually -10 to 100 ° C, preferably 0 to 50 ° C. The reaction time is 30 minutes to 24 hours, preferably 1 to 10 hours.

After completion of the reaction, the desired compound can be prepared by a conventional method,
For example, it is obtained by pouring the reaction solution into water and extracting it with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and distilling off the solvent from the extract solution, or by concentrating the reaction solution after the reaction. . Further, if desired, it can be purified by various kinds of chromatography.

The step B2 is a step for producing the compound (XIII), and is accomplished by heating the compound (XII) obtained in the previous step to cause Claisen rearrangement.

The reaction solvent can be used without particular limitation as long as it does not participate in the reaction. For example, aromatic hydrocarbons such as toluene and xylene, or anisole and ter-butylphenyl ether are preferred. Are aromatic hydrocarbon ethers, preferably aromatic hydrocarbons or aromatic hydrocarbon alkyl ethers, and particularly preferably xylene or anisole.

The reaction temperature is 80 ° C to 250 ° C,
It is preferably 110 ° C to 150 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 hour to 10 hours, and preferably 1 hour.
Hours to 5 hours.

After completion of the reaction, the desired compound can be prepared by a conventional method,
For example, it is obtained by pouring the reaction solution into water and extracting it with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and distilling off the solvent from the extract solution, or by concentrating the reaction solution after the reaction. . Further, if desired, it can be purified by various kinds of chromatography.

The step B3 is a step for producing the compound (Ib1), and the compound (XIII) obtained in the preceding step is converted to the following general formula (XIV)

[0081]

[Chemical 21]

This can be achieved by stirring in a lower alcohol represented by the formula (wherein R ⁸ represents a C ₁ -C ₃ alkyl group) in the presence of an acid catalyst. In this process,
Desilylation also proceeds at the same time.

The lower alcohol represented by the general formula (XIV) used is a C ₁ -C ₃ alcohol such as methanol, ethanol or propanol, preferably methanol.

The catalysts used are, for example, organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, preferably p-toluenesulfonic acid.
It is toluene sulfonic acid.

The reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C. The reaction time varies depending on the compound, the reaction temperature, etc., but it is usually 1 hour to 2 hours.
It is 0 hours, preferably 2 hours to 10 hours.

After completion of the reaction, the desired compound can be prepared by a conventional method,
For example, it can be obtained by pouring the reaction solution into water, extracting with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and distilling the solvent from the extract. Further, if desired, it can be purified by various kinds of chromatography.

The step B4 is a step for producing the compound (Ib2) and is accomplished by stirring the compound obtained in the previous step in acetone (deacetalization) in the presence of an acid catalyst.

The solvent used does not influence the reaction,
Any solvent that dissolves in water, such as tetrahydrofuran,
Water-soluble ethers such as dioxane, water-soluble ketones such as acetone, or a mixture thereof with water are preferable, and water-containing acetone is preferable. The catalyst used is, for example, an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, preferably p-toluenesulfonic acid.

The reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C. The reaction time varies depending on the compound, the reaction temperature, etc., but it is usually 1 hour to 2 hours.
It is 0 hours, preferably 2 hours to 10 hours.

After completion of the reaction, the desired compound can be prepared by a conventional method,
For example, it can be obtained by pouring the reaction solution into water, extracting with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and distilling the solvent from the extract. Further, if desired, it can be purified by various kinds of chromatography.

Method C is the same as formula (I) in which A is the formula:
A group represented by (V), wherein R ¹ is methyl, ethyl,
This is a method for producing the general formula (Ic) which is an isopropyl or sec-butyl group.

The step C1 (C-1) is carried out by the general formula (XVI)
Is a step of producing a compound represented by the formula (XV) and a compound represented by the general formula (VII) in an inert solvent.

[0093]

[Chemical formula 22]

(In the formula, X ³ has the same meaning as described above, and R 3
⁹ is a halogen atom, a hydroxyl group, a C ₆ -C ₁₀ arylcarbonyloxy or C ₂ -C ₇ alkanoyloxy group. ) Is achieved by reacting with a reagent represented by

The reaction method differs depending on the reagent used, as described below.

(1) In the presence or absence of a catalyst, (VII) is reacted with an acid halide (in the above XV, R ⁹ represents a halogen atom) together with an organic base or an inorganic base in an inert solvent. Method.

(2) In the presence of a catalyst, in an inert solvent, (VII
) And an acid anhydride (in the above XV, R ⁹ represents a C ₆ -C ₁₀ arylcarbonyloxy or C ₂ -C ₇ alkanoyloxy group).

(3) A method of reacting (VII) with a carboxylic acid (in the above XV, R ⁹ represents a hydroxyl group) together with a condensing agent in an inert solvent.

The method will be specifically described below.

As the catalyst for the reaction (1), for example, 4
An organic base such as dimethylaminopyridine or 4-pyrrolidinopyridine is used, but 4-dimethylaminopyridine is preferable. The solvent used is, for example,
Aromatic hydrocarbons such as benzene, toluene, xylene; aliphatic hydrocarbons such as petroleum ether and hexane; diethyl ether, diisopropyl ether,
Ethers such as dioxane and tetrahydrofuran;
Halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; acetic acid esters such as methyl acetate, ethyl acetate and amyl acetate, preferably halogenated hydrocarbons, and particularly preferably chloride. It is methylene.
The base used is an organic base such as pyridine or triethylamine, or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, preferably an organic base, and particularly preferably, It is pyridine. The reaction temperature is 0 to 100 ° C., preferably 10 to 50 ° C., and the reaction time is 30 minutes to 10 hours, preferably 1 to 5 hours.

The catalyst, solvent, base, reaction temperature and reaction time used in (2) are the same as in (1). However, this reaction proceeds without a base if a catalyst is used. Examples of the solvent used in the reaction (3) include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as petroleum ether and hexane; diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran. Such ethers; methylene chloride; acetic acid ester, preferably halogenated hydrocarbons, and particularly preferably methylene chloride. Examples of the condensing agent to be used include sulfonic acid chlorides such as dicyclohexylcarbodiimide, triisopropylbenzenesulfonyl chloride, triethylamine, and methylpyridinium halide, but dicyclohexylcarbodiimide is preferable. The reaction temperature is 0 to 50 ° C., preferably 10 to 30 ° C., and the reaction time is 30 minutes to 5 hours, preferably 1 to 3 hours.

In the step C2 (C-2), the compound (XVIII
) Is produced, and the compound (X
VI) in the presence of a catalyst, the Tebbe reagent (XVI
) Is achieved.

[0103]

[Chemical formula 23]

Tebbe's Reagent (XVI) is pure and applied chemistry (Pure & Appl. Chem., 55, 173).
3, 1983), but commercial products can be used. The reaction of this step is described in Journal of American Chemistry, 102, 3270 (19).
80 years).

Solvents used are, for example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as petroleum ether and hexane; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran. A compound; or a mixture of the above solvents, preferably a mixed solvent, and particularly preferably a toluene-tetrahydrofuran mixed solvent.

The catalyst is an organic base such as pyridine, 4-dimethylaminopyridine, lutidine, N, N-dialkylaniline or trialkylamine, and preferably pyridine.

The reaction temperature is -80 ° C to 40 ° C,
It is preferably -40 ° C to 30 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 hour to 10 hours, and preferably 2 hours.
Hours to 5 hours.

After completion of the reaction, the desired compound can be obtained, for example, by adding an aqueous sodium hydroxide solution to the reaction solution, removing insolubles by filtration, and distilling the solvent off from the filtrate. Further, if desired, it can be purified by various kinds of chromatography.

In the step C3 (C-3), the compound (XIX)
Which is a process for producing the compound (XVII
It is achieved by heating I) without isolation and causing the Claisen rearrangement.

This step can be carried out under the same conditions as the above-mentioned B2 step (B-2).

Step C4 is a step for producing compound (Ic) and is accomplished by deprotecting compound (XIX) obtained in the previous step in the presence of an acid catalyst.

This step can be carried out under the same conditions as in the above A3 step (A-3).

Method D is the same as formula (I) in which A is the formula:
A group represented by (VI), wherein R ¹ is methyl, ethyl,
This is a method for producing the general formula (Id) which is an isopropyl or sec-butyl group.

The step D1 is a step for producing the compound (XXI) and is achieved by treating the compound represented by the general formula (XX) with a reducing agent in an inert solvent.

The reducing agent in this step can be used without particular limitation as long as it is a reducing agent which converts a usual carbonyl group into an alcohol, but sodium borohydride is preferably used.

The solvent used is, for example, methanol,
Lower C ₁ -C ₃ alcohols such as ethanol and propanol, and preferably methanol.

The reaction temperature is -40 ° C to 30 ° C,
It is preferably -30 ° C to 0 ° C. The reaction time varies depending on the compound, reaction temperature, etc., but is usually 10 minutes to 5 minutes.
The time is preferably 20 minutes to 2 hours.

After completion of the reaction, the target compound can be prepared by a conventional method,
For example, the reaction solution is poured into water and extracted with a solvent immiscible with water, for example, a solvent such as benzene; ether; ethyl acetate,
It can be obtained by distilling off the solvent from the extract or by concentrating the reaction solution after completion of the reaction. Further, if desired, it can be purified by various kinds of chromatography.

Step D2 is a step for producing a compound represented by the general formula (Id), and is accomplished by deprotecting the compound (XXI) obtained in the previous step in the presence of an acid catalyst. This step can be performed under the same conditions as in the above A3 step (A-3).

[0121]

INDUSTRIAL APPLICABILITY The compound of the present invention having the above-mentioned formula (I) is a worm spider (Tetr) which is parasitic on fruit trees, vegetables and flowers.
anychus), apple spider mites and citrus spider mites (Panonych
us) and rust mites, and has excellent acaricidal activity against adult insects and eggs, ticks (Ixodidae), Arachnidae (Dermanysside), and Amblyidae (Sarcoptidae) that are parasitic on animals. It also has excellent activity against resistant mites, which have become a big problem in recent years because the acaricides are not effective.

The compounds of the present invention are further tested in sheep flies (Oest
us), fruit fly (Lucilia), bull fly (Hypoderma)
), Horse flies (Gautrophilus), etc., and phytoparasites of animals and birds such as chisel and whitefly, sanitary pests such as cockroaches and house flies, and a variety of horticultural pests such as aphids and lepidopteran larvae . Furthermore, root-knot beetles (Meloidogyne) and pinewood nematodes (Bursaphe) in soil
lenchus), and ticks (Rhizoglyphus). The compounds of the present invention are also active against insects which are harmful to plants, especially insects which are harmful by feeding on the plants.

Further, the compounds of the present invention have excellent parasiticidal activity as animal and human anthelmintic agents. Livestock, especially pigs, sheep, goats, cows, horses, dogs, cats and chickens
Effective against the following nematodes that infect poultry and pets:

Haemonchus, Trichostrongylus, Ostertergia (O
stertagia), genus Nematodirus (Nematodirus), genus Cooperia (Cooperia), genus Ascaris (Ascaris), genus Bunostomum (Bunostomum), genus Espagostomum (Oesop
hagostmum), genus Chabertia, genus Trichuris, genus Strongylus, genus Tricononema, genus Dichtyokaurs
ocaulus), Capillaria, Heterakis
(Heterakis), Toxocara (Toxocara), Ascaridia (Ascaridia), Oxyuris (Oxyuris), Ankylostoma (Ancylostoma), Uncinar (Uncinar)
ia), Toxascaris and Parascaris.

Some of the genera Nematodillus, Cooperia and Esagogostomum attack the intestinal tract, whereas only Hemonx and Ostertagia parasitize the stomach and parasites of Dictyocaurs are parasites. It is found in the lungs, but it also shows activity. In addition,
iidae) and Setariidae parasites are found in and are active in other tissues and organs, such as heart and blood vessels, subcutaneous and lymphatic tissues.

It is also useful against parasites that infect humans, and the most common parasites of the human digestive tract are Ancylostoma and Necator.
, Ascaris, Strongyroides
(Strongyloides), Trichinella, Capillaria, Trichyuri (Trichuri)
s) and Enterobius.

Other medically important parasites found in the blood or other tissues and organs outside the gastrointestinal tract, butterflies of the family Filaria, such as Wuchereria, Brussia (B
rugia), Onchocerca and Loa
(Loa) and Dracunculidae (Dracunculidae) parasites of the genus Dracunculus (Dracunculus), intestinal parasites are also active in the special intestinal parasitism states of the genus Strongiroides and Trichinella.

When the compound of the present invention is used as an anthelmintic in animals and humans, it can be orally administered as a liquid beverage. Beverages are usually solutions, suspensions or dispersions in suitable non-toxic solvents or water with suspending agents such as bentonite and wetting agents or other excipients. It generally contains a beverage or antifoam. Beverage formulations generally contain from about 0.01 to 0.5% by weight of active compound, preferably 0.01 to 0.1% by weight.

When it is desired to administer an oral dosage in a dry solid unit dosage form, capsules, pills or tablets containing the desired amount of the active compound are usually employed. These forms of use consist of homogeneous incorporation of the active ingredient with suitable finely divided diluents, fillers, disintegrants and / or binders, such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. Manufactured by

Such unit dosage formulations can vary widely in weight and content of anthelmintic agents depending on the type of host animal and parasite being treated and the body weight of the host.

When administered by animal feed, it is dispersed homogeneously in the feed, used as a top dressing or used in the form of pellets.
Usually, to achieve the desired antiparasitic effect, the final feed contains 0.0001-0.02% of the active compound.

Further, the substance dissolved or dispersed in a liquid carrier excipient can be parenterally administered to animals by injection in the forestomach, intramuscularly, intratracheally or subcutaneously. For parenteral administration, the active compounds are preferably mixed with suitable vegetable oils such as peanut oil, cottonseed oil. Such formulations generally comprise between 0.05 and 50% by weight of active compound.
It can also be administered topically by admixing it 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 pouring.

The optimum amount of active compound used for best results depends on the kind of animal to be treated and on the type and extent of the parasitic infection, but generally about 0.01 to 100 mg / kg of animal body weight, preferably Obtained by orally administering 0.5 to 50.0 mg. Such doses may be given in single or divided doses over a relatively short period of time, such as 1-5 days.

Next, the present invention will be described more specifically by way of examples.

[0135]

EXAMPLES 14,15-Epoxy-5-O- (tert-butyldimethylsilyl) -7-O- (trimethylsilyl)
Milbemycin A4 was synthesized and used according to the method described in Journal of Antibiotics Vol. 47, p. 812, 1994.

[0136]

Reference Example 1 15-Hydroxy-5-O- (tert-butyldimethyloxy)
Ryl) -7-O- (trimethylsilyl) -Δ13,14
-Milbemycin A ₄ 14,15-epoxy-5-O- (tert-butyldimethylsilyl) -7-O- (trimethylsilyl) milbemycin A ₄ (1.77 g, 2.38 mmol) and 2,6
-A hexane (7 ml) solution of lutidine (0.64 g, 5.94 mmol) was added dropwise with a hexane (3 ml) solution of trimethylsilyl triflate (1.05 g, 4.75 mmol) at 0 ° C, and the reaction was further performed at 0 ° C for 19 hours. Let The reaction solution was poured into water, the organic layer was extracted with ethyl acetate, the extract was washed with a 0.1N hydrochloric acid aqueous solution and a saturated sodium hydrogen carbonate aqueous solution, and then dried over sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was dissolved in 60 ml of tetrahydrofuran, and then 6 ml of 0.1N hydrochloric acid aqueous solution was added to the solution at 0 ° C. After 30 minutes, a saturated sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was extracted with ethyl acetate, and the extract was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the obtained crude product was purified by column chromatography to give 1.55.
15 g of 15-hydroxy compound was obtained (yield 88%).

IR (KBr) cm-1: 1745, 1250, 1167, 989, 84
0 MS m / z: 744 (M +), 484, 167, 73 1H NMR (400MHz, CDCl3): δ 5.80 (1H, dd, J = 11.4 and 1
4.7Hz, H-10), 5.65 (1H, br d, J = 11.4Hz, H-9), 5.
49 (1H, br s, H-3), 5.23 (1H, dd, J = 10.2 and 14.7Hz,
H-11), 5.16 (1H, d, J = 8.9Hz, H-13), 4.64-5.19 (2H,
m, H-19 and H-8a), 4.54 (1H, dd, J = 2.2 and 14.2Hz,
H-8a '), 4.37 (1H, m, H-5), 4.08 (1H, m, H-15), 3.86 (1
H, d, J = 5.6Hz, H-6), 3.42 (1H, m, H-17), 3.30 (1H,
m, H-2), 3.06-3.15 (1H, m, H-12), 3.00 (1H, dt, J = 2.
4 and 9.5Hz, H-25), 1.78 (3H, brs, H-4a), 1.62 (3H,
s, H-14a), 1.12 (3H, d, J = 6.5Hz, H-12a), 0.98 (3H,
t, J = 7.3Hz, H-25b), 0.94 (9H, s, t-butyl-Si), 0.82
(3H, d, J = 6.5Hz, H-24a), 0.15 (3H, s, MeSi), 0.14 (3
H, s, MeSi), 0.12 (9H, s, Me3Si). Anal.calcd for C41H68O8Si2: C, 66.09; H, 9.20.foun
d: C, 65.64; H, 9.21.

[0138]

Example 1 13- (Dimethylaminocarbonylmethyl) -5-O-
(Tert-Butyldimethylsilyl) -7-O- (trimethylene
Rushiriru) milbemycin A ₄ 13-dehydro-15-hydro-15-hydroxy -
5-O- (tert-butyldimethylsilyl) -7-O-
(Trimethylsilyl) milbemycin A ₄ (75 mg,
0.1 mmol) and N, N-dimethylacetamide A solution of dimethylacetal (133 mg, 1.0 mmol) in toluene (1 ml) was heated at 80 to 90 ° C. for 11 hours. After completion of the reaction, water was added to the reaction solution, the organic layer was extracted with ethyl acetate, and the extract was dried with sodium sulfate. The crude product obtained by distilling off the solvent was purified by column chromatography to obtain 61 mg of the title compound (yield 7
5%).

IR (KBr) cm-1: 1741, 1653, 1251, 1168, 1
129, 1094, 989, 840.MS m / z: 813 (M +), 571, 262, 223, 195, 167, 73.1H NMR (270MHz, CDCl3): δ 5.77 (1H, dd, J = 11.2 and 1
4.2Hz, H-10), 5.66 (1H, br d, J = 11.2Hz, H-9), 5.40-
5.49 (2H, m, H-3 and H-11), 5.22 (1H, m, H-15), 4.78
-4.86 (1H, m, H-19), 4.66 (1H, dd, J = 2.0 and 14.2Hz,
H-8a), 4.55 (1H, dd, J = 2.0 and 14.2Hz, H-8a '), 4.38
-4.40 (1H, m, H-5), 3.79 (1H, d, J = 5.4Hz, H-6), 3.50
-3.63 (1H, m, H-17), 3.21-3.24 (1H, m, H-2), 2.80-3.
08 (7H, m, H-25, Me2N-), 1.79 (3H, s, H-4a), 1.51 (3H,
s, H-14a), 1.06 (3H, d, J = 6.4Hz, H-12a), 0.95 (3H,
t, J = 7.3Hz, H-25b), 0.93 (9H, s, t-butyl-Si), 0.80
(3H, d, J = 6.3Hz, H-24a), 0.13 (6H, s, Me2Si), 0.11
(9H, s, Me3Si).

[0140]

Example 2 13- (Ethoxycarbonylmethyl) -5-O- (tert
-Butyldimethylsilyl) -7-O- (trimethylsilyl)
Le) milbemycin A ₄ 13-dehydro-15-hydro-15-hydroxy -
5-O- (tert-butyldimethylsilyl) -7-O-
(Trimethylsilyl) milbemycin A ₄ (75 mg,
0.1 mmol), triethyl orthoacetate (0.
2 ml, 1.1 mmol) and propionic acid (2 mg,
0.03 mmol) was heated at an oil bath temperature of about 130 ° C. for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by thin layer chromatography (TLC) to obtain 41 mg of the title compound A ₄ (yield 50%).

IR (KBr) cm-1: 1741, 1251, 1169, 989, 84
0.MS m / z: 814 (M +), 572, 223, 167, 73.1 1H NMR (400MHz, CDCl3): δ 5.77 (1H, dd, J = 11.5 and 1
4.7Hz, H-10), 5.65 (1H, br d, J = 11.5Hz, H-9), 5.46 (1
H, m, H-3), 5.42 (1H, dd, J = 9.9 and 14.7Hz, H-11),
5.18 (1H, m, H-15), 4.78-4.86 (1H, m, H-19), 4.65 (1
H, dd, J = 2.1 and14.2Hz, H-8a), 4.56 (1H, dd, J = 2.1
and 14.2Hz, H-8a '), 4.39 (1H, m, H-5), 3.99-4.16 (2H,
m, -CO2CH2-), 3.79 (1H, d, J = 5.2Hz, H-6), 3.54-3.6
0 (1H, m, H-17), 3.22 (1H, m, H-2), 3.02 (1H, dt, J = 2.
3 and 9.5Hz, H-25), 1.79 (3H, s, H-4a), 1.50 (3H, s,
H-14a), 1.20 (3H, t, J = 7.2Hz, -CO2CH2CH3), 1.05 (3H,
d, J = 6.6Hz, H-12a), 0.95 (3H, t, J = 7.1Hz, H-25b),
0.93 (9H, s, t-butyl-Si), 0.81 (3H, d, J = 6.5Hz, H-24
a), 0.14 (3H, s, MeSi), 0.13 (3H, s, MeSi), 0.12 (9H,
s, Me3Si). Anal.calcd for C45H74O9Si2: C, 66.30; H, 9.15.foun
d: C, 65.50; H, 8.90.

[0142]

Example 3 13-dehydro-15-hydro-15-acetoxy-
5-O- (tert-butyldimethylsilyl) -7-O-
(Trimethylsilyl) milbemycin A ₄ 13-dehydro-15-hydro-15-hydroxy-
5-O- (tert-butyldimethylsilyl) -7-O-
(Trimethylsilyl) milbemycin A ₄ (149m
g, 0.2 mmol) and acetic anhydride (0.05 ml, 0.
A methylene chloride (0.5 ml) solution of 5 mmol) was reacted at room temperature for 2 hours in the presence of a catalytic amount of dimethylaminopyridine (DMAP). The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, the organic layer was extracted with ethyl acetate, and the extract was dried with sodium sulfate. The crude product obtained by distilling off the solvent was purified by column chromatography to obtain 147 mg of the title compound (yield 93%).

IR (KBr) cm-1: 1743, 1250, 1237, 1166, 1
094, 990, 840.MS m / z: 786 (M +), 484, 167, 73.1 H NMR (400MHz, CDCl3): δ 5.80 (1H, dd, J = 11.2 and 1
4.6Hz, H-10), 5.64 (1H, br d, J = 11.2Hz, H-9), 5.49 (1
H, br s, H-3), 5.16-5.30 (3H, m, H-11, H-13 and H-1
5), 4.63-4.70 (2H, m, H-19 and H-8a), 4.53 (1H, dd,
J = 2.2 and 14.3Hz, H-8a '), 4.37 (1H, m, H-5), 3.85 (1
H, d, J = 5.8Hz, H-6), 3.41-3.47 (1H, m, H-17), 3.28 (1
H, m, H-2), 2.98-3.11 (2H, m, H-12 and H-25), 2.03
(3H, s, MeCO2-), 1.77 (3H, br s, H-4a), 1.60 (3H, s,
H-14a), 1.10 (3H, d, J = 6.5Hz, H-12a), 0.98 (3H, t,
J = 7.3Hz, H-25b), 0.93 (9H, s, t-butyl-Si), 0.81 (3H,
d, J = 6.5Hz, H-24a), 0.14 (3H, s, MeSi), 0.13 (3H, s,
MeSi), 0.12 (9H, s, Me3Si). Anal.calcd for C43H70O9Si2: C, 65.61; H, 8.96.fou
nd: C, 65.11; H, 8.87.

[0144]

Example 4 13-dehydro-15-hydro-15-benzoyl
Xy-5-O- (tert-butyldimethylsilyl) -7-
O- (Trimethylsilyl) milbemycin A method similar to that in Example 3 was used. : Yield 79% IR (KBr) cm-1: 1743, 1250, 1237, 1166, 1094, 990, 84
0.MS m / z: 848 (M +), 484, 167, 105, 73.1 H NMR (400MHz, CDCl3): δ 8.02 (2H, br d, J = 7.8Hz, H
-aro), 7.55 (1H, br t, J = 7.3Hz, H-aro), 7.44 (2H, m,
H-aro), 5.82 (1H, dd, J = 11.2 and 14.6Hz, H-10), 5.6
7 (1H, br d, J = 11.2Hz, H-9), 5.50 (1H, br s, H-3),
5.42-5.46 (1H, m, H-15), 5.38 (1H, dd, J = 1.0 and 9.5H
z, H-13), 5.26 (1H, dd, J = 10.2 and 14.6Hz, H-11),
4.67-4.75 (1H, m, H-19), 4.67 (1H, dd, J = 2.2 and 14.
4Hz, H-8a), 4.54 (1H, dd, J = 2.2 and 14.4Hz, H-8a '),
4.37-4.38 (1H, m, H-5), 3.86 (1H, d, J = 5.7Hz, H-6),
3.50-3.56 (1H, m, H-17), 3.30 (1H, m, H-2), 3.07-3.1
4 (1H, m, H-12), 3.04 (1H, dt, J = 2.2 and 9.4Hz, H-2
5), 1.78 (3H, br s, H-4a), 1.70 (3H, s, H-14a), 1.11
(3H, d, J = 6.4Hz, H-12a), 1.01 (3H, t, J = 7.3Hz, H-25
b), 0.94 (9H, s, t-butyl-Si), 0.81 (3H, d, J = 6.4Hz,
H-24a), 0.15 (3H, s, MeSi), 0.14 (3H, s, MeSi), 0.13
(9H, s, Me3Si).

[0145]

Example 5 13-dehydro-15-hydro-15- (p-methoxy
Cyphenylacetyloxy) -5-O- (tert-butyl
Dimethylsilyl) -7-O- (trimethylsilyl) mill
Bemaishin A ₄ 13-dehydro-15-hydro-15-hydroxy -
5-O- (tert-butyldimethylsilyl) -7-O-
(Trimethylsilyl) milbemycin A ₄ (149m
g, 0.2 mmol), p-methoxyphenylacetic acid (6
6 mg, 0.4 mmol) and dicyclohexylcarbodiimide (DCC, 82 mg, 0.4 mmol) in a catalytic amount of dimethylaminopyridine (DMAP, 2 mg, 0.
(02 mmol) in the presence of methylene chloride (2 ml) at room temperature for 1 hour. After completion of the reaction, ether was added to the reaction solution, insoluble materials were removed by filtration, the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over sodium sulfate. The crude product obtained by distilling off the solvent was purified by column chromatography to obtain 171 mg of the title compound (yield 96%).

IR (KBr) cm-1: 1743, 1613, 1514, 1251, 1
166, 989, 839.MS m / z: 892 (M +), 484, 195, 167, 121, 73.1 1H NMR (400MHz, CDCl3): δ 7.18 (2H, br d, J = 8.6Hz, H
-aro), 6.85 (2H, br d, J = 8.6Hz, H-aro), 5.78 (1H, dd,
J = 11.4 and 14.6Hz, H-10), 5.63 (1H, br d, J = 11.2H
z, H-9), 5.48 (1H, br s, H-3), 5.15-5.27 (3H, m, H-1
1, H-13 and H-15), 4.62-4.70 (2H, m, H-19 and H-8a),
4.53 (1H, dd, J = 2.2 and 14.4Hz, H-8a '), 4.36-4.37
(1H, m, H-5), 3.85 (1H, d, J = 5.6Hz, H-6), 3.80 (3H,
s, MeO-), 3.53 (2H, s, ArCH2CO2-), 3.39-3.45 (1H, m,
H-17), 3.27 (1H, m, H-2), 2.96-3.11 (2H, m, H-12 an
d H-25), 1.77 (3H, br s, H-4a), 1.54 (3H, s, H-14a),
1.08 (3H, d, J = 6.5Hz, H-12a), 0.96 (3H, t, J = 7.2Hz,
H-25b), 0.93 (9H, s, t-butyl).

Claims (6)

[Claims] 1. A milbemycin derivative represented by the following general formula (I). Embedded image [Wherein R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and A represents a compound represented by the general formula (II): A group represented by the formula (wherein X ¹ is a C ₁ -C ₆ alkoxy group; a di C ₁ -C ₆ alkylamino group; a C ₂ -C ₆ alkylene group has both ends bound to one nitrogen atom). And R ² represents a hydrogen atom; a C ₁ -C ₃ alkyl group), a general formula (III): (Wherein X ² represents a hydrogen atom, and R ³
Represents C ₁ -C ₃ alkyl. ), The general formula (IV): A group represented by the formula (wherein X ² represents a hydrogen atom), and a compound represented by the general formula (V): {In the formula, X ³ is a C ₁ -C ₆ alkyl group; a C ₂ -C ₉ alkenyl group optionally substituted with a C ₆ -C ₁₀ aryl group; a group selected from the following (substituent group A) A C ₆ -C ₁₀ aryl group which may be substituted with;
A C ₆ -C ₁₀ aryloxy group which may be substituted with a more selected group; a C ₇ -C ₁₂ aralkyl group which may be substituted with a group selected from the following (substituent group A); optionally substituted with a substituent group a) from selected the group C ₆ -C ₁₂ aralkyl group. (Substituent group A) halogen atom; hydroxyl group; C ₁ -C ₆ alkyl group; C ₁ -C ₃ alkoxy group}, general formula (VI) {In the formula, X ⁴ is a hydrogen atom; C ₁ -C ₆ alkyl group; C
₆ -C optionally substituted with ₁₀ aryl group C ₂ -C ₉
Alkenyl group; C ₆ -C ₁₀ aryl group optionally substituted with a group selected from the above (Substituent group A); C optionally substituted with a group selected from the above (Substituent group A)
_7- C _{12 represents an} aralkyl group. }] 2. A is a general formula (III) (wherein X ² is the same as above). }, The formula (V) {wherein, X ³ is as defined above. } Or the general formula (VI) {wherein, X ⁴ is as defined above. } The compound according to claim 1, wherein 3. R ¹ is a methyl group or an ethyl group, and A 1
Is a compound represented by the general formula (III) (wherein X ² represents a hydrogen atom, R 2
³ represents a hydrogen atom; C ₁ -C ₂ alkyl. }, The formula (V) {wherein, X ³ is C ₁ -C ₄ alkyl group; a styryl group; C ₃ -C ₆ alkenyl group; below (substituent group A ₁₎
A phenyl group which may be substituted with a more selected group;
A C ₇ -C ₉ aralkyl group which may be substituted with a group selected from the following (Substituent group A ₁ )} or the general formula (VI)
{In the formula, X ⁴ is a hydrogen atom; C ₁ -C ₄ alkyl group; C
₃ -C ₆ alkenyl group; substituted with a selected from the following (substituent group A ₁₎ group; below may be substituted by selected from (substituent group A ₁₎ a group C ₆ aryl group The compound according to claim 2, which is a C ₇ -C ₉ aralkyl group (substituent group A ₁ ) halogen atom; hydroxyl group; C ₁ -C ₂ alkyl group; C ₁ -C ₂ alkoxy group}. 4. R ¹ is an ethyl group and A is of the general formula (III
) {Wherein X ² is a hydrogen atom and R ³ is a methyl group}. 5. R ¹ is an ethyl group and A is a general formula (V).
{In the formula, X ³ is a C ₁ -C ₂ alkyl group; a C ₃ -C ₄ alkenyl group; a benzyl group which may be substituted with a group selected from the following (substituent group A ₂ ) (substituent group A ₂ ) The compound according to claim 3, which is a fluorine atom; a chlorine atom; a hydroxyl group; a methyl group; a methoxy group}. 6. R ¹ is an ethyl group and A is a general formula (VI).
The compound according to claim 3, wherein X ⁴ is a hydrogen atom.