KR100612634B1 - Process for producing 13-ester derivatives of milbemycins - Google Patents

Abstract

The present invention is represented by the following general formula (I):

[Formula I]

In the formula, R ¹ is a methyl group, ethyl group, isopropyl group or sec-butyl group.

The compound represented by the general formula (I) is useful as an intermediate for synthesizing a compound having excellent insecticidal activity.

Description

Process for producing 13-ester derivatives of milbamycins {PROCESS FOR PRODUCING 13-ESTER DERIVATIVES OF MILBEMYCINS}

The present invention is represented by the following general formula (I):

R <^1> is a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group in formula. It is related with the manufacturing method of the 5-keto-13-ester compound of the mildew mycins.

Milvemycin derivatives having an ester group at the 13-position have insecticidal activity and antiparasitic action are disclosed in, for example, Japanese Patent Application Laid-Open Nos. 1-04078, 5-255343 and 8-259570.

About the manufacturing method of such a 5-keto-13-ester derivative, the method of (A) and (B) shown next is known broadly.

(A) A method of esterifying 13-hydroxy-5-ketomylbemycins by reacting them with carboxylic acids or reactive derivatives thereof; this preparation method is disclosed in, for example, Japanese Patent Nos. 1-040-078 and 5-255343. have. Starting materials for this production process are 13-hydroxy-5-ketomylbemycins. No. 61-103884 describes the preparation of this starting material. The method described in this publication firstly yields 50% or less, secondly, that toxic selenium dioxide is contained in the waste, and thirdly, 13-hydroxy-5-ketomylbemycins, starting materials, are generally available. It has such problems as difficulty.

(B) A method of esterifying Δ13,14-15-hydroxy-5-ketomylbemycin by reacting with carboxylic acid in the presence of an acid catalyst.

This preparation method is disclosed, for example, in Japanese Patent Nos. 5-255343 and 8-259570. Starting materials of this production method are Δ13,14-15-hydroxy-5-ketomylbemycin. 60-158191 describes the preparation of this starting material. The method described in this publication firstly generates two reaction products to selectively produce only compounds, second, yield is about 50% or less, and third, toxic and explosive azide hydrofluoric acid is used as a reagent for the reaction. Fourth, there is a problem in that it involves risks, and fourth, starting materials? 13,14-15-hydroxy-5-ketomylbemycins are difficult to obtain.

For the above reason, the establishment of a new manufacturing method of the 5-keto- 13-ester intermediate of the milbemycins which does not accompany the said problem is requested | required.

An object of the present invention is to provide a safe and efficient method for producing a 5-keto-13-ester derivative of milbamycin represented by the general formula (I).

Disclosure of the Invention

The present invention is represented by the following general formula (II):

A silylating agent of a 14,15-epoxy-5-ketomylbemycin compound represented by [wherein R ¹ is a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and R ² is a hydrogen atom or a trimethylsilyl group] Reacted with the following general formula (III):

[Wherein, R ¹ is a methyl group, ethyl group, isopropyl group or sec-butyl group, R ² is hydrogen atom or trimethylsilyl group, R ³ is hydrogen atom or formula: SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵ and R ⁶ are each independently a group represented by C ₁ to C ₆ alkyl group.). An intermediate compound represented by the following formula is obtained, and the intermediate compound is isolated or purified in the presence of an acid without being isolated or purified. The following general formula (I) consisting of reacting with -methoxyimino-2-phenylacetic acid:

[Formula I]

In the formula, R ¹ is a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group.

Moreover, this invention relates to the manufacturing method whose R <^3> of the compound represented by General formula (III) is a trimethylsilyl group in the manufacturing method mentioned above.

The production method of the present invention uses a 14,15-epoxy body (see Japanese Patent Application Laid-Open No. 6-220068) of Milbemycin as a starting material, and the above general formula (III) in the compound represented by the above general formula (II) And a second step of guiding the intermediate compound represented by &lt; RTI ID = 0.0 &gt;) and &lt; / RTI &gt; to the compound represented by the above general formula (I) from the intermediate compound represented by the general formula (III).

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 is a methyl group, an ethyl group, an isopropyl group or sec- It is a butyl group, Preferably it is a methyl group or an ethyl group, More preferably, it is an ethyl group.

A compound represented by the above general formula (III) (wherein R ¹ is a methyl group, ethyl group, isopropyl group or sec-butyl group, R ² is a hydrogen atom or a trimethylsilyl group, R ³ is a hydrogen atom or a formula: SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵ and R ⁶ are each independently represented by a C ₁ to C ₆ alkyl group) is a Milbemycin disclosed in Japanese Unexamined Patent Publication No. 6-220068. Derivatives.

In formula: SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵ and R ⁶ each independently represents a C ₁ to C ₆ alkyl group) which is one of the R ³ substituents in the compound represented by the general formula (III). in, "C ₁ to C ₆ alkyl group" include a methyl group, an ethyl group, n- propyl, isopropyl, n- butyl, isobutyl, s- butyl or t- butyl group, preferably a methyl group.

(First process)

The first step is a step of converting the epoxy group of the compound represented by the general formula (II) into an allyl alcohol derivative represented by the general formula (III) by ring opening in the presence of a silylating agent and a base.

Examples of the silylating agent used in the reaction include trialkyl substituted silyltrifluoromethanesulfonate [CF ₃ SO ₂ OSiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵ and R ⁶ are each independently C ₁ to C _6). Alkyl group); and the like, for example, trimethylsilyltrifluoromethanesulfonate, triethylsilyltrifluoromethanesulfonate, triisopropylsilyltrifluoromethanesulfonate or t-butyldimethylsilyltrifluoro Methanesulfonate or the like, preferably trimethylsilyltrifluoromethanesulfonate or t-butyldimethylsilyltrifluoromethanesulfonate, and more preferably trimethylsilyltrifluoromethanesulfonate.

The amount of the silylating agent used in the reaction is usually in the range of 1.0 to 1.2 molar equivalents, 2.0 to 10 molar equivalents, with a preferred range of 1.2 to 5.0 molar equivalents, and more preferably 1.2 to 3.0 molar equivalents. It is equivalent. This amount of silylating agent may be added to the reaction system in several portions if necessary.

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

The amount of the base used for the reaction depends on the amount of the silylating agent or the like, but with respect to the silylating agent, the range is usually 1.0 to 2.0 molar equivalents, the upper limit is 6.0 to 10 molar equivalents, and the preferred range is 2.0 to 6.0 molar equivalents. to be.

The solvent used for the reaction is not particularly limited as long as it stably dissolves the reactants and products while not inhibiting the reaction. For example, hydrocarbons such as n-hexane, cyclohexane, methylcyclohexane, petroleum ether, benzene, toluene, and xylene Ryu; 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; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Nitriles such as acetonitrile and propionitrile, or mixtures containing two or more selected from these, and hydrocarbons such as methylcyclohexane and toluene; Halogenated hydrocarbons such as methylene chloride, or a mixture containing two or more selected from them, more preferably methylcyclohexane, methylene chloride or a mixture thereof.

The lower limit is -50 to -30 degreeC, the upper limit of the range of reaction temperature is 50-100 degreeC, and a preferable range is -30-50 degreeC.

The reaction time depends on the reaction temperature, the silylating agent used for the reaction, the base and the dissolution and the like, but the range is 1 hour, the upper limit is 2 to 12 hours, and the preferred range is 1 to 2 hours.

After completion of the reaction, the intermediate compound represented by the general formula (III) can be taken from the reaction mixture according to the conventional method. For example, after completion of the reaction, the reaction solution is washed with liquid-liquid distribution using a separating funnel in the order of 1 N hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, and concentrated to distill off the solvent. The concentration method is not particularly limited as long as it is a method of concentrating a liquid in general, and is, for example, natural drying, atmospheric pressure concentration, reduced pressure concentration and distillation, and the like. Concentration under reduced pressure can be performed in combination with a pump, a rotary evaporator, a flask for evaporate, a water bath, and the like, and the compound can be obtained in a dry state in this flask. The obtained intermediate compound can be used in the next step without isolation or purification.

(Second process)

In the second process, the intermediate compound represented by the general formula (III) obtained in the first process is reacted with 2-methoxyimino-2-phenylacetic acid in the presence of an acid to express milbamycin represented by the general formula (I). It is a process of preparing the 5-keto-13-ester derivative | guide_body.

The range of the amount of 2-methoxyimino-2-phenylacetic acid used for reaction has a lower limit of 1 to 1.5 molar equivalents, an upper limit of 2 to 20 molar equivalents, and a preferable range of 1.5 to 2 molar equivalents.

The acid used in the reaction is not particularly limited as long as it is an acid normally used in chemical reactions, but for example, an inorganic acid such as sulfuric acid or hydrochloric acid, or an organic acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, parachlorobenzenesulfonic acid, etc. These are mentioned, Preferably they are organic acids, such as a trifluoroacetic acid, a trifluoromethanesulfonic acid, benzenesulfonic acid, and a parachlorobenzene sulfonic acid, More preferably, they are a trifluoromethanesulfonic acid.

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

The addition of an inorganic compound powder to the reaction system can promote the reaction. In the production method of the present invention, if necessary, a powder of such an inorganic compound may be added.

The inorganic compound is not particularly limited as long as it is an inorganic compound which is usually added to accelerate the reaction. For example, copper trifluoromethanesulfonic acid, cuprous iodide, zinc iodide, cobalt iodide, nickel iodide, celite, silica gel, Alumina etc. are mentioned, Preferably it is copper salt like copper trifluoromethanesulfonic acid and the cuprous iodide, More preferably, it is cuprous iodide.

The solvent used for the reaction is not particularly limited as long as it stably dissolves the reactants and products while not inhibiting the reaction. For example, hydrocarbons such as n-hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, and xylene Ryu; Halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chloroform; Esters such as ethyl acetate and propyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide; Nitriles such as acetonitrile and propionitrile; Or mixtures containing two or more selected from these, and hydrocarbons such as petroleum ether, cyclohexane, methylcyclohexane and toluene; Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; Or a mixture containing two or more selected from these, more preferably methylcyclohexane, methylene chloride or a mixture thereof.

The range of reaction temperature is -10-0 degreeC with a minimum, 50-100 degreeC with an upper limit, Preferably it is 0-50 degreeC.

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

After completion of the reaction, the target compound represented by the general formula (I) can be collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the reaction solution is obtained by washing with liquid-liquid distribution using a separating funnel in the order of water, aqueous sodium bicarbonate solution and water, and distilling off the solvent by concentration. The concentration method is not particularly limited as long as it is a method of concentrating a liquid in general, and is, for example, natural drying, atmospheric pressure concentration, reduced pressure concentration and distillation, and the like. The compound can be obtained in a dried state as described above by vacuum concentration.

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

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

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

Best Mode for Carrying Out the Invention

Although an Example is given to the following and this invention is demonstrated in more detail, this invention is not limited to this.

Example 1

Preparation of 13- (α-methoxyiminophenylacetoxy) -5-ketomylbemycin A4

(First process)

0.92 g (1.67 mmol) of 14,15-epoxy-5-ketomylbemycin A4 was dissolved in a mixed solvent of 1.5 ml of methylene chloride and 10.9 ml of methylcyclohexane, and then 2,6-lutidine at 0 to 5 DEG C under a nitrogen stream. 1.16 mL (9.96 mmol) is added and stirred for 1 hour. 0.64 mL (3.33 mmol) of trimethylsilyltrifluoromethanesulfonate was added to this, and it stirred at 0-5 degreeC for 1 hour. Further, 0.32 ml (1.67 mmol) of trimethylsilyltrifluoromethanesulfonate is added and stirred at 0 to 5 ° C for 1 hour. The reaction solution was washed with water, a 10% aqueous sulfuric acid solution, a 5% aqueous sodium hydrogen carbonate solution and water in the order of liquid-liquid distribution, and 1.42 g of a crude product of an intermediate compound was obtained by vacuum concentration using an evaporator. The crude product is used in the next second step without purification.

(Second process)

1.42 g of the crude product of the intermediate compound was dissolved in 10 ml of methylene chloride, and 15 ml of methylene chloride solution containing 511 mg (2.85 mmol) of α-methoxyiminophenylacetic acid and 0.063 ml (3.62 mmol) of trifluoromethanesulfonic acid. And dropwise at 0 to 5 ° C under argon stream, and stirred at 0 to 5 ° C for 3 hours. The reaction solution was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in the order of liquid-liquid distribution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure using an evaporator.

The residue was dissolved in an n-hexane-ethyl acetate mixed solution (90:10), added to a silica gel column equilibrated with an n-hexane-ethyl acetate mixed solution (90:10), and the compound was adsorbed to this column to obtain n. Eluting with a stepwise gradient of ethyl-hexane-ethyl acetate solution (increasing ethyl acetate in steps of 10 to 50% in n-hexane in steps of 10%) and eluting fractions containing the desired compound were evaporated. The solvent is distilled off by concentration under reduced pressure using to obtain 0.99 g (82.1%) of the target compound.

Example 2

Preparation of 13- (α-methoxyiminophenylacetoxy) -5-ketomylbemycin A4

(First process)

4.60 g (8.4 mmol) of 14,15-epoxy-5-ketomylbemycin A4 is dissolved in a mixed solvent of 7.5 ml of methylene chloride and 54.5 ml of methylcyclohexane, and is dissolved in a nitrogen stream at 2,6-ruti at 0 to 5 캜. 5.80 ml (49.8 mmol) of Dean were added and stirred for 1 hour. 3.2 ml (16.7 mmol) of trimethylsilyltrifluoromethanesulfonate was added to this, and it stirred at 0-5 degreeC for 1 hour. Furthermore, 1.60 mL (8.3 mmol) of trimethylsilyltrifluoromethanesulfonate is added, and it stirred at 0-5 degreeC for 1 hour. The reaction solution was washed with water, a 10% aqueous sulfuric acid solution, water, a 5% aqueous sodium bicarbonate solution and water in the order of liquid-liquid distribution, and 7.10 g of a crude product of the intermediate compound was obtained by vacuum concentration using an evaporator. . The crude product is used in the next second step without purification.

(Second process)

7.10 g of the crude product of the intermediate compound and 2.55 g (14.3 mmol) of α-methoxyiminophenylacetic acid were dissolved in 100 ml of methylene chloride, and 0.32 ml (0.71 mmol) of trifluoromethanesulfonic acid was dried at 0 to 5 DEG C under an argon stream. It is added dropwise and stirred at 0 to 5 ° C for 5 hours. The reaction solution was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in the order of liquid-liquid distribution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure using an evaporator.

The residue was dissolved in an n-hexane-ethyl acetate mixed solution (90:10), added to a silica gel column equilibrated with an n-hexane-ethyl acetate mixed solution (90:10), and the compound was adsorbed to this column to obtain n. Eluted with a step gradient of -hexane-ethyl acetate mixed solution (increased ethyl acetate in steps of 10 to 50% in n-hexane by 10%), and the elution fraction containing the target compound was evaporated using an evaporator. The solvent is distilled off by concentration under reduced pressure to obtain 5.06 g (84.0%) of the target compound.

Example 3

Preparation of 13- (α-methoxyiminophenylacetoxy) -5-ketomylbemycin A3

(First process)

15.5 g (28.6 mmol) of 14,15-epoxy-5-ketomylbemycin A3 is dissolved in a mixed solvent of 26.0 ml of methylene chloride and 187.5 ml of methylcyclohexane, and 2,6-lutidine at 0 to 5 DEG C under a nitrogen stream. 20.0 mL (171.4 mmol) is added and stirred for 1 hour. Furthermore, 11.0 ml (57.1 mmol) of trimethylsilyltrifluoromethanesulfonate was added, and it stirred at 0-5 degreeC for 1 hour. Furthermore, 2.3 ml (11.9 mmol) of trimethylsilyltrifluoromethanesulfonate is added, and it stirred at 0-5 degreeC for 1 hour. The reaction solution was washed with a liquid-liquid distribution method in the order of water, an aqueous 10% sulfuric acid solution, an aqueous 5% sodium bicarbonate solution, and water, and then 19.7 g of a crude product of an intermediate compound was obtained by vacuum concentration using an evaporator. The crude product is used in the next second step without purification.

(Second process)

19.7 g of the crude product of the intermediate compound and 9.14 g (51.1 mmol) of α-methoxyiminophenylacetic acid were dissolved in a mixed solvent of 105 ml of methylene chloride and 245 ml of methylcyclohexane, and 1.13 ml (12.8 mmol) of trifluoromethanesulfonic acid Is added dropwise at 0? 5 占 폚 under argon stream, and stirred at 0? 5 占 폚 for 3 hours 30 minutes. The reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution, and then water by liquid-liquid partitioning, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure using an evaporator.

The residue was dissolved in an n-hexane-ethyl acetate mixed solution (90:10), added to a silica gel column equilibrated with an n-hexane-ethyl acetate mixed solution (90:10), and the compound was adsorbed to this column to obtain n. Eluted with a step gradient of -hexane-ethyl acetate mixed solution (increased ethyl acetate in steps of 10 to 50% in n-hexane by 10%), and the elution fraction containing the target compound was evaporated using an evaporator. The solvent is distilled off by concentration under reduced pressure, to obtain 17.3 g (86%) of the target compound.

By the production method of the present invention, 5-keto-13-ester derivatives of milbemicins represented by the general formula (I) can be efficiently produced.

Furthermore, the following general formula (IV) having excellent insecticidal activity by carrying out the reduction reaction of the compound represented by the above general formula (I) according to the method described in JP-A-6-220068 or JP-A-8-259570:

[Wherein R ¹ is a methyl group, ethyl group, isopropyl group or sec-butyl group, R ⁷ is a hydrogen atom or a lower alkyl group, A is a substituted heterocyclic group or a substituted C6 to C10 aryl group, m and n are Since each compound represents 0 or 1 independently and cannot be 0 at the same time.], The production method of the present invention is useful for industrially producing the compound represented by the general formula (IV). .

Claims (2)

The following general formula (II): [Formula II]

A silylating agent of a 14,15-epoxy-5-ketomylbemycin compound represented by [wherein R ¹ is a methyl group, an ethyl group, an isopropyl group or a sec-butyl group, and R ² is a hydrogen atom or a trimethylsilyl group] Silylation using trialkylsilyltrifluoromethanesulfonate as the following general formula (III): [Formula III]

[Wherein, R ¹ is a methyl group, ethyl group, isopropyl group or sec-butyl group, R ² is hydrogen atom or trimethylsilyl group, R ³ is hydrogen atom or formula: SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵ and R ⁶ are each independently a group represented by C ₁ to C ₆ alkyl group.). An intermediate compound represented by the following formula is obtained, and the intermediate compound is isolated or purified in the presence of an acid without being isolated or purified. The following general formula (I) consisting of reacting with -methoxyimino-2-phenylacetic acid: [Formula I]

[In formula, R <^1> is a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group.] The manufacturing method of the 5-keto-13-ester derivative of milbimecins. The manufacturing method of Claim 1 whose R <^3> of the compound represented by general formula (III) is a trimethylsilyl group.