JP2698250B2 - Process for producing 5,15-dihydroxymilbemycin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The object of the present invention is to provide a useful synthetic intermediate for a milbemycin derivative having an ether bond at the 13-position.
An object of the present invention is to provide a method for producing a -hydroxymilbemycin derivative and a 5-hydroxy-15-hydroxymilbemycin derivative which is a useful synthetic intermediate thereof.

[0002]

The present invention relates to a process for producing an intermediate of a 13-ethermilbemycin derivative having excellent anthelmintic activity.

[0003]

2. Description of the Related Art Milbemycin derivatives having an ether bond at the 13-position have high anthelmintic activity.
No. 174780.

A method for producing a 13-ether-substituted milbemycin derivative is described in JP-A-2-174780 and JP-A-61-178986.

The method described in JP-A-2-174780 is a method in which a phenethyl alcohol is reacted with a 13-iodomylbemycin derivative in the presence of a silver or mercury catalyst.

[0006]

However, Japanese Patent Laid-Open No. 2-1
In the method described in Japanese Patent No. 74780, silver is expensive and mercury is toxic, so that industrial use of these catalysts is difficult.

[0007] The present inventors have determined that the milbemycin derivative 13
As a result of intensive studies on the method of introducing an ether substituent at the position, the alcohol was allowed to act on 15-hydroxymilbemycin in the presence of a catalyst such as trifluoromethane and copper iodide to obtain a high yield of the 13-ether compound. It was found that it can be manufactured at a high rate.

However, Japanese Patent Application Laid-Open No. 60-158191 and Helvetica chimica act Vol. 73 (1990), 1905-19
The 15-hydroxymilbemycins described in No. 17 are not suitable as raw materials for this etherification reaction. Further, Japanese Patent Application Laid-Open No.
No. 0-158191 and Helvetica chimica act V
ol. 73 (1990), 1905-1917, the yield of synthesis to 15-hydroxymilbemycins was low and was not a satisfactory method for use in the preparation of 13-ethermilbemycin derivatives.

The present inventors have determined that 5-hydroxy, 5-oxo or a 15-hydroxymilbemycin derivative which is a hydroxyl group protected at the 5-position is suitable as a raw material for the above-mentioned etherification reaction, and a novel production thereof. A method was found and the present invention was completed.

[0010]

Configuration of the Invention

[0011]

According to the present invention, there is provided a compound represented by the general formula (I)
I)

[0012]

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A silylating agent and a deoxidizing agent act on a milbemycin derivative represented by the formula (wherein, R represents a methyl group, ethyl group, isopropyl group or sec-butyl group, and TMS represents a trimethylsilyl group). After letting you generate 1
General formula (I), wherein the 5-silyl form is desilylated.

[0014]

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(Wherein R is as defined above), a method for producing a milbemycin derivative represented by the general formula (III):

[0016]

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Wherein the milbemycin derivative represented by the formula (wherein R and TMS have the same meanings as described above) is oxidized with a peracid to obtain an epoxide compound represented by the general formula (II); to the epoxide compound, Siri
After the action of the oxidizing agent and the deoxidizing agent,
Wherein the compound of formula (I) is desilylated.
The method for producing a 15-hydroxymilbemycin derivative represented by the general formula (IV) is corrected.

[0018]

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A silylating agent is allowed to act on a milbemycin derivative represented by the formula (wherein R is as defined above) to obtain a bistrimethylsilyl compound represented by the above general formula (III). The milbemycin derivative represented by (III) is oxidized with a peracid to obtain an epoxide compound represented by the general formula (II), and then a silylating agent and a deoxidizing agent are added to the epoxide compound.
After acting, the produced 15-silyl form is desilylated.
A method for producing a 15-hydroxymilbemycin derivative represented by the above general formula (I).

The milbemycin derivative represented by the general formulas (I) to (IV) of the present invention is preferably a milbemycin derivative in which R is a methyl group or an ethyl group,
More preferably, R is a milbemycin derivative of an ethyl group.

The 5-oxo-15-hydroxymilbemycin derivative of the present invention is produced from milbemycin according to the following steps.

(First Step)

[0023]

(IV) → (III) In the first step, chlorotrimethyl is added to a compound represented by the general formula (IV) (wherein R has the same meaning as described above) in the presence of a deoxidizing agent. By reacting a trimethylsilylating agent such as silane, 5,7-bistrimethylsilylmilbemycin represented by the general formula (III) (wherein, R has the same meaning as described above and TMS represents a trimethylsilyl group) This is the manufacturing process.

[0024] As acid acceptor to be used in this step, such as imidazole, 4-dimethylaminopyridine, such as triethylamine, typically acid acceptor can be used to be used for silylation, preferably, imidazole, 4- Organic bases such as dimethylaminopyridine and triethylamine.

The solvent used in the reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene and xylene. And methylene chloride, 1,
Halogenated hydrocarbons such as 2-dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethylacetamide, hexa Amides such as methyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile and propyl nitrile, more preferably methylene chloride, toluene or acetonitrile.

The reaction is carried out at a temperature of from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the kind of the solvent used, but is usually from 1 hour to 20 hours, preferably from 2 hours to 10 hours.

After completion of the reaction, the target substance can be easily collected from the reaction mixture according to a conventional method. For example, it can be obtained by diluting the reaction mixture with a water-immiscible organic solvent, filtering off insolubles, washing with cold dilute acid and then with water, and distilling off the solvent. Further, if necessary, it can be purified by a conventional method, for example, recrystallization, column chromatography and the like.

The milbemycin derivative represented by the general formula (IV), which is a starting compound in this step, is a kind of macrolide compound called antibiotic B-41,
For example, it is described in Japanese Patent No. 1112991 and is known to have insecticidal, acaricidal and anthelmintic activities.

(Second step)

[0031]

(III) → (II) In the second step, the compound represented by the general formula (II) obtained in the first step
A compound having I) is reacted with a peracid in a solvent to give a compound of the general formula (II) (wherein R and TMS are as defined above)
This is the step of obtaining 14,15-monoepoxide represented by

The peracid used is, for example, a peracid used in usual epoxidation such as m-chloroperbenzoic acid, monoperphthalic acid, benzoic acid and peracetic acid. m-chloroperbenzoic acid, monoperphthalic acid, benzoic acid, peracetic acid and the like.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene and xylene. And methylene chloride, 1,
Halogenated hydrocarbons such as 2-dichloroethane and chloroform, more preferably methylene chloride and 1,2-dichloroethane.

The reaction is carried out at a temperature of from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of solvent used, but is usually from 10 minutes to 2 hours, preferably from 20 minutes to 1 hour.

After completion of the reaction, the target substance can be easily collected from the reaction mixture according to a conventional method. For example, insoluble materials are filtered off, the filtrate is diluted with a water-immiscible organic solvent, and sodium persulfate solution is added to decompose excess peracid. Then, it can be obtained by washing with water and distilling off the solvent.
Further, if necessary, it can be purified by a conventional method, for example, recrystallization, column chromatography and the like.

(Third Step)

[0038]

(II) → (I) In the third step, the compound having the general formula (II) obtained in the second step is treated with a silylating agent to open the epoxide, and then the 5-position, The 15-hydroxy-Δ13,14-milbemycin derivative represented by the above general formula (I) (wherein R has the same meaning as described above) is produced by removing the silyl protecting groups at the 7-position and 3-position hydroxyl groups. This is the step of performing

As the silylating agent for opening the epoxy group, a conventional silylating agent such as trimethylsilyl triflate or iodotrimethylsilane can be used, and preferably trimethylsilyl triflate or iodotrimethylsilane. .

This step can be performed in the presence of a deoxidizing agent.
desirable.

The deoxidizing agent is an organic base such as 2,6-lutidine, pyridine, 2,6-di-t-butylpyridine, triethylamine and the like.
Jin.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene and xylene; Methylene chloride, 1,2-
Halogenated hydrocarbons such as dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; nitriles such as acetonitrile; More preferably, they are toluene, methylene chloride and acetonitrile.

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

The reaction time varies depending mainly on the reaction temperature, the starting compound and the kind of the solvent used, but is usually from 20 minutes to 5 hours, preferably from 30 minutes to 4 hours.

After completion of the reaction, the target substance can be easily collected from the reaction mixture according to a conventional method. For example, it can be obtained by diluting the reaction mixture with a water-immiscible organic solvent, filtering off insolubles, washing with 1N hydrochloric acid, water, 4% sodium hydrogen carbonate and water in that order, and distilling off the solvent. . The silyl derivative of the target compound obtained by this operation can be subjected to the next desilyl step without further purification.

For the desilyl reaction in this step, for example, a normal desilyl reaction such as a method using tetrabutylammonium fluoride as a reagent can be used, but preferably, an acidic catalyst in a lower alcohol solvent is used. The processing is performed by

The acidic catalyst used is an organic acidic catalyst such as toluenesulfonic acid and methanesulfonic acid, and the like.
Preferably, they are toluenesulfonic acid and methanesulfonic acid.

The solvent used is a lower alcohol such as methanol or ethanol.

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

The reaction time varies depending mainly on the reaction temperature, the starting compound and the kind of the solvent used, but is usually from 5 minutes to 1 hour, preferably from 15 minutes to 25 minutes.

After completion of the reaction, the target substance can be easily collected from the reaction mixture according to a conventional method. For example, it can be obtained by diluting the reaction mixture with a water-immiscible organic solvent, washing with 4% sodium hydrogen carbonate and water in that order, and distilling off the solvent. Further, if necessary, it can be purified by a conventional method, for example, recrystallization, column chromatography and the like.

The compound represented by the general formula (I) produced according to the present invention can be obtained by subjecting the compound represented by the general formula (VI) to 5-oxo-13-ethermilbemycin according to the following fourth and fifth steps. Guided to derivatives.

(Fourth Step) In the fourth step, the milbemycin derivative represented by the general formula (I) produced in the third step is contacted with manganese dioxide in a solvent to obtain a compound of the general formula (V)

[0054]

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(Wherein R has the same meaning as described above). This is a process for producing a 5-oxo-15-hydroxymilbemycin derivative represented by the following formula:

Performing the reaction under a nitrogen stream is effective for shortening the reaction time.

The manganese dioxide used is preferably
Γ-type manganese dioxide described in JP-A-1-197487.

The solvent used in the reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene and xylene. And methylene chloride, 1,
Halogenated hydrocarbons such as 2-dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethylacetamide, hexa Amides such as methyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide; and more preferably, methylene chloride and 1,2-dichloroethane.

The reaction is carried out at a temperature of from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the kind of the solvent used, but is usually from 5 minutes to 5 hours, preferably from 30 minutes to 2 hours.

After completion of the reaction, the target substance can be easily collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering the reaction mixture to remove insolubles and distilling off the solvent from the filtrate. And if needed,
Purification can be performed by a conventional method, for example, recrystallization, column chromatography, or the like.

(Fifth Step) In this step, a 15-hydroxymilbemycin derivative having the general formula (V) is added to a strong organic acid, trifluoromethanesulfonic acid, in the presence of
General formula (VII)

[0063]

R ¹ OH (VII) wherein R ¹ is a C ₁ -C ₆ alkyl group [where the alkyl group is one to three identical or different substituents selected from Substituent Group B below] May be substituted. ], C ₃ ~
C ₆ cycloalkyl group [The cycloalkyl group may be substituted with 1 to 3 identical or different substituent (s) selected from Substituent Group A below. ]. By reacting the alcohol represented by｝, the compound represented by the general formula (VI)

[0064]

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(Wherein R and R ¹ have the same meanings as described above).

[Substituent group A] halogen atom, C ₁ -C ₃
Alkyl group, C ₁ -C ₃ alkoxy group, nitro group, cyano group.

[Substituent group B] halogen atom, C ₁ -C ₃
Alkyl group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₃
An alkoxy group, a C ₁ -C ₆ alkoxycarbonyl group, a nitro group, a cyano group, a phenyl group (the phenyl group is substituted with 1 to 3 identical or different substituents selected from Substituent Group C below) May be.).

[Substituent group C] halogen atom, C ₁ -C ₃
Alkyl group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₃
An alkoxy group, a C ₁ -C ₆ alkoxycarbonyl group, a nitro group, a cyano group, a group represented by the formula R ⁵ SO ₂ (R ⁶ ) N— (wherein R ⁵ is a C ₁ -C ₆ alkyl group; , R ⁶
Represents a hydrogen atom or a C ₁ -C ₃ alkyl group. ), C ₁
A heterocyclic ring containing at least one -C ₈ acylamino group, C ₁ -C ₆ alkoxycarbonylamino group or nitrogen atom.

In this step, since trifluoromethanesulfonic acid is used as a catalyst, no equivalent is required.

Further, when an inorganic compound powder is added to the reaction system, the reaction is promoted and good results are obtained. Examples of such inorganic compounds include metal salts such as copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, and nickel iodide, celite, silica gel, and alumina. Is a copper salt such as copper trifluoromethanesulfonate and cuprous iodide, most preferably copper trifluoromethanesulfonate or cuprous iodide.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. The alcohol itself represented by the general formula (VII) may be used as the solvent. Can also. Preferably, aromatic hydrocarbons such as benzene, toluene, xylene;
Halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide , Dimethylacetamide,
Examples include amides such as hexamethyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide.

The reaction is carried out at a temperature of from -10 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of the solvent used, but is usually 5 minutes to 2 hours, preferably 10 minutes to 1 hour.

After the completion of the reaction, the desired reaction product can be easily collected from the reaction mixture according to a conventional method. For example,
It can be obtained by diluting the reaction mixture with a water-immiscible organic solvent, filtering off insolubles, washing with 4% sodium hydrogen carbonate and water in that order, and distilling off the solvent. Further, if necessary, it can be purified by a conventional method, for example, recrystallization, column chromatography and the like.

The milbemycin derivative represented by the general formula (V) is a milbemycin derivative having trifluoromethanesulfonic acid as a catalyst.
It is extremely excellent as a raw material for synthesizing 3-ether-substituted derivatives. That is, since the milbemycin derivative represented by the general formula (V) is a ketone having a carbonyl group at the 5-position, it is extremely stable under acidic conditions using trifluoromethanesulfonic acid as a catalyst, and does not generate decomposition products. And the desired 13-ether compound can be obtained in high yield. Further, by treating the 13-ether compound with a reducing agent such as sodium borohydride, it can be easily converted to a 5-alcohol compound.

According to the present invention, 15-
The method for producing the hydroxymilbemycin derivative has a good yield and is superior to the conventional method in the following two points.

Conventionally, milbemycin itself or a compound in which only the hydroxyl group at the 5-position is protected is oxidized with a peracid to give 14,14.
Since 15-epoxide was obtained, the oxidized diepoxide was also produced as a by-product in the double bond at the 8-position and the 9-position, and the yield of the target monoepoxide was reduced. On the other hand, in the present invention, a monoepoxide can be selectively produced by epoxidation after protecting also the hydroxyl group at the 7-position with a silyl group. That is, the first point is that a monoepoxide can be selectively obtained.

For ring opening of the epoxy group, a silylating agent such as trimethylsilyl triflate or iodotrimethylsilane is used. That is, the second point is that the silylating agent is easily available and the post-treatment of the reaction is also easy.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0080]

【Example】

[0081]

Example 1 Preparation of 15-hydroxy-Δ13,14-milbemycin A ₄ Step A Imidazole (2.99 g) was dissolved in dichloromethane (88 ml), and chlorotrimethylsilane (5.60 ml) and milbemycin A ₄ (9.55 g) were added. In addition, after heating under reflux for 7 hours, the mixture was left at room temperature overnight. The reaction solution was filtered to remove insolubles, and the filtrate was washed with cold 0.1 M citric acid, then with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (88 ml), and 70% m-chloroperbenzoic acid (5.27 g) was added thereto under ice cooling, followed by stirring at the same temperature for 40 minutes. The reaction solution was filtered to remove insolubles, and the filtrate was washed with 10% sodium thiosulfate, 4% sodium hydrogen carbonate and water in that order, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 5,7-bistrimethylsilyl-
14,15-Epoxymilbemycin was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.13 (9H, s , CH 3 Si), 0.19 (9H, s, CH 3 Si), 1.77 (3H, s, C 4 -
CH ₃ ), 2.66 (1H, d, J = 8.8Hz, C ₁₅ -H), 3.81 (1H, d, J = 5.4Hz, C ₅
-H) This was used for the next step without purification.

Step B The epoxide obtained in the preceding step was dissolved in toluene (88 ml), 2,6-lutidine (6.14 ml) and trimethylsilyl triflate (5.10 ml) were added at -25 ° C, and the mixture was added at 4 ° C.
Stirred for hours. Cyclohexane (50 ml) was added to the reaction solution,
The filtrate was washed with 1N hydrochloric acid, water, 4% sodium hydrogen carbonate and water in that order, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Residue in methanol (230m
l) and dissolved in p-toluenesulfonic acid monohydrate (1.88
g) was added and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate (700 ml) was added to the reaction solution, washed with 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was subjected to column chromatography (silica gel,
Purification with ethyl acetate / cyclohexane = 1: 1) afforded the desired compound (9.38 g, 95.3%).

Mass spectrum m / e: 558 (M +, C ₃₂ H ₄₆ O ₈ ),
Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 1.88 (3H,
s, C ₄ -CH ₃ ), 4.03 (1H, d, J = 6.3Hz, C ₆ -H), 4.29 (1H, d, J = 1.5H
z, C ₅ -H), 5.15 (1H, d, J = 9.3Hz, C ₁₃ -H)

[0085]

Example 2 Preparation of 15-hydroxy-Δ13,14-milbemycin A ₃ Step A 4-Dimethylaminopyridine (1.525 g) was added to acetonitrile
(25 ml), chlorotrimethylsilane (1.590 ml) and milbemycin A ₄ (2.645 g) were added, and the mixture was stirred at 45 ° C. for 7 hours and left at room temperature overnight. The reaction mixture was filtered to remove insolubles, and the filtrate was washed twice with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (50 ml), 70% m-chloroperbenzoic acid (1.488 g) was added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. The reaction solution was filtered to remove insolubles, and the filtrate was washed with 10% sodium thiosulfate, 4% sodium hydrogen carbonate and water in that order, and dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, 5,7-bistrimethylsilyl-14,15-
To obtain an epoxy milbemycin A _3.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.13 (9H, s , CH 3 Si), 0.19 (9H, s, CH 3 Si), 1.78 (3H, s, C 4 -
CH ₃ ), 2.66 (1H, d, J = 8.8Hz, C ₁₅ -H), 3.82 (1H, d, J = 5.4Hz, C ₅
-H) This was used for the next step without purification.

Step B The epoxide obtained in Step A was dissolved in acetonitrile (25 ml), and at -30 ° C., 2,6-lutidine (1.74 ml) and iodotrimethylsilane (1.07 ml) were added. 25
Stir at 45 ° C. for 45 minutes. Cyclohexane (50 ml) was added to the reaction solution.
, And the filtrate was washed with 1N hydrochloric acid, water, 4% sodium hydrogen carbonate and water in that order, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Residue in methanol
(75 ml) and p-toluenesulfonic acid monohydrate
(0.25 g) was added and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate (300 ml) was added to the reaction solution, washed with 4% sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with ethyl acetate / cyclohexane = 1: 1) to give the desired compound (1.99 g, 74.5%).

Mass spectrum m / e: 544 (M +, C ₃₁ H ₄₄ O ₈ ),
Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 1.87 (3H,
s, C ₄ -CH ₃ ), 4.02 (1H, d, J = 6.3Hz, C ₆ -H), 5.14 (1H, d, J = 9.3H
z, C ₁₃ -H)

[0089]

[Reference example]

[0090]

Reference Example 1 Production of 5-oxo-15-hydroxy-Δ13,14-milbemycin A ₄ 15-hydroxy-Δ13,14-milbemycin A ₄ (9.38 g) obtained in Example 1 was treated with dichloromethane (150 ml). And manganese dioxide (53 g) was added thereto under ice cooling, followed by stirring at room temperature for 80 minutes under a nitrogen atmosphere. The insolubles are filtered off using Celite, and the filtrate is evaporated to dryness under reduced pressure to give the desired compound.
(8.6 g, 93.4%).

Mass spectrum m / e: 556 (M +, C ₃₂ H ₄₄ O ₈ ),
Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 1.
_{89 (3H, s, C 4} -CH3), 3.92 (1H,
_{s, C 6 -H), 4.08} (1H, d-d, J = 10.
_{8,4.4Hz, C 15 -H), 5.16} (1H, d,
J = _9.3Hz, C 13 -H)

[0092]

Reference Example 2 Production of 5-oxo-15-hydroxy-Δ13,14-milbemycin A ₃ 15-hydroxy-Δ13,14-milbemycin A ₃ (1.98 g) obtained in Example 2 was added to dichloromethane (30 ml). And manganese dioxide (11 g) was added thereto under ice cooling, followed by stirring at room temperature for 70 minutes under a nitrogen atmosphere. The insolubles are filtered off using Celite, and the filtrate is evaporated to dryness under reduced pressure to give the desired compound.
(1.76 g, 89.1%).

Mass spectrum m / e: 542 (M +, C ₃₁ H ₄₂ O ₈ ),
Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 1.88 (3H,
s, C ₄ -CH ₃ ), 3.92 (1H, s, C ₆ -H), 4.07 (1H, dd, J = 10.8,4.4H
z, C ₁₅ -H), 5.15 (1H, d, J = 9.3Hz, C ₁₃ -H)

[0094]

[Reference Example 3] 5-oxo-15-hydroxy -Δ13,14 - 13- from milbemycin A ₄ [2- (4-nitrophenyl) ethyloxy] production process A 4-nitro Fe milbemycin A ₄ phenethyl alcohol (4.35 g Was dissolved in 1,2-dichloroethane (25 ml), trifluoromethanesulfonic acid (0.770 ml) and cuprous iodide (1.05 g) were added, and the mixture was stirred at room temperature for 5 minutes. 5-oxo-15-hydroxy-Δ
13,14-Milbemycin A ₄ (3.00 g) was dissolved in 1,2-dichloroethane (5 ml) and added to the above mixture.
Stirred for minutes. Ethyl acetate (200 ml) was added to the reaction mixture, and the insolubles were filtered off using celite. The filtrate was washed with water, 4% sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate and dried under reduced pressure. Evaporated to dryness. The residue was purified by column chromatography (silica gel, eluted with ethyl acetate / hexane = 3: 7) to give 5-oxo-
13- [2- (4-Nitrophenyl) ethyloxy] milbemycin A ₄ (3.12 g, 82.5%) was obtained.

Mass spectrum m / e: 705 (M +, C ₄₀ H ₅₁ NO ₁₀ )
, Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 1.89 (3
H, s, C ₄ -CH ₃ ), 2.94 (2H, t, J = 6.3Hz, PhCH ₂ ), 3.20 (1H, d, J =
9.8 Hz, C ₁₃ -H), 3.84 (1H, s, C ₇ -OH), 3.93 (1H, s, C ₆ -H) Step B 5-oxo-13- [2- ( 4-nitrophenyl) ethyloxy] milbemycin A ₄ (0.200
g) was dissolved in methanol (7.6 ml), sodium borohydride (0.010 g) was added at −25 ° C., and the mixture was stirred for 20 minutes. Ethyl acetate (30 ml) was added to the reaction solution, washed twice with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with ethyl acetate / cyclohexane = 2: 8) to give 0.19
8 g of the desired compound were obtained.

Mass spectrum m / e: 707 (M +, C ₄₀ H ₅₃ NO ₁₀ )
, Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm):
_{1.87 (3H, s, C 4} -CH 3), 3.24 (1
_{H, d, J = 9.5Hz,} C 13 -H), 3.95 (1
H, d, J = 6.2 Hz, C ₆ -H)

Claims (3)

(57) [Claims] 1. A compound of the general formula (II) (Wherein R is a methyl group, an ethyl group, an isopropyl group or
It indicates sec- butyl group, a milbemycin derivative TMS is represented by showing a trimethylsilyl group), the silylating agent及
And the action of a deoxidizer, the resulting 15-silyl form is removed.
General formula (I) characterized by being silyl (Wherein, R has the same meaning as described above). 2. A compound of the general formula (III) (Wherein R is a methyl group, an ethyl group, an isopropyl group or
A milbemycin derivative represented by a sec-butyl group and TMS represents a trimethylsilyl group) is oxidized with a peracid to give a compound of the general formula (II): (Wherein, R and TMS have the same meanings as described above), and the epoxide compound was formed by reacting a silylating agent and a deoxidizing agent on the epoxide compound .
General formula (I) wherein the 15-silyl form is desilylated. (Wherein, R has the same meaning as described above). 3. A compound of the general formula (IV) (Wherein R is a methyl group, an ethyl group, an isopropyl group or
A silylating agent is allowed to act on a milbemycin derivative represented by the following formula: (Wherein, R has the same meaning as described above, and TMS represents a trimethylsilyl group). General formula (II) (Wherein, R and TMS have the same meanings as described above) .
General formula (I) wherein the 15-silyl compound is desilylated. (Wherein, R has the same meaning as described above).