JP2000044571A - Production of 13-ester derivatives of milbemycin compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely and efficiently obtain a 5-keto-13-ester derivative of a milbemycin compound by reacting a specific epoxy-ketomilbemycin compound with a silylating agent and subsequently reacting the reaction product with methoxyimino-phenylacetic acid in the presence of an acid. SOLUTION: This method for producing the 5-keto-13-ester derivative of a milbemycin of formula III comprises reacting a 14,15-epoxy-5-keto-milbemycin compound of formula I (R1 is methyl, ethyl or the like; R2 is H or trimethylsilyl) with a silylating agent preferably in an amount of 1.2-3.0 moles (equivalents) based on the compound of formula I preferably at -30 to 50 deg.C for 1-2 hr and subsequently reacting the obtained intermediate compound of formula II [R3 is H or a group of the formula: SiR4R5R6 (R4-R6 are each a 1-6C alkyl)] with 1.5-2 moles of 2-methoxyimino-2-phenylactic acid preferably in the presence of 0.1-0.8 mole of an acid preferably at 0-50 deg.C for 10 min to 5 hr without isolating or purifying the compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

Embedded image [In the formula, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group. And a method for producing a 5-keto-13-ester compound of a milbemycin represented by the formula:

[0003]

2. Description of the Related Art The fact that a milbemycin derivative having an ester group at the 13-position has an insecticidal activity and an anthelmintic effect is disclosed in, for example, JP-A-1-104078 and JP-A-5-255.
No. 343 and JP-A-8-259570.

With respect to the method for producing such 5-keto-13-ester derivatives, the following methods (a) and (b) are generally known. (A) A method of esterifying 13-hydroxy-5-ketomylbemycins by reacting with carboxylic acid or a reactive derivative thereof:
No. 4078 and JP-A-5-255343. The starting material for the production method is 13-hydroxy-5-ketomylbemycins. JP-A-61-1
No. 03884 describes a method for producing the starting material. The method described in the publication is firstly that the yield is 50% or less, secondly that toxic selenium dioxide is contained in the waste, and thirdly that the starting material 13-
Hydroxy-5-ketomylbemycins generally have problems such as being difficult to obtain. (B) A method of reacting 13,14-15-hydroxy-5-ketomilbemycins with a carboxylic acid in the presence of an acid catalyst to esterify.

The manufacturing method is described in, for example, Japanese Patent Application Laid-Open No.
No. 43 and JP-A-8-259570. Starting materials for the production method are: # 13, 14-15
-Hydroxy-5-ketomylbemycins. JP-A-60-158191 describes a method for producing the starting material. The method described in the publication firstly produces two reaction products and cannot selectively produce only the compound, secondly, the yield is about 50% or less, thirdly, The use of hydrazic acid, which is highly toxic and explosive, as a reagent for the reaction involves danger. Fourth, it is difficult to obtain 出 発 13,14-15-hydroxy-5-ketomylbemycins as starting materials. There are problems such as that.

[0006] For the above reasons, without the above problems,
There has been a need to establish a new method for producing a 5-keto-13-ester intermediate of milbemycins.

[0007]

The present inventors have conducted intensive studies on a method for producing a 13-ester derivative of a milbemycin represented by the above general formula (I).
After ring-opening the 5-epoxy-5-ketomylbemycin derivative with a silylating agent and then reacting it with a carboxylic acid in the presence of a strong acid without isolation or purification,
A method for safely and efficiently producing a 5-keto-13-ester derivative of milbemycins has been found, and the present invention has been completed.

[0008]

That is, the present invention provides:
(1) The following general formula (II)

[0009]

Embedded image [In the formula, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and R ² represents a hydrogen atom or a trimethylsilyl group. And the reaction of a 14,15-epoxy-5-ketomylbemycin compound represented by the following general formula (III)

[0010]

Embedded image [Wherein, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, R ² represents a hydrogen atom or a trimethylsilyl group, R ³ represents a hydrogen atom or a formula: SiR ⁴ R ⁵ R ⁶
(Wherein, R ⁴ , R ⁵ and R ⁶ each independently represent a C ₁ -C ₆ alkyl group). Is obtained without isolating or purifying the intermediate compound represented by the formula (2) in the presence of an acid.
-The following general formula (I) comprising reacting with phenylacetic acid

[0011]

Embedded image[Wherein, R¹Represents a methyl group, an ethyl group, an isopropyl group or
Represents a sec-butyl group. Milbemycin represented by
For the production of 5-keto-13-ester derivatives of the class
(2) In the production method described in (1), the compound represented by the general formula (III)
R of the compound represented by ^ThreeIs a trimethylsilyl group
Manufacturing method.

[0012]

DETAILED DESCRIPTION OF THE INVENTION The production method of the present invention relates to a 14,15-epoxy derivative of milbemycins (JP-A-6-22006).
No. 8) as a starting material and using the general formula (I)
A first step of deriving the intermediate compound represented by the general formula (III) from the compound represented by I), and converting the intermediate compound represented by the general formula (III) into the compound represented by the general formula (I) It comprises a second step of guiding.

In the compound represented by the general formula (I), the compound represented by the general formula (II) and the intermediate compound represented by the general formula (III), R ¹ represents a methyl group, an ethyl group, an isopropyl group. Or a sec-butyl group, preferably a methyl group or an ethyl group, and more preferably an ethyl group.

A compound represented by the general formula (III) (wherein, R ¹ represents a methyl group, ethyl group, isopropyl group or sec-butyl group, R ² represents a hydrogen atom or trimethylsilyl group, and R ³ represents Hydrogen atom or formula: SiR ⁴ R ⁵ R ⁶
(Wherein, R ⁴ , R ⁵ and R ⁶ each independently represent a C ₁ -C ₆ alkyl group). )
Milbemycin derivatives disclosed in JP-A-6-220068.

A compound represented by one of the R ³ substituents in the compound represented by the general formula (III): SiR ⁴ R ⁵ R
⁶ (wherein R ⁴ , R ⁵ and R ⁶ each independently represent a C ₁ -C ₆ alkyl group), “C ₁ -C ₆ alkyl group” means a methyl group, an ethyl group, A propyl group,
It is an isopropyl group, n-butyl group, isobutyl group, s-butyl group or t-butyl group, preferably a methyl group. (First step) In the first step, the epoxy group of the compound represented by the general formula (II) is opened in the presence of a silylating agent and a base to convert the compound into an allyl alcohol derivative represented by the general formula (III). This is the step of performing

The silylating agent used in the reaction includes trialkyl-substituted silyl trifluoromethanesulfonate [CF ₃ SO ₂ OSiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵ and R ⁶
Each independently represents a C _{1 to} C ₆ alkyl group)]
And the like, for example, trimethylsilyltrifluoromethanesulfonate, triethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate or t-butyldimethylsilyltrifluoromethanesulfonate and the like, preferably trimethylsilyltrifluoromethanesulfonate or t-
Butyldimethyltrifluoromethanesulfonate, more preferably trimethylsilyltrifluoromethanesulfonate.

The range of the amount of the silylating agent used in the reaction is usually from 1.0 to 1.2 molar equivalents at the lower limit and from 2.0 to 10 molar equivalents at the upper limit. The range is from 2 to 5.0 molar equivalents, and a more preferable range is from 1.2 to 3.0 molar equivalents. If necessary, such an amount of the silylating agent can be added to the reaction system in multiple portions.

The base used in the reaction is not particularly limited as long as it does not inhibit the reaction. For example, triethylamine, tributylamine, diethylisopropylamine, pyridine, 2,6-lutidine, 2,6-di- t-butylpyridine, 1,4-diazabicyclo [2,
2,2] octane, 1,8-diazabicyclo [5,4,
Organic amines such as 0] -7-undecene; amides such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide; alkali metals such as sodium and lithium; alkalis such as sodium hydroxide and potassium hydroxide. Metal base and the like, preferably triethylamine, tributylamine, diethylisopropylamine, pyridine, 2,6-lutidine, 2,6-di-
t-butylpyridine, 1,4-diazabicyclo [2,
2,2] octane, 1,8-diazabicyclo [5,4,
Organic amines such as [0] -7-undecene, and more preferably 2,6-lutidine.

The amount of the base used in the reaction depends on the amount of the silylating agent used and the like.
In the range, the lower limit is 1.0 to 2.0 molar equivalents, and the upper limit is 6.0 to 10 molar equivalents, and the preferred range is 2.0 to 6.0 molar equivalents.

The solvent used for the reaction is not particularly limited as long as it is a solvent which stably dissolves the reactants and products and does not inhibit the reaction. Examples thereof include n-hexane, cyclohexane, methylcyclohexane, petroleum ether. Hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane; ethers such as ethyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxyethane. Esters such as ethyl acetate and propyl acetate; N, N-dimethylformamide, N, N-
Amides such as dimethylacetamide; sulfoxides such as dimethylsulfoxide; nitriles such as acetonitrile and propionitrile; and mixtures containing two or more selected from these, preferably Methylcyclohexane, toluene and the like, hydrocarbons such as halogenated hydrocarbons; halogenated hydrocarbons such as methylene chloride, or a mixture containing two or more selected from these, more preferably methylcyclohexane,
Methylene chloride or a mixture thereof.

The lower limit of the reaction temperature range is from -50 to -3.
0 ° C., the upper limit is 50 to 100 ° C., and the preferred range is −
30 to 50 ° C.

The reaction time depends on the reaction temperature, the silylating agent used in the reaction, the base and the solvent, etc., and the range is as follows: the lower limit is 1 hour, the upper limit is 2 to 12 hours, and the preferred range is One to two hours.

After completion of the reaction, the intermediate compound represented by the above general formula (III) can be collected from the reaction mixture by a conventional method. For example, after completion of the reaction, the reaction solution is washed by 1N hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water in the order of liquid-liquid distribution using a separating funnel, and the solvent is distilled off by concentration. . The concentration method is not particularly limited as long as it is a method of concentrating a liquid, and examples thereof include air drying, normal pressure concentration, reduced pressure concentration, and distillation, and preferably reduced pressure concentration. The concentration under reduced pressure can be performed by combining a pump, a rotary evaporator, a flask for the evaporator, a water bath-type constant temperature bath, and the like, and the compound can be obtained in a state where the compound is dried in the flask. The obtained intermediate compound can be used for the next step without isolation or purification. (Second step) In the second step, the intermediate compound represented by the general formula (III) obtained in the first step is converted into a compound in the presence of an acid.
This is a step of producing a 5-keto-13-ester derivative of a milbemycin represented by the general formula (I) by reacting with 2-methoxyimino-2-phenylacetic acid.

2-methoxyimino-2 used in the reaction
The range of the amount of phenylacetic acid is from 1 to 1.5 molar equivalents at the lower limit and from 2 to 20 molar equivalents at the upper limit, and a preferred range is from 1.5 to 2 molar equivalents.

The acid used in the reaction is not particularly limited as long as it is an acid usually used in a chemical reaction. For example, an inorganic acid such as sulfuric acid or hydrochloric acid, or trifluoroacetic acid, trifluoromethanesulfonic acid or benzene Sulfonic acid, organic acids such as parachlorobenzenesulfonic acid can be mentioned, preferably trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, organic acids such as parachlorobenzenesulfonic acid, more preferably It is trifluoromethanesulfonic acid.

The amount of the acid used in the reaction depends on the kind of the acid and the like, and the range is from 0.01 to 0.1 molar equivalent at the lower limit and from 0.8 to 0.9 molar equivalent at the upper limit. The preferred range is from 0.1 to 0.8 molar equivalents.

When a powder of an inorganic compound is added to the reaction system, the reaction may be accelerated. In the production method of the present invention, a powder of such an inorganic compound may be added as necessary. The inorganic compound is not particularly limited as long as it is an inorganic compound usually added for accelerating the reaction.For example, copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, nickel iodide Such metal salts, celite, silica gel, alumina and the like can be mentioned, preferably copper trifluoromethanesulfonate,
It is a copper salt such as cuprous iodide, more preferably cuprous iodide.

The solvent used for the reaction is not particularly limited as long as it is a solvent which stably dissolves the reactants and products and does not inhibit the reaction. Examples thereof include n-hexane, petroleum ether, cyclohexane and methylcyclohexane. Hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; esters such as ethyl acetate and propyl acetate; diethyl ether, tetrahydrofuran, dioxane; Ethers such as dimethoxyethane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide: nitriles such as acetonitrile and propionitrile; Mixtures containing the above can be mentioned, and hydrocarbons such as petroleum ether, cyclohexane, methylcyclohexane, and toluene; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; It is a mixture containing two or more selected, more preferably methylcyclohexane, methylene chloride or a mixture thereof.

The lower limit of the reaction temperature is from -10 to 0.
℃, the upper limit is 50 to 100 ℃, preferably 0 to 5
0 ° C.

The reaction time depends on the reaction temperature, the acid used in the reaction, the solvent, the inorganic additive, and the like.
The lower limit is 5 to 10 minutes and the upper limit is 5 to 10 hours, preferably 10 minutes to 5 hours.

After completion of the reaction, the target compound represented by the above general formula (I) can be collected from the reaction mixture by a conventional method. For example, after completion of the reaction, the reaction solution is obtained by washing the reaction solution in the order of water, an aqueous solution of sodium hydrogen carbonate and water by liquid-liquid distribution using a separating funnel, and distilling off the solvent by concentration. The concentration method is not particularly limited as long as it is a method for concentrating a liquid in general, and includes, for example, air drying, normal pressure concentration, reduced pressure concentration and distillation, and preferably reduced pressure concentration. As described above, the compound can be obtained in a dried state by concentration under reduced pressure.

The target compound represented by the above general formula (I) obtained by the reaction can be further purified, if necessary, by means such as column chromatography.

The carrier to be packed in the column for column chromatography is not particularly limited as long as it is a carrier usually used for purifying an organic compound, and examples thereof include silica gel, C18 reverse phase gel, alumina, activated carbon and the like. And preferably silica gel.

The behavior of the target compound can be tracked based on a quantitative analysis by high performance liquid chromatography. The quantitative analysis method can also be applied to the determination of the purity of a compound.

[0035]

The present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to these examples. Example 1. Preparation of 13- (α-methoxyiminophenylacetoxy) -5-ketomylbemycin A4 (First step) 0.92 g (1.67 mmol) of 14,15-epoxy-5-ketomylbemycin A4 was added to methylene chloride 1 In a mixed solvent of 0.5 ml and 10.9 ml of methylcyclohexane, and the mixture was dissolved in 2,6-
1.16 ml (9.96 mmol) of lutidine was added and stirred for 1 hour. To this was added 0.64 ml (3.33 mmol) of trimethylsilyl trifluoromethanesulfonate,
For 1 hour. Further, 0.32 ml (1.67 mmol) of trimethylsilyltrifluoromethanesulfonate was added, and the mixture was stirred at 0 to 5 ° C. for 1 hour. The reaction solution is water, 10%
The mixture was washed with a sulfuric acid aqueous solution, water, a 5% aqueous sodium hydrogen carbonate solution and water in this order by a liquid-liquid distribution method, and concentrated under reduced pressure using an evaporator to obtain 1.42 g of a crude intermediate compound. The crude product was used in the next second step without purification. (Second step) 1.42 g of a crude intermediate compound was dissolved in 10 ml of methylene chloride, and methylene chloride containing 511 mg (2.85 mmol) of α-methoxyiminophenylacetic acid and 0.063 ml (0.71 mmol) of trifluoromethanesulfonic acid was used. To 15 ml of the solution was added dropwise at 0 to 5 ° C under an argon stream, and the mixture was stirred at 0 to 5 ° C for 3 hours. The reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order by a liquid-liquid partition method, dried over magnesium sulfate, and concentrated under reduced pressure using an evaporator to distill off the solvent.

The residue was dissolved in a mixed solution of n-hexane / ethyl acetate (90:10), added to a silica gel column equilibrated with a mixed solution of n-hexane / ethyl acetate (90:10), and the compound was added to the column. And a stepwise gradient of an n-hexane-ethyl acetate mixed solution (from 10 to 50% of ethyl acetate in n-hexane to 1%).
Increase stepwise by 0%. ), And the solvent was distilled off from the eluted fraction containing the target compound by concentration under reduced pressure using an evaporator to obtain 0.99 g (82.1%) of the target compound. Example 2. Preparation of 13- (α-methoxyiminophenylacetoxy) -5-ketomylbemycin A4 (first step) 4.60 g (8.4 mmol) of 14,15-epoxy-5-ketomylbemycin A4 was treated with methylene chloride. 5 ml and 54.5 ml of methylcyclohexane in a mixed solvent.
5.80 ml (49.8 mmol) of lutidine was added and stirred for 1 hour. To this, 3.2 ml (16.7 mmol) of trimethylsilyltrifluoromethanesulfonate was added, and the mixture was stirred at 0 to 5 ° C. for 1 hour. Further, 1.60 ml (8.3 mmol) of trimethylsilyltrifluoromethanesulfonate was added, and the mixture was stirred at 0 to 5 ° C. for 1 hour. The reaction solution is water, 10%
The mixture was washed with a sulfuric acid aqueous solution, water, a 5% aqueous sodium hydrogen carbonate solution and water in that order by a liquid-liquid distribution method, and concentrated under reduced pressure using an evaporator to obtain 7.10 g of a crude intermediate compound. The crude product was used in the next second step without purification. (Second step) 7.10 g of a crude intermediate compound and α-
Methoxyiminophenylacetic acid (2.55 g, 14.3 mmol) was dissolved in methylene chloride (100 ml), and trifluoromethanesulfonic acid (0.32 ml, 0.71 mmol) was added dropwise at 0 to 5 ° C under an argon stream, followed by stirring at 0 to 5 ° C for 5 hours. did.
The reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order by a liquid-liquid partition method, dried over magnesium sulfate, and concentrated under reduced pressure using an evaporator to distill off the solvent.

The residue was dissolved in a mixed solution of n-hexane / ethyl acetate (90:10), added to a silica gel column equilibrated with a mixed solution of n-hexane / ethyl acetate (90:10), and the compound was added to the column. And a stepwise gradient of an n-hexane-ethyl acetate mixed solution (from 10 to 50% of ethyl acetate in n-hexane to 1%).
Increase stepwise by 0%. ), And the eluted fraction containing the target compound was concentrated under reduced pressure using an evaporator to distill off the solvent, thereby obtaining 5.06 g (84.0%) of the target compound. Example 3.1 Preparation of 13- (α-methoxyiminophenylacetoxy) -5-ketomylbemycin A3 (First step) 15.5 g (28.6 mmol) of 14,15-epoxy-5-ketomylbemycin A3 was added to methylene chloride 26. 2.0 ml and 187.5 ml of methylcyclohexane
In a mixed solvent of 0 to 5 ° C. under a nitrogen stream at 2,
20.0 ml (171.4 mmol) of 6-lutidine was added and stirred for 1 hour. Further, 11.0 ml (57.1 mmol) of trimethylsilyltrifluoromethanesulfonate was added,
The mixture was stirred at 乃至 5 ° C. for 1 hour. Further, 2.3 ml (11.9 mmol) of trimethylsilyltrifluoromethanesulfonate was added, and the mixture was stirred at 0 to 5 ° C. for 1 hour. The reaction solution was washed by a liquid-liquid distribution method in the order of water, a 10% aqueous sulfuric acid solution, water, a 5% aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure using an evaporator to obtain a crude product 1 of the intermediate compound.
9.7 g were obtained. The crude product was used in the next second step without purification. (Second step) 19,7 g of a crude intermediate compound and α-
9.14 g (51.1 mmol) of methoxyiminophenylacetic acid was added to 105 ml of methylene chloride and 245 of methylcyclohexane.
The mixture was dissolved in 1 ml of a mixed solvent, and 1.13 ml (12.8 mmol) of trifluoromethanesulfonic acid was added dropwise at 0 to 5 ° C under an argon stream, followed by stirring at 0 to 5 ° C for 3 hours and 30 minutes. The reaction solution was washed by a liquid-liquid partitioning method in the order of water, a 5% aqueous sodium hydrogen carbonate solution and water, and dried over magnesium sulfate.
The solvent was distilled off by concentration under reduced pressure using an evaporator.

The residue was dissolved in a mixed solution of n-hexane and ethyl acetate (90:10), added to a silica gel column equilibrated with a mixed solution of n-hexane and ethyl acetate (90:10), and the compound was added to the column. And a stepwise gradient of an n-hexane-ethyl acetate mixed solution (from 10 to 50% of ethyl acetate in n-hexane to 1%).
Increase stepwise by 0%. ) And eluted fractions containing the target compound were concentrated under reduced pressure using an evaporator to distill off the solvent, thereby obtaining 17.3 g (86%) of the target compound.

[0039]

According to the production method of the present invention, 5-keto-13 of milbemycins represented by the aforementioned general formula (I) is obtained.
-An ester derivative could be produced efficiently.

Further, the compound represented by the general formula (I) is disclosed in JP-A-6-220068 or JP-A-8-259.
By performing a reduction reaction according to the method described in JP-A-570-570, the following general formula (IV) having excellent insecticidal activity

[0041]

Embedded image [Wherein, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, R ⁷ represents a hydrogen atom or a lower alkyl group, A represents a substituted heterocyclic group or a substituted C _{6 to} C
Represents a ₁₀ aryl group, m and n each independently represent 0 or 1, and are not 0 at the same time. The compound described in JP-A-8-259570, which is represented by the general formula (IV), can be obtained.
Is useful for industrially producing the compound represented by

Claims (2)

[Claims] 1. A compound represented by the following general formula (II): [In the formula, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and R ² represents a hydrogen atom or a trimethylsilyl group. A 15,15-epoxy-5-ketomylbemycin compound represented by the following general formula (III): [Wherein, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, R ² represents a hydrogen atom or a trimethylsilyl group, R ³ represents a hydrogen atom or a formula: SiR ⁴ R ⁵ R ⁶
(Wherein, R ⁴ , R ⁵ and R ⁶ each independently represent a C ₁ -C ₆ alkyl group). Is obtained without isolating or purifying the intermediate compound represented by the formula (2) in the presence of an acid.
-Reacting with phenylacetic acid, represented by the following general formula (I): [In the formula, R ¹ represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group. A method for producing a 5-keto-13-ester derivative of a milbemycin represented by the formula: 2. The method according to claim 1, wherein R ^{3 of the} compound represented by the general formula (III) is a trimethylsilyl group.