JP2002121195A - Method for producing 13-position-substituted milbemycin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for readily producing 13-position-substituted milbemycin derivative. SOLUTION: This method for producing 13-position-substituted milbemycin derivative having general formula (IV) [Y is a group represented by the formulas R1O or R1COO; R is a methyl group, ethyl group, isopropyl group or s-butyl group; and R1 is a 1-6C linear or branched alkyl group which may have a substituent, or a 3-6C cycloalkyl group which may have a substituent] is characterized in that a compound having general formula (I) [X is a hydrogen atom or a tri(a 1-4C alkyl)silyl group; and R has the same meaning defined before] is reacted with a compound having the formula R1OH or R1COOH [R1 is as previously defined] in the presence of a catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a milbemycin derivative having an ether-type or ester-type substituent at the 13-position.

[0002]

2. Description of the Related Art Milbemycin derivatives having an ether-type or ester-type substituent at the 13-position have high anthelmintic activity against internal and ectoparasites.
It is described in Japanese Patent Application No. 8-259445.

[0003] As a method for producing the compound, first, a ring-opening reaction of milbemycin 14,15-epoxide is performed (see Japanese Patent No. 2698250) to obtain a 15-hydroxy form of milbemycin, and the milbemycin 13-position is obtained from the 15-hydroxy form of milbemycin. Production method for obtaining a transformant (Patent No. 2656865)
Reference).

[0004]

SUMMARY OF THE INVENTION The present inventors have conducted intensive studies to solve the problem of reducing the number of steps in the method for producing the above-mentioned milbemycin 13-substituted product. A process for producing a milbemycin derivative having an ether-type or ester-type substituent at the 13-position in one step without going through the process was found, and the present invention was completed.

[0005]

The present invention provides a compound represented by the following general formula (I):

[0006]

Embedded image Wherein R is methyl, ethyl, isopropyl or s-
X represents a hydrogen atom or a tri (alkyl having 1 to 4 carbon atoms) silyl group. To a compound represented by the following general formula (II) in the presence of an acid catalyst:

[0007]

Embedded image Or the following general formula (III)

[0008]

Embedded image [Wherein, R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent selected from the following substituent group A or a substituent selected from the following substituent group A] And represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted. Characterized by the following general formula (IV):

[0009]

Embedded image [Wherein, Y represents a group represented by the formula R ¹ O or R ¹ COO;
R and R ¹ have the same meaning as described above. This is a method for producing a 13-substituted milbemycin derivative having the formula:

Here, the substituent group A is a cycloalkyl group having 3 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, An alkoxycarbonyl group having 5 groups, an aryl group having 6 to 10 carbon atoms which may have a substituent selected from the following substituent group B, a halogen atom, a nitro group or a cyano group, Substituent group B is a cycloalkyl group having 3 to 6 carbon atoms,
A group consisting of an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a halogen atom, a nitro group or a cyano group is shown.

A compound having the general formula (II) (hereinafter, compound (II)), a compound having the general formula (III) (hereinafter, compound (III)) or a compound having the general formula (IV) ( Hereinafter, in the compound (IV)), the unsubstituted “linear or branched alkyl group having 1 to 6 carbon atoms” for R ¹ is, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, s-pentyl, t-pentyl, 2-methylbutyl, neopentyl, hexyl, isohexyl, s-hexyl, 3-methylpentyl, 2-methylpentyl, Examples include a 3,3-dimethylbutyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group, preferably a methyl, ethyl, propyl or isopropyl group, and more preferably a methyl or ethyl group. Can be

Compound (II), compound (III) or compound (I
In V), the unsubstituted “cycloalkyl group having 3 to 6 carbon atoms” for R ¹ includes a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group,
Preferably, a cyclopentyl or cyclohexyl group is used, and more preferably, a cyclopentyl group is used.

The "cycloalkyl group having 3 to 6 carbon atoms" in the definition of Substituent Group A or Substituent Group B includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl or cyclohexyl. Groups.

The “alkoxy group having 1 to 4 carbon atoms” in the definition of the substituent group A or the substituent group B includes:
Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy or t-butoxy groups, preferably methoxy or ethoxy groups.

The "alkylthio group having 1 to 4 carbon atoms" in the definition of Substituent Group A or Substituent Group B includes methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio or t-butylthio. A butylthio group is preferred, and a methylthio or ethylthio group is preferred.

"Alkoxycarbonyl group having 2 to 5 carbon atoms" in the definition of substituent group A or substituent group B
Is an alkoxy group having 1 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group is a carbonyl group. A bonded group, preferably a methoxycarbonyl or ethoxycarbonyl group.

The unsubstituted "aryl group having 6 to 10 carbon atoms" in the definition of the substituent group A includes, for example, a phenyl, 1-naphthyl or 2-naphthyl group, preferably a phenyl group. .

An aryl group in the definition of the substituent group A is
When it represents a substituted aryl group, it may be substituted with 1 to 3 substituents, preferably 1 or 2 substituents. When a plurality of substitutions are present, they may be the same or different.

The "halogen atom" in the definition of the substituent group A or the substituent group B includes, for example, a fluorine atom, a chlorine atom,
A bromine atom or an iodine atom is mentioned. Examples of the tri (alkyl having 1 to 4 carbons) silyl group for X include trimethylsilyl, triethylsilyl and t-butyldimethylsilyl groups, and preferably a trimethylsilyl group.

Examples of the acid catalyst include acids capable of cleaving the carbon-oxygen bond of the epoxy ring, such as Lewis acids such as BF ₃ and SbCl ₃ ; or methanesulfonic acid, trifluorosulfonic acid Sulfonic acids such as romethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; and sulfonic acids are preferred, and trifluoromethanesulfonic acid is more preferred.

As for the carboxylic acids and sulfonic acids, trimethylsilyl ester,
Tri (C1-4 alkyl) silyl esters such as triethylsilyl ester and t-butyldimethylsilyl ester can be used, and preferably sulfonic acid tri (C1-4 alkyl) Examples thereof include silyl esters, and more preferably, trimethylsilyl ester of trifluoromethanesulfonic acid (trimethylsilyl triflate).

[0022]

DETAILED DESCRIPTION OF THE INVENTION The reaction of the present invention is carried out in the presence or absence of a solvent in the presence of a catalyst in the presence of a 14,15-epoxy derivative of milbemycin having the general formula (I) (hereinafter referred to as compound (I)
That. ) With compound (II) which is an alcohol or compound (III) which is a carboxylic acid.

The compound (I) as a raw material of the present invention is disclosed in
-220068 can be produced by the method of Step A2 or Step B1 described in -220068.

This reaction can be carried out in the presence or absence of a solvent, but is preferably carried out in the presence of a solvent.

When the reaction is carried out in the presence of a solvent, the solvent used for the reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Examples thereof include hexane, heptane and petroleum ether. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Ethers, and the like, preferably, halogenated hydrocarbons and aromatic hydrocarbons, more preferably, halogenated hydrocarbons, and particularly preferably. Can include dichloromethane.

The amount of the alcohol or carboxylic acid used in the reaction is not particularly limited, but is preferably from 1.0 to 10 equivalents, more preferably from 1.5 to 4 equivalents to compound (I). Use equivalent.

When a hardly soluble carboxylic acid is used, a trialkylsilyl ester of the carboxylic acid can be used instead of the carboxylic acid. As an example of this case, first, a carboxylic acid is reacted with a trialkylsilyl allyl such as trimethylsilyl allyl in a solvent and an equivalent amount of trimethylsilyl triflate as a catalyst in a solvent (the trimethyl silyl triflate added here is directly used in the next step). ), A solution of a silyl ester of a carboxylic acid is prepared, and then the compound (I) is added.

The amount of the acid catalyst used in the reaction is 0.00
It is 1 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.1 equivalent.

The reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.

The reaction time varies depending on the reaction temperature and the like, but is usually 5 minutes to 2 hours, preferably 15 minutes to 1 hour.
Time.

After completion of the reaction, the target compound can be easily collected from the reaction mixture by a conventional method. For example, it can be obtained by diluting the reaction mixture with a water-immiscible organic solvent, filtering off insolubles, washing the organic layer with an aqueous sodium hydrogen carbonate solution and water, and distilling off the organic solvent. Further, if necessary, purification is carried out by a conventional method, for example, recrystallization, column chromatography or the like.

In the compound (IV) produced by the above method, the oxo group at the 5-position can be easily converted to a hydroxyl group by reduction, if necessary, or to an oxime by treatment with hydroxylamine.

In a preferred embodiment of the production method of the present invention, the following general formula (I)

[0034]

Embedded image In the presence of a sulfonic acid or a tri (alkyl having 1 to 4 carbon atoms) silyl ester of a sulfonic acid, a compound represented by the following general formula (II)

[0035]

Embedded image Or the following general formula (III)

[0036]

Embedded image Characterized by reacting a compound having the following general formula (IV)

[0037]

Embedded image [Wherein, Y represents a group represented by the formula R ¹ O or R ¹ COO. ]
This is a method for producing a 13-substituted milbemycin derivative having the following formula:

[0038]

EXAMPLES The present invention will be specifically described below with reference to examples and reference examples, but the present invention is not limited to these examples.

Example 1 5-oxo-13- [2- (4-nitrophenyl) ethyl
Ruoxy] milbemycin A4 (in the compound (IV),
R is an ethyl group, Y is R ¹ O, and R ¹ is 2- (4-nitrophen
N)) Preparation of a compound which is an ethyl group

[0040]

Embedded image 5-oxo-7-O-trimethylsilylmilbemycin A ₄ 14,15-epoxide obtained in Reference Example 1.
(Compound (I) in which R is an ethyl group and X is a trimethylsilyl group) 629 mg (1.0 mmol)
Was dissolved in 20 ml of dichloromethane, and 669 mg of 4-nitrophenethyl alcohol and 0.02 ml of trimethylsilyl triflate (trifluoromethylsulfonic acid trimethylsilyl ester) were added, followed by stirring at room temperature for 30 minutes. 150 ml of ethyl acetate was added to the reaction solution, and insolubles were filtered off. The filtrate was washed with 4% sodium hydrogen carbonate and water in that order, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (filler: silica gel, eluent: ethyl acetate / cyclohexane = 1: 4).
By purifying with the above, the target compound was obtained. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MHz, δ ppm) = 8.1
4 (2H, d, J = 8.5), 7.38 (2H, d, J = 8.5Hz), 6.54 (1H, d, J = 1.4
7Hz), 5.86-5.72 (2H, m), 5.44-5.32 (2H, m), 5.18 (1H, m
m), 4.76 & 4.72 (2H, ABq, J = 11.7Hz), 3.94 (1H, s), 3.85
(1H, s), 3.55 (3H, m), 3.38 (1H, m), 3.20 (1H, d, J = 9.5Hz),
3.05 (1H, m), 2.94 (2H, t, J = 6.6Hz), 1.89 (3H, s), 1.00
(3H, d, J = 6.6Hz), 0.99 (3H, t, J = 7.7Hz), 0.83 (3H, d, J = 6.
6 Hz) Mass spectrum m / e:.. 706 ( M + H, M = C 40 H 51 NO 10) [ Example 2] 5-oxo-13- (4-nitro-phenylacetyl) Mi
Rubemycin A ₄ (in the compound (IV), R is ethyl
A compound wherein Y is R ¹ COO and R ¹ is 4-NO ₂ -PhCH ₂
Manufacture

[0041]

Embedded image 5-oxo-7-O-trimethylsilylmilbemycin A ₄ 14,15-epoxide obtained in Reference Example 1.
(Compound (I) in which R is an ethyl group and X is a trimethylsilyl group) 629 mg (1.0 mmol)
l) was dissolved in 20 ml of dichloromethane, and 725 mg (4.0 mmol) of 4-nitrophenylacetic acid and 0.02 ml of trimethylsilyl triflate were added.
For a minute. 150 ml of ethyl acetate was added to the reaction solution, and insolubles were filtered off. The filtrate was washed with 4% sodium hydrogen carbonate and water in that order, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (filler: silica gel, eluent: ethyl acetate / cyclohexane = 1: 4) to give 304 mg (yield: 4).
(2.3%) of the desired compound. ¹ H- nuclear magnetic resonance spectrum _{(CDCl 3, 400MHz, δppm)} = 8.
19 (2H, d, J = 8.8Hz), 7.45 (2H, d, J = 8.8Hz), 6.55 (1H, t, J =
1.8Hz), 5.89-5.79 (2H, m), 5.45-5.36 (3H, m), 4.97 (1H,
d, J = 10.3Hz), 4.76 & 4.72 (2H, ABq, J = 14.6Hz), 4.02
(1H, s), 3.85 (1H, s), 3.74 (2H, s), 3.55 (2H, m), 3.03 (1
H, m), 2.54 (1H, m), 1.90 (3H, s), 0.98 (3H, t, J = 7.3Hz),
0.93 (3H, d, J = 6.6Hz), 0.82 (3H, d, J = 6.6Hz) Mass spectrum m / e:.. = 720 (M + H, M = C 40 H 49 NO 11) [ Example 3] 13- [1- (4-nitrophenyl) cyclopentaneca
Rubonyloxy] -5-oxomilbemycin A ₄
(In the compound (IV), R is an ethyl group, Y is R ¹ O, R ¹
Is 1- (4-nitrophenyl) cyclopentanecarbonyl
Production of a compound

[0042]

Embedded image 1- (4-nitrophenyl) cyclopentanecarboxylic acid 7
56 mg (3.0 mmol) of dichloromethane in 20 m
l, trimethylsilyl allyl 0.32 ml
(2.0 mmol) and trimethylsilyl triflate 0.02ml stirred for 30 minutes at room temperature was added and the resulting solution, obtained in Reference Example 1, 5-oxo -7-O-trimethylsilyl milbemycin A ₄ 14, 15 Epoxide (compound (I) in which R is an ethyl group and X is a trimethylsilyl group) 629 mg (1.0 mmol)
l) is dissolved in 5 ml of dichloromethane and added. The mixture is stirred for 60 minutes under a nitrogen stream, and then poured into a mixture of 100 ml of 4% sodium hydrogen carbonate and 100 ml of ethyl acetate with stirring. The ethyl acetate layer is separated, washed with 4% sodium hydrogen carbonate and water in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (filler: silica gel, eluent: ethyl acetate / hexane = 1: 3),
556 mg (yield 71.8%) of the target compound was obtained. ¹ H- nuclear magnetic resonance spectrum _{(CDCl 3, 400MHz, δppm)} =.
8.16 (2H, d, J = 8.9Hz), 7.50 (2H, d, J = 8.9Hz), 6.53 (1H, t,
J = 1.9Hz), 5.87-5.71 (2H, m), 5.46-5.31 (3H, m), 4.84 (1
H, d, J = 10.6Hz), 4.74 & 4.67 (ABq, J = 14.8Hz), 3.84 (1H,
s), 3.59-3.53 (2H, m), 3.01 (1H, m), 1.88 (3H, s), 0.98 (3H
H, t, J = 7.3Hz), 0.82 (3H, d, J = 6.4Hz), 0.78 (3H, d, J = 6.6
Hz) Mass spectrum m / e:.. = 774 (M + H, M = C 44 H 55 NO 11) [ Example 4] 13- [1- (4-nitrophenyl) cyclopentanol tanker
Rubonyloxy] -5-oxomilbemycin A ₄
(In the compound (IV), R is an ethyl group, Y is R ¹ O, R ¹
Is 1- (4-nitrophenyl) cyclopentanecarbonyl
Obtained in Reference Example 1 compound) is group, 5-oxo -7-O-trimethylsilyl milbemycin A ₄ 14,15-epoxide
(In compound (I), 629 mg (1.0 mmol) of a compound wherein R is an ethyl group and X is a trimethylsilyl group
Was dissolved in 20 ml of dichloromethane, and 941 mg of 1- (4-nitrophenyl) cyclopentanecarboxylic acid (4.
0 mmol) and trifluoromethanesulfonic acid.
02 ml was added, and the mixture was stirred at room temperature for 30 minutes. 150 ml of ethyl acetate was added to the reaction solution, and insolubles were removed by filtration.
% Sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (filler: silica gel, eluent: ethyl acetate / cyclohexane = 1: 4) to obtain 417 mg (yield 53.9%) of the target compound. The physical constants of this product coincided with those obtained in Example 3. Example 5 13- [1- (4-nitrophenyl) cyclopentaneca
Rubonyloxy] -5-oxomilbemycin A ₄
(In the compound (IV), R is an ethyl group, Y is R ¹ O, R ¹
Is 1- (4-nitrophenyl) cyclopentanecarboni
In Preparation Example 3 of a Le group compound), 5-oxo -7-O-trimethylsilyl milbemycin A ₄ 14,15-epoxide (Compound (I) in the compound X with R is an ethyl group is a trimethylsilyl group) instead of 5-oxo-milbemycin a ₄ 14,15-epoxide (compound (I), compound X in R is an ethyl group is H) 557m
g (1.0 mmol) was treated in the same manner as in Example 3 to obtain 485 mg (yield: 62.7%) of the target compound. The physical constants of this product coincided with those obtained in Example 3.

Example 6 13- [1- (4-nitrophenyl) cyclopentane
Rubonyloxy] -5-oxomilbemycin A ₃
(In the compound (IV), R is a methyl group, Y is R ¹ O and R ¹
Is 1- (4-nitrophenyl) cyclopentanecarbonyl
Production of a compound

[0044]

Embedded image In Example 3, (in the compound (I), R is X is trimethylsilyl group with an ethyl group compound) 5-oxo -7-O-trimethylsilyl milbemycin A ₄ 14,15-epoxide in place of 5-oxo - 7-O-trimethylsilyl milbemycin a ₃ 14,15-epoxide (compound (I), a compound wherein R is X is trimethylsilyl group with a methyl group) 615 mg (1.0 mm
530 mg (yield: 69.7%) of the target compound was obtained by treating in the same manner as in Example 3 using ol). ¹ H- nuclear magnetic resonance spectrum _{(CDCl 3, 400MHz, δppm)} =.
8.15 (2H, d, J = 8.9Hz), 7.49 (2H, d, J = 8.9Hz), 6.53 (1H, t, J
= 1.9Hz), 5.87-5.71 (2H, m), 5.46-5.31 (3H, m), 4.84 (1
H, d, J = 10.5Hz), 4.74 & 4.67 (ABq, J = 14.8Hz), 4.04 (1H,
broad-s), 3.84 (1H, s), 3.59-3.53 (2H, m), 3.22 (1H,
m), 1.88 (3H, s), 1.14 (3H, d, J = 6.5Hz), 0.83 (3H, d,
.. J = 6.5Hz), 0.77 (3H, d, J = 6.5Hz) Mass spectrum m / e: = 760 (M + H, M = C 43 H 53 NO 11) [ Reference Example 1] 5-oxo - 7-O-trimethylsilylmilbemycin
A ₄ 14,15-epoxide (compound (I) smell
Wherein R is an ethyl group and X is a trimethylsilyl group
)Manufacturing of

[0045]

Embedded image Milbemycin A ₄ 8.80 g of (16.2 mmol) was dissolved in dichloromethane 100 ml, at 4 ° C., was added manganese dioxide 44.0 mg, stirred at room temperature for 90 minutes.
The insoluble material is removed by filtration from the reaction solution, and the filtrate is evaporated to dryness. The residue was dissolved in 100 ml of dichloromethane, and
2.79 ml (24 mmol) of lutidine and 4.34 ml (24 mmol) of trimethylsilyl triflate
And stirred at the same temperature for 30 minutes. The reaction solution was 0.1
Wash with citric acid, water, 4% sodium bicarbonate and water, dry over anhydrous sodium sulfate and evaporate to dryness under reduced pressure. The residue was dissolved in 100 ml of dichloromethane, and 4
At 70 ° C., 4.72 g of 70% m-chloroperbenzoic acid (19.
(4 mmol) dissolved in 50 ml of dichloromethane is added and stirred at the same temperature for 40 minutes. Insolubles were removed by filtration from the reaction solution, and the filtrate was washed with 10% sodium thiosulfate, 4% sodium hydrogen carbonate and water in this order, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The obtained target product is used in the next step without further purification. ¹ H- nuclear magnetic resonance spectrum _{(CDCl 3, 400MHz, δppm)} = 6.
84 (1H, s), 5.93 (1H, dd, J = 11.5 and 14.4Hz), 5.8.3 (1
H, d, J = 11.5Hz), 5.54 (1H, dd, J = 9.7 and 14.4Hz),
5.05 (IH, m), 4.76 & 4.72 (ABq, J = 15.7Hz), 3.90 (1H, s),
3.79 (1H, m), 3.47 (1H, m), 3.07 (1H, m), 2.64 (1H, m
d, J = 10.1Hz), 1.90 (3H, s), 1.06 (3H, d, J = 6.7Hz),
1.00 (3H, t, J = 6.5Hz), 0.83 (3H, d, J = 6.5Hz), 0.03
[9H, s]. [Reference Example 2] 5-oxo-7-O-trimethylsilylmilbemycin
A ₃ 14,15-epoxide (R in compound (I)
Is a methyl group and X is a trimethylsilyl group)
Manufacture

[0046]

Embedded image Using milbemycin A milbemycin A ₃ instead of _4, to obtain a similar processing to the objective compound as in Reference Example 1, as a raw material in Example 6 without purification.

[0047]

According to the present invention, the method for producing milbemacincin 14,1
This is a method for producing a milbemycin derivative having an ether-type or ester-type substituent at the 13-position in one step from 5-epoxide without passing through a 15-hydroxy form of milbemacisin.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C071 AA04 AA08 BB03 CC14 EE04 FF17 GG01 HH05 HH08 HH09 KK11 LL01 4H039 CA61 CA66 CD10

Claims (1)

[Claims] 1. A compound represented by the following general formula (I): Wherein R is methyl, ethyl, isopropyl or s-
X represents a hydrogen atom or a tri (alkyl having 1 to 4 carbon atoms) silyl group. To a compound of the following general formula (II) in the presence of an acid catalyst: Or the following general formula (III): [Wherein, R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent selected from the following substituent group A or a substituent selected from the following substituent group A] And represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted. Wherein the compound has the following general formula (IV): [Wherein, Y represents a group represented by the formula R ¹ O or R ¹ COO;
R and R ¹ have the same meaning as described above. Of a 13-substituted milbemycin derivative having the formula: Substituent group A: a cycloalkyl group having 3 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkoxycarbonyl having 2 to 5 carbon atoms And a group consisting of an aryl group having 6 to 10 carbon atoms which may have a substituent selected from the following substituent group B, a halogen atom, a nitro group or a cyano group.
Substituent group B: cycloalkyl group having 3 to 6 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 1 carbon atom
A group consisting of an alkylthio group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, a halogen atom, a nitro group or a cyano group.