WO1999061447A1 - Procede de production de derives de 13-ester de milbemycines - Google Patents

Procede de production de derives de 13-ester de milbemycines Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
group
reaction
general formula
acid
formula
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PCT/JP1999/002697
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English (en)
Japanese (ja)
Inventor
Kazuo Sato
Takahiro Tsukiyama
Mutsuo Suzuki
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Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Publication of WO1999061447A1 publication Critical patent/WO1999061447A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

L'invention concerne un procédé de production de dérivés de 5-kéto-13-ester de milbémycines représentés par la formule générale (I). Dans cette formule, R1 représente méthyle, éthyle, isopropyle ou sec-butyle. Ces composés sont utilisés comme intermédiaires permettant de produire des composés possédant une excellente activité bactérienne.
PCT/JP1999/002697 1998-05-25 1999-05-24 Procede de production de derives de 13-ester de milbemycines WO1999061447A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/142492 1998-05-25
JP14249298 1998-05-25

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WO1999061447A1 true WO1999061447A1 (fr) 1999-12-02

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KR (1) KR100612634B1 (fr)
CN (1) CN1111536C (fr)
TW (1) TW568913B (fr)
WO (1) WO1999061447A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06220068A (ja) * 1992-09-01 1994-08-09 Sankyo Co Ltd １３−エーテル置換ミルベマイシン誘導体の新規中間体
JPH08259570A (ja) * 1994-04-01 1996-10-08 Sankyo Co Ltd １３位にオキシム基を含んだ置換基を有する殺虫性ミルベマイシン誘導体
JPH09143183A (ja) * 1995-09-22 1997-06-03 Sankyo Co Ltd １３位にオキシム基を含んだ置換基を有する殺虫性ミルベマイシン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06220068A (ja) * 1992-09-01 1994-08-09 Sankyo Co Ltd １３−エーテル置換ミルベマイシン誘導体の新規中間体
JPH08259570A (ja) * 1994-04-01 1996-10-08 Sankyo Co Ltd １３位にオキシム基を含んだ置換基を有する殺虫性ミルベマイシン誘導体
JPH09143183A (ja) * 1995-09-22 1997-06-03 Sankyo Co Ltd １３位にオキシム基を含んだ置換基を有する殺虫性ミルベマイシン誘導体

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CN1111536C (zh) 2003-06-18
CN1310719A (zh) 2001-08-29
TW568913B (en) 2004-01-01
KR20010025100A (ko) 2001-03-26
KR100612634B1 (ko) 2006-08-14

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