WO1999061447A1 - Process for producing 13-ester derivatives of milbemycins - Google Patents
Process for producing 13-ester derivatives of milbemycins Download PDFInfo
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- WO1999061447A1 WO1999061447A1 PCT/JP1999/002697 JP9902697W WO9961447A1 WO 1999061447 A1 WO1999061447 A1 WO 1999061447A1 JP 9902697 W JP9902697 W JP 9902697W WO 9961447 A1 WO9961447 A1 WO 9961447A1
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- C—CHEMISTRY; METALLURGY
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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- R 1 represents a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group.
- the present invention relates to a method for producing a 5-keto-13-ester compound of a milbemycin represented by the formula:
- a milbemycin derivative having an ester group at the 13-position has insecticidal activity and anthelmintic activity is described in, for example, Japanese Patent Application Laid-Open Nos. H01-110408 and H05-22555. It is disclosed in Japanese Patent Publication No. 3443 and Japanese Patent Application Laid-Open No. 08-259570. Regarding the method for producing such a 5-keto 13-ester derivative, methods (A) and (B) shown below are roughly classified.
- the production method is described in, for example, Japanese Patent Application Laid-Open No. H01-104007. No. 8 and Japanese Unexamined Patent Publication No. H05-2553543.
- the starting material for the process is 13-hydroxy-5-ketomylbemycins.
- Japanese Patent Application Laid-Open No. 61-103844 describes a method for producing the starting material. According to the method described in the publication, first, the yield is 50% or less, second, toxic selenium dioxide is contained in the waste, and third, the starting material 13 —Hydroxy-5-ketomylbemycins have problems such as generally being difficult to obtain.
- (B) A method in which ⁇ 13, 141-15-hydroxy-5-ketomylbemycins are esterified by reacting them with a carboxylic acid in the presence of an acid catalyst.
- the production method is disclosed, for example, in Japanese Patent Application Laid-Open Nos. H05-2553543 and H08-259590.
- Starting materials for the production process are ⁇ 13, 14-15-hydroxy-15-ketomylbemycins.
- Japanese Patent Application Laid-Open No. 60-15891 discloses a method for producing the starting material.
- An object of the present invention is to provide a safe and efficient method for producing a 5-keto 13 monoester derivative of a milbemycin represented by the general formula (I).
- the present invention provides a compound represented by the following general formula (II):
- R 1 represents a methyl group, a tyl group, an isopropyl group or a sec-butyl group
- R 2 represents a hydrogen atom or a trimethylsilyl group.
- 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: Si R 4 R 5 R 6 (Wherein, R 4 , R 5 and R 6 each independently represent a C 6 alkyl group).
- R 1 represents a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group.
- the present invention relates to a method for producing a 5-keto-13-ester derivative of a milbemycin represented by the formula:
- the present invention also relates to the above-mentioned production method, wherein R 3 of the compound represented by the general formula (III) is a trimethylsilyl group.
- the production method of the present invention uses a 14,15-epoxy derivative of milbemycins (see Japanese Patent Application Laid-Open No. 06-220068) as a starting material, and converts the compound represented by the general formula (II) into a compound represented by the general formula (II).
- R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec group. -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, 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 Is a group represented by the formula: Si R 4 R 5 R 6 (wherein R 4 , R 5 and R 6 each independently represent a C ⁇ alkyl group). — A milbemycin derivative disclosed in JP 220068.
- trimethylsilinoletrifluoromethanesulfonate triethylsilinoletritrifluoromethane, methanesulfonate, and triisopropinolesirinoletriflenoreo Methanesulfonate or t-butyldimethylsilyltrifluoromethanesulfonate, and more preferably trimethylsilyltrinofluorenolomethanesulfonate or t-butyldimethylolefluoromethanesulfonate, more preferably Is 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, and preferably from 1.2 to 10 molar equivalents. A more preferred range is from 5.0 molar equivalents to 1.2 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.
- Organic amines such as butylpyridine, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] -7-ndecene; lithium disopropylamide, lithium bis Amides such as (trimethylsilyl) amide; alkali metals such as sodium and lithium; alkali metal bases such as sodium hydroxide and hydroxylated lime; and the like, preferably triethylamine, Triptylamine, ethynoleisopropylamine, pyridine, 2,6-lutidine, 2,6-di-t-butylpyridine, 1,4- Organic amines such as diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] -7-pandacene, and more preferably 2,6-lutidine.
- the amount of the base used in the reaction depends on the amount of the silylating agent used, but the range of the silylating agent is usually from 1.0 to 2.0 molar equivalents, and from 6.0 to 2.0 molar equivalents. It is from 0 to 10 molar equivalents, with a preferred range being from 2.0 to 6.0 molar equivalents.
- the solvent used for the reaction is not particularly limited as long as it is a solvent that stably dissolves the reactants and products and does not inhibit the reaction.
- hydrocarbons such as halogenated hydrocarbons such as methylcyclohexane and toluene are preferable.
- 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 of the reaction temperature is from 150 to ⁇ 30 ° C.
- the upper limit is from 50 to 100 ° C.
- the preferable range is from 130 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 1 hour at the lower limit and 2 to 12 hours at the upper limit, and the preferred range is 1 to 12 hours. 2 hours.
- the intermediate compound represented by the general formula (III) can be collected from the reaction mixture according to a conventional method.
- the reaction solution is washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogen carbonate 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 carried out by combining a pump, a tally evaporator, a flask for the evaporator, a water bath type thermostat, 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.
- the acid used in the reaction is not particularly limited as long as it is an acid generally used in a chemical reaction.
- an inorganic acid such as sulfuric acid or hydrochloric acid, or trifluoroacetic acid, trifluoromethanesulfonic acid, or benzenesulfonic acid
- organic acids such as parachlorobenzenesulfonic acid, preferably organic acids such as trifluoroacetic acid, trifluoromethanesnolephonic acid, benzenesulfonic acid and parachlorobenzenesulfonic acid, and more preferably trifluoroacetic acid.
- Methanesulfonic acid preferably organic acids such as trifluoroacetic acid, trifluoromethanesnolephonic acid, benzenesulfonic acid and parachlorobenzenesulfonic acid, and more preferably trifluoroacetic acid.
- the amount of the acid used in the reaction depends on the type of the acid, etc., and the range is preferably from 0.1 to 0.1 mole equivalent at the lower limit and from 0.8 to 0.9 mole equivalent at the upper limit. The preferred range is 0.1 to 0.8 molar equivalents.
- the addition of inorganic compound powder to the reaction system may accelerate the reaction. 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 which is usually added to promote the reaction. Examples thereof include copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, and nickel iodide.
- Metal salts such as, for example, celite, silica gel, alumina and the like, preferably copper salts such as copper trifluoromethanesulfonate and cuprous iodide, more preferably iodide It is cuprous.
- the solvent used in the reaction is not particularly limited as long as it is a solvent that stably dissolves the reactants and products and does not inhibit the reaction.
- n-hexane, petroleum ether, cyclohexane Hydrocarbons such as methionolecyclohexane, benzene, tonolene and xylene; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform; esters such as ethyl acetate and propyl acetate; Ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide: acetonitrile and propioni Nitriles such as tolyl; or these Can be mentioned mixtures comprising two or more of Bareru et election, preferably petroleum ether, Hydrocarbons such as chlorohexane, methylcyclohexane, and tolu
- the lower limit of the reaction temperature is from 110 to 0 C
- the upper limit is from 50 to 100 C, and preferably from 0 to 50 C.
- the reaction time depends on the reaction temperature, the acid used for the reaction, the solvent, the inorganic additive, and the like, and the range is 5 to 10 minutes at a lower limit and 5 to 10 hours at an upper limit. Is 10 minutes to 5 hours.
- the target compound represented by the general formula (I) can be collected from the reaction mixture by a conventional method.
- the reaction solution can be obtained by washing the reaction solution in the order of water, an aqueous solution of sodium hydrogen carbonate and water by one-liquid distribution using a liquid separation port, 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, and examples thereof include air drying, normal pressure concentration, reduced pressure concentration and distillation, and preferably reduced pressure concentration.
- 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, using a means such as column chromatography.
- the carrier to be packed in a 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, and activated carbon. And preferably a silica gel.
- the behavior of the target compound can be tracked based on a quantitative analysis method using high performance liquid chromatography.
- the quantitative analysis method can also be applied to the determination of the purity of a compound.
- the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order by a liquid-liquid distribution 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-xanyl-ethyl ester (90:10), and n-
- the mixture is added to a silica gel column equilibrated with a mixed solution of hexane monoethyl acetate (90:10), the compound is adsorbed to the column, and a stepwise gradient of the mixed solution of n hexane monoethyl acetate (ethyl acetate to n In 10 to 50%,
- the solvent was distilled off by vacuum concentration used.
- the residue was dissolved in a mixed solution of n-hexane monoethyl acetate (90:10), added to a silica gel column equilibrated with a mixed solution of n-hexane monoethyl acetate (90:10), and applied to the column.
- the compound is adsorbed and eluted with a stepwise gradient of a mixed solution of n-hexane / ethyl acetate (ethyl acetate is gradually increased by 10% from 10 to 50% in n-hexane).
- the solvent was distilled off from the eluted fraction containing the compound by concentration under reduced pressure using an evaporator to obtain 5.06 g (84.0%) of the desired compound.
- the reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order by a liquid-liquid distribution 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 / monoethyl 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.
- the mixture is adsorbed and eluted with a stepwise gradient of a mixed solution of n-hexane / ethyl acetate (ethyl acetate is gradually increased from 10 to 50% in n-hexane in steps of 10%).
- the solvent was distilled off from the eluted fraction containing the solution by concentration under reduced pressure using an evaporator to obtain 17.3 g (86%) of the desired compound.
- the 5-keto 13-ester derivative of a milbemycin represented by the general formula (I) can be efficiently produced by the production method of the present invention. Further, the compound represented by the general formula (I) is subjected to a reduction reaction according to the method described in JP-A-06-220068 or JP-A-08-259570.
- the following general formula (IV) having excellent insecticidal activity is described in JP-A-06-220068 or JP-A-08-259570.
- 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 1
- 0 represents an aryl group
- m and ⁇ each independently represent 0 or 1, and cannot be 0 at the same time. Can be obtained, and thus the production method of the present invention is useful for industrially producing the compound represented by the general formula (IV).
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Abstract
A process for producing 5-keto-13-ester derivatives of milbemycins represented by general formula (I) wherein R1 represents methyl, ethyl, isopropyl or sec-butyl. The compounds of general formula (I) are useful as intermediates in producing compounds having excellent bactericidal activity.
Description
明 細 書 Specification
シン類の 1 3—エステル誘導体の製造法 Method for producing 13-ester derivatives of syns
「技術分野 J 本発明は下記の一般式 （ I ) "Technical field J The present invention relates to the following general formula (I)
[式中、 R 1はメチル基、 ェチル基、 イソプロピル基又は sec-ブチル基を示す。] で表わされるミルべマイシン類の 5—ケト— 1 3—エステル化合物の製造法に関 する。 [Wherein, R 1 represents a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group. The present invention relates to a method for producing a 5-keto-13-ester compound of a milbemycin represented by the formula:
「背景技術」 "Background technology"
1 3位にエステル基を有するミルべマイシン誘導体が殺虫活性や駆虫作用を有 することは、 例えば、 日本特開平 0 1— 1 0 4 0 7 8号公報、 日本特開平 0 5— 2 5 5 3 4 3号公報及び日本特開平 0 8— 2 5 9 5 7 0号公報等に開示されてい る。
このような 5—ケトー 1 3—エステル誘導体の製造法に関しては、 大別して下 記に示す （A ) 及び （B ) の方法が知られている。 The fact that a milbemycin derivative having an ester group at the 13-position has insecticidal activity and anthelmintic activity is described in, for example, Japanese Patent Application Laid-Open Nos. H01-110408 and H05-22555. It is disclosed in Japanese Patent Publication No. 3443 and Japanese Patent Application Laid-Open No. 08-259570. Regarding the method for producing such a 5-keto 13-ester derivative, methods (A) and (B) shown below are roughly classified.
( A ) 1 3—ヒ ドロキシー 5—ケトミルべマイシン類を、 カルボン酸又はその反 応性誘導体と反応させてエステル化する方法：該製造法は、 例えば、 日本特開平 0 1 - 1 0 4 0 7 8号公報及び日本特開平 0 5— 2 5 5 3 4 3号公報に開示され ている。 該製造法の出発原料は、 1 3—ヒ ドロキシ— 5—ケトミルべマイシン類 である。 特開昭 6 1— 1 0 3 8 8 4号公報には、 該出発原料の製造法が記載され ている。 該公報記載の方法は、 第一に、 収率が 5 0 %以下であること、 第二に、 毒性を有する二酸化セレンが廃棄物中に含まれること、 第三に、 出発原料である 1 3—ヒ ドロキシー 5—ケトミルべマイシン類は一般に入手が困難であること等 の問題点を有する。 (A) Method of esterifying 13-hydroxy-5-ketomylbemycin by reacting it with a carboxylic acid or a reactive derivative thereof. The production method is described in, for example, Japanese Patent Application Laid-Open No. H01-104007. No. 8 and Japanese Unexamined Patent Publication No. H05-2553543. The starting material for the process is 13-hydroxy-5-ketomylbemycins. Japanese Patent Application Laid-Open No. 61-103844 describes a method for producing the starting material. According to the method described in the publication, first, the yield is 50% or less, second, toxic selenium dioxide is contained in the waste, and third, the starting material 13 —Hydroxy-5-ketomylbemycins have problems such as generally being difficult to obtain.
( B ) △ 1 3、 1 4一 1 5—ヒ ドロキシ一 5—ケトミルべマイシン類を、 酸触媒 の存在下、 カルボン酸と反応させてエステル化する方法。 該製造法は、 例えば、 日本特開平 0 5— 2 5 5 3 4 3号公報及び日本特開平 0 8— 2 5 9 5 7 0号公報に開示されている。 該製造法の出発原料は、 Δ 1 3、 1 4— 1 5—ヒ ドロキシ一 5—ケトミルべマイシン類である。 特開昭 6 0 - 1 5 8 1 9 1号公報には、該出発原料の製造法が記載されている。該公報記載の方法は、 第一に、 2つの反応生成物を生じ、 化合物のみを選択的に生成し得ないこと、 第 二に、 収率が約 5 0 %以下であること、 第三に、 反応の試薬として毒性及び爆発 性が強いアジ化水素酸を用いるので危険を伴うこと、 第四に、 出発原料である△ 1 3、 1 4一 1 5—ヒ ドロキシ一 5—ケトミルべマイシン類は入手が困難である こと等の問題点を有する。 以上の理由から、 上記問題点を伴わない、 ミルべマイシン類の 5—ケト一 1 3 —エステル中間体の新しい製造法の確立が求められていた。 本発明は、 前記一般式 （I ) で表わされるミルべマイシン類の 5—ケトー 1 3 一エステル誘導体の安全且つ効率のよい製造法を提供することを目的としている。
「発明の開示」 本発明は、 下記の一般式 （I I ) (B) A method in which Δ13, 141-15-hydroxy-5-ketomylbemycins are esterified by reacting them with a carboxylic acid in the presence of an acid catalyst. The production method is disclosed, for example, in Japanese Patent Application Laid-Open Nos. H05-2553543 and H08-259590. Starting materials for the production process are Δ13, 14-15-hydroxy-15-ketomylbemycins. Japanese Patent Application Laid-Open No. 60-15891 discloses a method for producing the starting material. The method described in this publication firstly produces two reaction products and cannot selectively produce only the compound, secondly, the yield is about 50% or less, and thirdly, The use of hydrazic acid, which is highly toxic and explosive, as a reagent for the reaction involves danger. Fourth, the starting materials △ 13, 14-15-hydroxy-15-ketomylbemycins Has a problem that it is difficult to obtain. For the above reasons, there has been a demand for the establishment of a new process for producing a 5-keto13-ester intermediate of milbemycins, which does not have the above problems. An object of the present invention is to provide a safe and efficient method for producing a 5-keto 13 monoester derivative of a milbemycin represented by the general formula (I). "Disclosure of the invention" The present invention provides a compound represented by the following general formula (II):
[式中、 R1はメチル基、 チル基、 イソプロピル基又は sec-ブチル基を示し、 R 2は水素原子又はトリメチルシリル基を示す。] で表わされる 1 4、 1 5—ェ ポキシ一 5—ケトミ 物をシリル化剤と反応させて下記の一般式[Wherein, R 1 represents a methyl group, a tyl group, an isopropyl group or a sec-butyl group, and R 2 represents a hydrogen atom or a trimethylsilyl group. The 14-, 15-epoxy-15-ketomi compound represented by the formula
( I I I ) (I I I)
[式中、 R1はメチル基、 ェチル基、 イソプロピル基又は sec-ブチル基を示す。] で表わされるミルべマイシン類の 5—ケト— 13—エステル誘導体の製造法に関 する。 また、 本発明は、 上述の製造法において、 一般式 （I I I ) で表わされる化合 物の R3がトリメチルシリル基である製造法に関する。 本発明の製造法は、 ミルべマイシン類の 14， 1 5—エポキシ体 （日本特開平 06 - 220068号公報参照） を出発物質として用い、 前記一般式 （ I I ) で 表わされる化合物から前記一般式 （I I I ) で表わされる中間体化合物に導く第 1工程と、 前記一般式 （ I I I ) で表わされる中間体化合物から前記一般式 （I ) で表わされる化合物に導く第 2工程からなる。
前記一般式 （I ) で表わされる化合物、 前記一般式 （ I I ) で表わされる化合 物及び前記一般式 （ I I I ) で表わされる中間体化合物において、 R1はメチル 基、 ェチル基、 イソプロピル基又は sec-ブチル基であり、 好適にはメチル基又 はェチル基であり、 より好適にはェチル基である。 前記一般式 （I I I ) で表わされる化合物 （式中、 R1はメチル基、 ェチル基、 イソプロピル基又は sec-ブチル基を示し、 R 2は水素原子又はトリメチルシリル 基を示し、 R3は水素原子又は式： S i R4R5R6 (式中、 R4、 R5及び R6は それぞれ独立して、 乃至 C βアルキル基を示す） で表わされる基を示す。） は、 日本特開平 06— 220068号公報に開示されたミルべマイシン誘導体でる。 前記一般式 （ I I I ) で表わされる化合物中の R3置換基の一つに挙げられた 式： S i R4R5R6 (式中、 R4、 R5及び R6はそれぞれ独立して、 乃至 C6 アルキル基を示す） において、 「C i乃至 Ceアルキル基」 とは、 メチル基、 ェチ ル基、 n—プロピル基、 イソプロピル基、 n—ブチル基、 イソブチル基、 s—ブ チル基又は t一ブチル基であり、 好適にはメチル基である。 [Wherein, R 1 represents a methyl group, an ethyl group, an isopropyl group, or a sec-butyl group. The present invention relates to a method for producing a 5-keto-13-ester derivative of a milbemycin represented by the formula: The present invention also relates to the above-mentioned production method, wherein R 3 of the compound represented by the general formula (III) is a trimethylsilyl group. The production method of the present invention uses a 14,15-epoxy derivative of milbemycins (see Japanese Patent Application Laid-Open No. 06-220068) as a starting material, and converts the compound represented by the general formula (II) into a compound represented by the general formula (II). It comprises a first step of leading to an intermediate compound represented by (III), and a second step of leading from the intermediate compound represented by the general formula (III) to a compound represented by the general formula (I). 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 group. -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, 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 Is a group represented by the formula: Si R 4 R 5 R 6 (wherein R 4 , R 5 and R 6 each independently represent a C β alkyl group). — A milbemycin derivative disclosed in JP 220068. Formulas listed as one of the R 3 substituents in the compound represented by the general formula (III): S i R 4 R 5 R 6 (wherein R 4 , R 5 and R 6 are each independently , or the C 6 represents an alkyl group), and "C i to C e alkyl group" include methyl group, e Ji Le group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, s- Bed It is a tyl group or a t-butyl group, preferably a methyl group.
(第 1工程） 第 1工程は、 前記一般式 （ I I ) で表わされる化合物のエポキシ基をシリル化 剤及び塩基の存在下で開環し前記一般式 （I I I ) で表わされるァリルアルコ一 ル誘導体に変換する工程である。 反応に使用されるシリル化剤としては、 トリアルキル置換シリルトリフルォロ メタンスルホネート [C F3S02OS i R4R5R6 (式中、 R4、 R5及び R6は それぞれ独立して、 C t乃至 C6アルキル基を示す）] 等が挙げられ、 例えば、 ト リメチルシリノレトリフルォロメタンスルホネート、 トリェチルシリノレトリフルォ 口メタンスノレホネート、 トリイソプロピノレシリノレトリフノレオ口メタンスノレホネー ト又は tーブチルジメチルシリルトリフルォロメタンスルホネ一ト等であり、 好 適にはトリメチルシリルトリフノレオロメタンスルホネート又は t—ブチルジメチ ノレトリフルォロメタンスルホネ一トであり、 より好適にはトリメチルシリルトリ フルォロメタンスルホネ一トである。
反応に使用されるシリル化剤の使用量の範囲は、 通常、 下限が 1 . 0乃至 1 . 2モル当量、 上限が 2 . 0乃至 1 0モル当量であり、 好適な範囲は 1 . 2乃至 5 . 0モル当量でぁリ、 より好適な範囲は 1 . 2モル当量乃至 3 . 0モル当量である。 このような量のシリル化剤は、 必要ならば、 複数回に分けて反応系に添加するこ ともできる。 反応に使用される塩基としては、 反応を阻害しない塩基であれば特に限定され ないが、 例えば、 トリェチルァミン、 トリプチルァミン、 ジェチルイソプロピル ァミン、 ピリジン、 2 , 6—ルチジン、 2， 6—ジ一 t 一ブチルピリジン、 1、 4—ジァザビシクロ [ 2、 2、 2 ] オクタン、 1、 8—ジァザビシクロ [ 5、 4、 0 ] - 7 —ゥンデセンのような有機アミン類； リチウムジィソプロピルァミ ド、 リチウムビス （トリメチルシリル） アミ ドのようなアミ ド類；ナトリウム、 リチ ゥムのようなアルカリ金属類；水酸化ナトリゥム、 水酸化力リゥムのようなアル カリ金属塩基等であり、 好適にはトリエチルァミン、 トリプチルァミン、 ジェチ ノレイソプロピルァミン、 ピリジン、 2 , 6—ルチジン、 2， 6—ジ一 t—ブチル ピリジン、 1、 4ージァザビシクロ [ 2、 2、 2 ] オクタン、 1、 8—ジァザビ シクロ [ 5、 4、 0 ] —7—ゥンデセンのような有機アミン類であり、 より好適 には 2、 6—ルチジンである。 反応に使用される塩基の使用量は、 シリル化剤の使用量等に依存するが、 通常 シリル化剤に対し、 その範囲は、 下限が 1 . 0乃至 2 . 0モル当量、 上限が 6 . 0乃至 1 0モル当量であり、 好適な範囲は 2 . 0乃至 6 . 0モル当量である。 反応に使用される溶媒としては、 反応物及び生成物を安定に溶解し且つ反応を 阻害しない溶媒であれば特に限定されないが、 例えば、 n—へキサン、 シクロへ キサン、 メチノレシクロへキサン、 石油ェ一テノレ、 ベンゼン、 トノレェン、 キシレン のような炭化水素類； クロ口ホルム、 塩化メチレン、 1、 2—ジクロロェタンの ようなハロゲン化炭化水素類；ェチルエーテル、 テトラヒ ドロフラン、 1、 4一 ジォキサン、 ジメ トキシェタンのようなェ一テル類；酢酸ェチル、 酢酸プロピル のようなエステル類； N、 N—ジメチルホルムアミ ド、 N , N—ジメチノレアセタ ミ ドのようなアミ ド類； ジメチルスルホキシドのようなスルホキシド類； ァセト
二トリル、 プロピオ二トリルのような二トリル類、 又はこれらから選ばれる二つ 以上を含む混合物を挙げることができ、 好適にはメチルシクロへキサン、 トルェ ン等、 ハロゲン化炭化水素のような炭化水素類；塩化メチレンのようなハロゲン 化炭化水素類、 又はこれらから選ばれる二つ以上を含む混合物であり、 より好適 にはメチルシク口へキサン、 塩化メチレン又はこれらの混合物である。 反応温度の範囲は、 下限が一 5 0乃至— 3 0 ¾：、 上限が 5 0乃至 1 0 0 °Cであ り、 好適な範囲は一 3 0乃至 5 0 °Cである。 反応時間は、 反応温度、 反応に使用されるシリル化剤、 塩基及び溶媒等に依存 するが、 その範囲は、 下限が 1時間、 上限が 2乃至 1 2時間であり、 好適な範囲 は 1乃至 2時間である。 反応終了後、 常法に従って、 反応混合物から、 前記一般式 （I I I ) で表わさ れる中間体化合物を採取することができる。 例えば、 反応終了後、 反応液を 1規 定塩酸、 水、 炭酸水素ナトリウム水溶液及び水の順で、 分液ロートを用いた液一 液分配により洗浄し、 濃縮により溶媒を留去して得られる。。 濃縮法としては、 通常液体を濃縮する方法であれば特に限定されないが、 例えば、 風乾、 常圧濃縮、 減圧濃縮及び蒸留等であり、 好適には減圧濃縮である。 減圧濃縮は、 ポンプ、 口 —タリーエバポレータ、 該エバポレータ用フラスコ及び水浴式恒温槽等を組合わ せて行うことができ、 化合物を該フラスコ中に乾固された状態で得ることができ る。 得られた中間体化合物は、 単離又は精製せずに次の工程に使用することがで さる。 (First Step) In the first step, the epoxy group of the compound represented by the general formula (II) is ring-opened in the presence of a silylating agent and a base to give an aryl alcohol derivative represented by the general formula (III). This is the step of conversion. The silylating agent used in the reaction, 4 R 5 R 6 (wherein trialkyl-substituted silyl triflates Ruo B methanesulphonate [CF 3 S0 2 OS i R , R 4, R 5 and R 6 are each independently , C t to C 6 alkyl groups)], and the like. For example, trimethylsilinoletrifluoromethanesulfonate, triethylsilinoletritrifluoromethane, methanesulfonate, and triisopropinolesirinoletriflenoreo Methanesulfonate or t-butyldimethylsilyltrifluoromethanesulfonate, and more preferably trimethylsilyltrinofluorenolomethanesulfonate or t-butyldimethylolefluoromethanesulfonate, more preferably Is 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, and preferably from 1.2 to 10 molar equivalents. A more preferred range is from 5.0 molar equivalents to 1.2 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. Organic amines such as butylpyridine, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] -7-ndecene; lithium disopropylamide, lithium bis Amides such as (trimethylsilyl) amide; alkali metals such as sodium and lithium; alkali metal bases such as sodium hydroxide and hydroxylated lime; and the like, preferably triethylamine, Triptylamine, ethynoleisopropylamine, pyridine, 2,6-lutidine, 2,6-di-t-butylpyridine, 1,4- Organic amines such as diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] -7-pandacene, and more preferably 2,6-lutidine. The amount of the base used in the reaction depends on the amount of the silylating agent used, but the range of the silylating agent is usually from 1.0 to 2.0 molar equivalents, and from 6.0 to 2.0 molar equivalents. It is from 0 to 10 molar equivalents, with a preferred range being from 2.0 to 6.0 molar equivalents. The solvent used for the reaction is not particularly limited as long as it is a solvent that stably dissolves the reactants and products and does not inhibit the reaction. For example, n-hexane, cyclohexane, methinocyclohexane, petroleum Hydrocarbons such as tenorene, benzene, tonolene, xylene; halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane; ethyl ether, tetrahydrofuran, 1,4-dioxane and dimethoxetane Esters such as ethyl acetate and propyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylinoleacetamide; sulfoxides such as dimethyl sulfoxide; Examples include nitriles such as nitrile and propionitrile, and mixtures containing two or more selected from these. Preferably, hydrocarbons such as halogenated hydrocarbons such as methylcyclohexane and toluene are preferable. And 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 of the reaction temperature is from 150 to −30 ° C., the upper limit is from 50 to 100 ° C., and the preferable range is from 130 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 1 hour at the lower limit and 2 to 12 hours at the upper limit, and the preferred range is 1 to 12 hours. 2 hours. After completion of the reaction, the intermediate compound represented by the general formula (III) can be collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the reaction solution is washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogen carbonate 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 carried out by combining a pump, a tally evaporator, a flask for the evaporator, a water bath type thermostat, 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.
(第 2工程） 第 2工程は、 第 1工程で得た前記一般式 （I I I ) で表わされる中間体化合物 を、 酸の存在下、 2—メ トキシィミノ— 2—フエニル酢酸と反応させ、 前記一般 式 （ I ) で表わされるミルべマイシン類の 5—ケト— 1 3—エステル誘導体を製 造する工程である。 反応に使用される 2—メ トキシィミノー 2—フエニル酢酸の量の範囲は、 下限 が 1乃至 1 . 5モル当量、 上限が 2乃至 2 0モル当量であり、 好適な範囲は 1 .
5乃至 2モル当量である。 反応に使用される酸としては、 通常化学反応に使用される酸であれば特に限定 されないが、 例えば、 硫酸、 塩酸のような無機酸、 又はトリフルォロ酢酸、 トリ フルォロメタンスルホン酸、 ベンゼンスルホン酸、 パラクロロベンゼンスルホン 酸のような有機酸を挙げることができ、 好適にはトリフルォロ酢酸、 トリフルォ ロメタンスノレホン酸、 ベンゼンスルホン酸、 パラクロロベンゼンスルホン酸のよ うな有機酸であり、 より好適にはトリフルォロメタンスルホン酸である。 反応に使用される酸の量は酸の種類等に依存するが、 その範囲は、 下限が 0 . 0 1乃至 0 . 1モル当量、 上限が 0 . 8乃至 0 . 9モル当量であり、 好適な範囲 は 0 . 1乃至 0 . 8モル当量である。 反応系中に、 無機化合物の粉末を添加すると、 反応を促進することがある。 本 発明の製造法においても、 必要に応じ、 このような無機化合物の粉末を添加して もよい。 無機化合物としては、 通常反応を促進するために添加する無機化合物で あれば特に限定されないが、 例えば、 トリフルォロメタンスルホン酸銅、 沃化第 一銅、 沃化亜鉛、 沃化コバルト、 沃化ニッケルのような金属塩、 セライ ト、 シリ 力ゲル、 アルミナ等を挙げることができ、 好適にはトリフルォロメタンスルホン 酸銅、 沃化第一銅のような銅塩であり、 より好適には沃化第一銅である。 反応に使用される溶媒としては、 反応物及び生成物を安定に溶解し且つ反応を 阻害しない溶媒であれば特に限定はないが、 例えば、 n—へキサン、 石油ェ一テ ノレ、 シクロへキサン、 メチノレシクロへキサン、 ベンゼン、 トノレェン、 キシレンの ような炭化水素類；塩化メチレン、 1 , 2—ジクロロェタン、 クロ口ホルムのよ うなハロゲン化炭化水素類；酢酸ェチル、 酢酸プロピルのようなエステル類； ジ ェチルエーテル、 テトラヒ ドロフラン、 ジォキサン、 ジメ トキシェタンのような エーテル類； ジメチルホルムアミ ド、 ジメチルァセトアミ ド、 へキサメチルホス ホロ トリアミ ドのようなァミ ド類； ジメチルスルホキシドのようなスルホキシド 類：ァセトニトリル、 プロピオ二トリルのような二トリル類；又はこれらから選 ばれる二つ以上を含む混合物等を挙げることができ、 好適には石油エーテル、 シ
クロへキサン、 メチルシクロへキサン、 トルエンのような炭化水素類；塩化メチ レン、 1， 2—ジクロロェタンのようなハロゲン化炭化水素類；又はこれらから 選ばれる二つ以上を含む混合物であり、 より好適にはメチルシクロへキサン、 塩 化メチレン又はこれらの混合物である。 反応温度の範面は、 下限が一 1 0乃至 0 C、 上限が 5 0乃至 1 0 0 Cであり、 好適には 0乃至 5 0 Cである。 反応時間は、 反応温度、 反応に使用される酸、 溶媒及び無機添加物等に依存す るが、 その範囲は、 下限が 5乃至 1 0分、 上限が 5乃至 1 0時間であり、 好適に は 1 0分乃至 5時間である。 反応終了後、 前記一般式 （ I ) で表わされる目的化合物は、 反応混合物から常 法に従って採取することができる。 例えば、 反応終了後、 反応液を水、 炭酸水素 ナトリゥム水溶液及び水の順で、 分液口一トを用いた液一液分配により洗浄し、 濃縮により溶媒を留去することによって得られる。 濃縮法は、 通常液体を濃縮す る方法であれば特に限定されないが、 例えば、 風乾、 常圧濃縮、 減圧濃縮及び蒸 留等であり、 好適には減圧濃縮である。 減圧濃縮により、 前述の通り、 化合物を 乾固された状態で得ることができる。 反応により得られた前記一般式 （ I ) で表わされる目的化合物は、 必要ならば、 カラムクロマトグラフィ一等の手段を用いてさらに精製することができる。 カラムクロマトグラフィ一用のカラムに充填する担体としては、 通常有機化合 物を精製するのに用いられる担体であれば特に限定されないが、 例えば、 シリカ ゲル、 C 1 8逆相ゲル、 アルミナ、 活性炭等を挙げることができ、 好適にはシリ 力ゲルである。 目的化合物の挙動は、 高速液体クロマトグラフィ一法による定量的分析法に 基づいて追跡することができる。 該定量的分析法は、 化合物の純度の測定にも適 用することができる。
「発明を実施するための最良の形態」 以下に実施例をあげて本発明を更に詳細に説明するが、 本発明はこれらに限定 されるものではない。 (Second step) In the second step, the intermediate compound represented by the general formula (III) obtained in the first step is reacted with 2-methoxyimino-2-phenylacetic acid in the presence of an acid, This is a process for producing a 5-keto-13-ester derivative of a milbemycin represented by the formula (I). The lower limit of the amount of 2-methoxyiminot 2-phenylacetic acid used in the reaction is 1 to 1.5 molar equivalents, the upper limit is 2 to 20 molar equivalents, and the preferred range is 1. 5 to 2 molar equivalents. The acid used in the reaction is not particularly limited as long as it is an acid generally used in a chemical reaction.For example, an inorganic acid such as sulfuric acid or hydrochloric acid, or trifluoroacetic acid, trifluoromethanesulfonic acid, or benzenesulfonic acid And organic acids such as parachlorobenzenesulfonic acid, preferably organic acids such as trifluoroacetic acid, trifluoromethanesnolephonic acid, benzenesulfonic acid and parachlorobenzenesulfonic acid, and more preferably trifluoroacetic acid. Methanesulfonic acid. The amount of the acid used in the reaction depends on the type of the acid, etc., and the range is preferably from 0.1 to 0.1 mole equivalent at the lower limit and from 0.8 to 0.9 mole equivalent at the upper limit. The preferred range is 0.1 to 0.8 molar equivalents. The addition of inorganic compound powder to the reaction system may accelerate the reaction. 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 which is usually added to promote the reaction. Examples thereof include copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, and nickel iodide. Metal salts such as, for example, celite, silica gel, alumina and the like, preferably copper salts such as copper trifluoromethanesulfonate and cuprous iodide, more preferably iodide It is cuprous. The solvent used in the reaction is not particularly limited as long as it is a solvent that stably dissolves the reactants and products and does not inhibit the reaction. For example, n-hexane, petroleum ether, cyclohexane Hydrocarbons such as methionolecyclohexane, benzene, tonolene and xylene; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform; esters such as ethyl acetate and propyl acetate; Ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide: acetonitrile and propioni Nitriles such as tolyl; or these Can be mentioned mixtures comprising two or more of Bareru et election, preferably petroleum ether, Hydrocarbons such as chlorohexane, methylcyclohexane, and toluene; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; or a mixture containing two or more selected from these; Is methylcyclohexane, methylene chloride or a mixture thereof. The lower limit of the reaction temperature is from 110 to 0 C, the upper limit is from 50 to 100 C, and preferably from 0 to 50 C. The reaction time depends on the reaction temperature, the acid used for the reaction, the solvent, the inorganic additive, and the like, and the range is 5 to 10 minutes at a lower limit and 5 to 10 hours at an upper limit. Is 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 by a conventional method. For example, after completion of the reaction, the reaction solution can be obtained by washing the reaction solution in the order of water, an aqueous solution of sodium hydrogen carbonate and water by one-liquid distribution using a liquid separation port, 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, and examples thereof include 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, using a means such as column chromatography. The carrier to be packed in a 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, and activated carbon. And preferably a silica gel. The behavior of the target compound can be tracked based on a quantitative analysis method using high performance liquid chromatography. The quantitative analysis method can also be applied to the determination of the purity of a compound. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
実施例 1. Example 1.
1 3— （α—メ トキシィミノフエ二ルァセトキシ） 一 5—ケトミルべマイシン A 4の製造 1 3— (α-Methoxyoximinophenylacetoxy) Production of 1-5-Ketomilbemycin A4
(第 1工程） (First step)
14, 1 5—エポキシ一 5—ケトミノレべマイシン A 4 0. 92 g (1.67 ミリモ ル） を、 塩化メチレン 1. 5m 1及びメチルシクロへキサン 1 0. 9m lの混合 溶媒に溶解させ、 窒素気流下 0乃至 5°Cで、 2、 6—ルチジン 1. 1 6m l (9.96 ミリモル） を加え、 1時間撹拌した。 これにトリメチルシリルトリフルォロメタンス ルホネート 0. 64m l (3.33 ミリモル） を加え、 0乃至 5 °Cで 1時間攪拌した。 さらに、 トリメチルシリノレトリフノレオロメタンスルホネート 0. 32m l (1.67 ミリモル） を加え、 0乃至 5°Cで 1時間攪拌した。 反応液を水、 1 0%硫酸水溶液、 水、 5%炭酸水素ナトリゥム水溶液、 水の順で液一液分配法により洗浄し、 エバ ポレータを用いた減圧濃縮により、 中間体化合物の粗生成物 1. 42 gを得た。 その粗生成物を精製せず、 次の第 2工程に用いた。 14,15-Epoxy-5-ketominorebemycin A 0.99 g (1.67 mmol) of A is dissolved in a mixed solvent of 1.5 ml of methylene chloride and 10.9 ml of methylcyclohexane, and the mixture is dissolved under a nitrogen stream. At 0-5 ° C, 2,6-lutidine 1.16 ml (9.96 mmol) was added and stirred for 1 hour. To this was added 0.64 ml (3.33 mmol) of trimethylsilyltrifluoromethanesulfonate, and the mixture was stirred at 0 to 5 ° C for 1 hour. Further, 0.32 ml (1.67 mmol) of trimethylsilinole trifnorolelomethanesulfonate was added, and the mixture was stirred at 0 to 5 ° C for 1 hour. The reaction mixture was washed with water, a 10% aqueous sulfuric acid 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 a crude product of an intermediate compound. 42 g were obtained. The crude product was used in the next second step without purification.
(第 2工程） 中間体化合物の粗生成物 1. 42 gを塩化メチレン 1 Om 1に溶解させ、 α— メ トキシィミノフエニル酢酸 5 1 1 mg (2.85 ミリモル） と ト リフルォロメタンス ルホン酸 0. 063tn l (0.71 ミリモル） を含む塩化メチレン溶液 1 5 m 1に、 了 ルゴン気流下 0乃至 5 °Cで滴下し、 0乃至 5 °Cで 3時間撹拌した。 反応液を水、 5%炭酸水素ナトリウム水溶液、 水の順で液一液分配法により洗浄し、 硫酸マグ ネシゥムで乾燥後、 エバポレータを用いた減圧濃縮により溶媒を留去した。 残留物を n キサン—齚酸ェチル混合溶液 （90 ： 1 0) に溶解させ、 n—
へキサン一酢酸ェチル混合溶液 （90 : 1 0) で平衡化したシリカゲルカラムに 添加し、 該カラムに化合物を吸着させ、 n キサン一酢酸ェチル混合溶液のス テップワイズグラジェント （酢酸ェチルを n キサン中で 1 0乃至 50%迄、(Second step) 1.42 g of a crude product of the intermediate compound was dissolved in 1 Om 1 of methylene chloride, and α- methoxyiminophenylacetic acid 51 mg (2.85 mmol) and trifluoromethanesulfonic acid were added. To a methylene chloride solution (15 ml) containing 0.063tn l (0.71 mmol) was added dropwise at 0 to 5 ° C under a stream of argon gas, followed by stirring 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 distribution 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-xanyl-ethyl ester (90:10), and n- The mixture is added to a silica gel column equilibrated with a mixed solution of hexane monoethyl acetate (90:10), the compound is adsorbed to the column, and a stepwise gradient of the mixed solution of n hexane monoethyl acetate (ethyl acetate to n In 10 to 50%,
1 0%ずつ段階的に増加させる。） で溶出し、 目的化合物を含む溶出画分をエバ ポレ一タを用いた減圧濃縮により溶媒を留去し、 目的化合物 0. 99 g (8 2.Increase step by step by 10%. ) And eluted fractions containing the target compound were evaporated under reduced pressure using an evaporator to remove the solvent.
1 %) を得た。 1%).
実施例 2. Example 2.
1 3— （α—メ トキシィミノフエ二ルァセトキシ） 一 5—ケトミルべマイシン A 4の製造 1 3— (α-Methoxyoximinophenylacetoxy) Production of 1-5-Ketomilbemycin A4
(第 1工程） (First step)
14 1 5—エポキシ一 5—ケトミルべマイシン A 4 4. 60 g (8.4ミリモル） を塩化メチレン 7. 5m 1及びメチルシクロへキサン 54. 5 m 1の混合溶媒に 溶解させ、 窒素気流下 0乃至 5 °Cで、 2 6—ルチジン 5. 80m l (49.8 ミリモ ル） を加え、 1時間撹拌した。 これにトリメチルシリルトリフルォロメタンスル ホネート 3. 2 m 1 (16.7 ミリモル） を加え、 0乃至 5 °Cで 1時間攪拌した。 さら に、 トリメチノレシリノレトリフノレオロメタンスノレホネ—ト 1. 60m l (8.3ミリモル） を加え、 0乃至 5 °Cで 1時間攪拌した。反応液を水、 1 0%硫酸水溶液、水、 5% 炭酸水素ナトリウム水溶液、 水の順で液一液分配法により洗浄し、 エバポレータ を用いた減圧濃縮により、 中間体化合物の粗生成物 7. 1 0 gを得た。 その粗生 成物を精製せず、 次の第 2工程に用いた。 14 15-Epoxy-5-ketomylbemycin A 4. Dissolve 4.60 g (8.4 mmol) in a mixed solvent of 7.5 ml of methylene chloride and 54.5 ml of methylcyclohexane, and place in a stream of nitrogen from 0 to 5 under a stream of nitrogen. At 80 ° C., 5.80 ml (49.8 mmol) of 26-lutidine was added, and the mixture was stirred for 1 hour. To this was added 3.2 ml (16.7 mmol) of trimethylsilyltrifluoromethanesulfonate, and the mixture was stirred at 0 to 5 ° C for 1 hour. Further, 1.60 ml (8.3 mmol) of trimethinolecinoleletrifurenoleolomethanesnorrehonate was added, and the mixture was stirred at 0 to 5 ° C for 1 hour. The reaction solution is 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 of an intermediate compound. 10 g were obtained. The crude product was used in the next second step without purification.
(第 2工程） 中間体化合物の粗生成物 7. 10 gと α—メ トキシィミノフエニル酢酸 2. 5 5 g (14.3 ミリモ;レ） を塩化メチレン 1 00 m 1に溶解させ、 トリフルォロメタン スルホン酸 0. 3 2m l (0.71 ミリモル） をアルゴン気流下 0乃至 5 Cで滴下し、 0乃至 5 Cで 5時間撹拌した。 反応液を水、 5%炭酸水素ナトリ ウム水溶液、 水 の順で液一液分配法により洗浄し、 硫酸マグネシウムで乾燥後、 エバポレータを
用いた減圧濃縮により溶媒を留去した。 残留物を n—へキサン一酢酸ェチル混合溶液 （90 ： 1 0) に溶解させ、 n— へキサン一酢酸ェチル混合溶液 （90 ： 1 0) で平衡化したシリカゲルカラムに 添加し、 該カラムに化合物を吸着させ、 n キサン一酢酸ェチル混合溶液のス テツプワイズグラジェント （酢酸ェチルを n キサン中で 10乃至 50%迄、 1 0%ずつ段階的に増加させる。） で溶出し、 目的化合物を含む溶出画分をエバ ポレータを用いた減圧濃縮により溶媒を留去し、 目的化合物 5. 06 g (84. 0%) を得た。 (Second step) 7.10 g of a 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 trifluoromethane was added. 0.32 ml (0.71 mmol) of sulfonic acid was added dropwise at 0 to 5 C under a stream of argon, and the mixture was stirred at 0 to 5 C for 5 hours. The reaction mixture is washed with water, a 5% aqueous solution of sodium hydrogen carbonate and water in that order by a liquid-liquid distribution method, dried over magnesium sulfate, and then the evaporator is removed. The solvent was distilled off by vacuum concentration used. The residue was dissolved in a mixed solution of n-hexane monoethyl acetate (90:10), added to a silica gel column equilibrated with a mixed solution of n-hexane monoethyl acetate (90:10), and applied to the column. The compound is adsorbed and eluted with a stepwise gradient of a mixed solution of n-hexane / ethyl acetate (ethyl acetate is gradually increased by 10% from 10 to 50% in n-hexane). The solvent was distilled off from the eluted fraction containing the compound by concentration under reduced pressure using an evaporator to obtain 5.06 g (84.0%) of the desired compound.
実施例 3. Example 3.
1 3 - (α—メ トキシィミノフエ二ルァセトキシ） 一 5—ケトミルべマイシン A 3の製造 1 3-(α-Methoxyiminophenylacetoxy) Production of 1-5-ketomylbemycin A 3
(第 1工程） (First step)
14, 1 5—エポキシ一 5—ケトミルべマイシン A 3 1 5. 5 g (28.6 ミリモ レ） を、 塩化メチレン 26 · 0 m 1及びメチルシクロへキサン 1 8 7. 5 m 1の 混合溶媒に溶解させ、 窒素気流下 0乃至 5°Cで、 2、 6—ルチジン 20. 0m l14,15-Epoxy-5-ketomylbemycin A 35.5 g (28.6 millimoles) was dissolved in a mixed solvent of 20.6 ml of methylene chloride and 18.7 ml of methylcyclohexane. 2,6-lutidine 20.0 ml at 0-5 ° C under nitrogen flow
(171.4 ミリモル） を加え、 1時間撹拌した。 さらに、 ト リメチルシリノレト リ フルォ ロメタンスルホネート 1 1. 0m l (57.1 ミリモル） を加え、 0乃至 5 Cで 1時間 攪拌した。 さらに、 トリメチルシリルトリフルォロメタンスルホネート 2. 3 m(171.4 mmol) was added and stirred for 1 hour. Further, 11.0 ml (57.1 mmol) of trimethylsilinoletrifluoromethanesulfonate was added, and the mixture was stirred at 0 to 5 C for 1 hour. In addition, trimethylsilyl trifluoromethanesulfonate 2.3 m
1 (11.9 ミリ Ϊ;レ） を加え、 0乃至 5°Cで 1時間攪拌した。 反応液を水、 1 0%硫 酸水溶液、 水、 5%炭酸水素ナトリウム水溶液、 水の順で液一液分配法により洗 浄し、 エバポレータを用いた減圧濃縮により、 中間体化合物の粗生成物 1 9. 7 gを得た。 その粗生成物を精製せず、 次の第 2工程に用いた。 1 (11.9 milliliters) was added, and the mixture was stirred at 0 to 5 ° C for 1 hour. The reaction solution is washed by water, 10% sulfuric acid aqueous solution, water, 5% aqueous sodium hydrogen carbonate solution and water in that order by liquid-liquid distribution method, and concentrated under reduced pressure using an evaporator to obtain a crude product of an intermediate compound. 19.7 g were obtained. The crude product was used in the next second step without purification.
(第 2工程） 中間体化合物の粗生成物 1 9， 7 gと α—メ トキシィミノフエニル酢酸 9. 1 4 g (51.1 ミリモル） を塩化メチレン 1 0 5 m 1 とメチルシク口へキサン 24 5m
1 の混合溶媒に溶解させ、 トリフルォロメタンスルホン酸 1 · 1 3m l (12.8 ミ |)モル） をアルゴン気流下 0乃至 5 '3Cで滴下し、 0乃至 5。Cで 3時間 3 0分撹拌し た。 反応液を水、 5%炭酸水素ナトリウム水溶液、 水の順で液一液分配法により 洗浄し、 硫酸マグネシウムで乾燥後、 エバポレータを用いた減圧濃縮により溶媒 を留去した。 残留物を n キサン一酢酸ェチル混合溶液 （90 ： 1 0) に溶解させ、 n— へキサン一酢酸ェチル混合溶液 （90 ： 1 0) で平衡化したシリカゲルカラムに 添加し、 該カラムに化合物を吸着させ、 n キサン一酢酸ェチル混合溶液のス テツプワイズグラジェント （酢酸ェチルを n キサン中で 1 0乃至 50%迄、 1 0%ずつ段階的に増加させる。） で溶出し、 目的化合物を含む溶出画分をエバ ポレータを用いた減圧濃縮により溶媒を留去し、 目的化合物 1 7. 3 g (8 6%) を得た。 (Second step) 19,7 g of a crude product of the intermediate compound and 9.14 g (51.1 mmol) of α-methoxyiminophenylacetic acid were mixed with methylene chloride (105 m 1) and methylcyclohexane (245 m). The mixture was dissolved in the mixed solvent of 1 and trifluoromethanesulfonic acid (1.13 ml (12.8 mi |) mol) was added dropwise at 0 to 5 ' 3 C under an argon stream to give 0 to 5. The mixture was stirred at C for 3 hours and 30 minutes. The reaction solution was washed with water, a 5% aqueous sodium hydrogen carbonate solution and water in that order by a liquid-liquid distribution 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 / monoethyl 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. The mixture is adsorbed and eluted with a stepwise gradient of a mixed solution of n-hexane / ethyl acetate (ethyl acetate is gradually increased from 10 to 50% in n-hexane in steps of 10%). The solvent was distilled off from the eluted fraction containing the solution by concentration under reduced pressure using an evaporator to obtain 17.3 g (86%) of the desired compound.
「産業上の利用可能性」 本発明の製造法により、 前記一般式 （I ) で表わされるミルべマイシン類の 5 ーケトー 1 3—エステル誘導体を効率よく製造することができる。 また前記一般式 （I ) で表わされる化合物を日本特開平 0 6— 2 20 0 6 8号 公報又は日本特開平 0 8— 2 5 9 5 70号公報記載の方法に順じて還元反応を行 うことにより、 優れた殺虫活性を有する下記一般式 （ I V)
[Industrial Applicability] The 5-keto 13-ester derivative of a milbemycin represented by the general formula (I) can be efficiently produced by the production method of the present invention. Further, the compound represented by the general formula (I) is subjected to a reduction reaction according to the method described in JP-A-06-220068 or JP-A-08-259570. The following general formula (IV) having excellent insecticidal activity
(I V) (I V)
[式中、 R1はメチル基、 ェチル基、 イソプロピル基又は sec-ブチル基を示し、 R 7は水素原子又は低級アルキル基を示し、 Aは置換可複素環基又は置換可 C 6 乃至 C 1 0ァリール基を示し、 m及び ηはそれぞれ独立して 0又は 1を示し、 同 時に 0であることはない。] で表わされる化合物を得ることができるので、 本発 明の製造法は前記一般式 （I V) で表わされる化合物を工業的に製造するために 有用である。
[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 1 0 represents an aryl group, m and η each independently represent 0 or 1, and cannot be 0 at the same time. Can be obtained, and thus the production method of the present invention is useful for industrially producing the compound represented by the general formula (IV).
Claims
1. 下記の一般式 （ I I ) 1. The following general formula (II)
[式中、 R1はメチル基、 ェチル基、 イソプロピル基又は sec-ブチル基を示 し、 R2は水素原子又はトリメチルシリル基を示す。] で表わされる 14、 1 5一エポキシ一 5—ケトミルべマイシン化合物をシリル化剤と反応させて 下記の一般式 （I I I ) [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. The reaction of a 14,15-epoxy-15-ketomylbemycin compound represented by the formula (III)
[式中、 R1はメチル基、 ェチル基、 イソプロピル基又は sec -ブチル基を示 す。] で表わされるミルべマイシン類の 5—ケトー 1 3—エステル誘導体の 製造法。 [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. 請求の範囲第 1項記載の製造法において、 一般式 （ I I I ) で表わされ る化合物の R 3がトリメチルシリル基である製造法。
2. The production method according to claim 1, wherein R 3 of the compound represented by the general formula (III) is a trimethylsilyl group.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14249298 | 1998-05-25 | ||
| JP10/142492 | 1998-05-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999061447A1 true WO1999061447A1 (en) | 1999-12-02 |
Family
ID=15316595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1999/002697 WO1999061447A1 (en) | 1998-05-25 | 1999-05-24 | Process for producing 13-ester derivatives of milbemycins |
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| Country | Link |
|---|---|
| KR (1) | KR100612634B1 (en) |
| CN (1) | CN1111536C (en) |
| TW (1) | TW568913B (en) |
| WO (1) | WO1999061447A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06220068A (en) * | 1992-09-01 | 1994-08-09 | Sankyo Co Ltd | New intermediate for 13-ether-substituted milbemycin derivative |
| JPH08259570A (en) * | 1994-04-01 | 1996-10-08 | Sankyo Co Ltd | Insecticidal milbemycin derivative having substituent group containing oxime group at 13-position |
| JPH09143183A (en) * | 1995-09-22 | 1997-06-03 | Sankyo Co Ltd | Insecticidal milbemycin derivative having oxime group-containing substituent group at 13-position |
-
1999
- 1999-05-24 WO PCT/JP1999/002697 patent/WO1999061447A1/en active IP Right Grant
- 1999-05-24 KR KR1020007013184A patent/KR100612634B1/en not_active IP Right Cessation
- 1999-05-24 CN CN99809029A patent/CN1111536C/en not_active Expired - Lifetime
- 1999-05-25 TW TW088108547A patent/TW568913B/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06220068A (en) * | 1992-09-01 | 1994-08-09 | Sankyo Co Ltd | New intermediate for 13-ether-substituted milbemycin derivative |
| JPH08259570A (en) * | 1994-04-01 | 1996-10-08 | Sankyo Co Ltd | Insecticidal milbemycin derivative having substituent group containing oxime group at 13-position |
| JPH09143183A (en) * | 1995-09-22 | 1997-06-03 | Sankyo Co Ltd | Insecticidal milbemycin derivative having oxime group-containing substituent group at 13-position |
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| TW568913B (en) | 2004-01-01 |
| CN1310719A (en) | 2001-08-29 |
| CN1111536C (en) | 2003-06-18 |
| KR20010025100A (en) | 2001-03-26 |
| KR100612634B1 (en) | 2006-08-14 |
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