JP2004203757A - Method for purifying milbemycins - Google Patents
Method for purifying milbemycins Download PDFInfo
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- milbemycin
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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
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、ミルベマイシン類の工業的スケールでの精製法に関する。
【０００２】
【従来の技術】
微生物代謝産物から得られる１６員環マクロライド化合物であるミルベマイシン類は、殺虫、殺ダニ活性又は駆虫活性を有することが知られており、例えば下記表１に示される化合物を挙げることが出来る。
【０００３】
【表１】
これらの化合物を製造する際、通常すべての微生物代謝産物と同様に、類縁体及び不純物が多く含まれる。従って、工業的にこれらの化合物を製造する場合、工業的製造法として使える方法で精製を行う必要がある。
【０００５】
一般的な上記化合物の精製法としては、発酵培養物から有機溶媒にて上記化合物を抽出した後、シリカゲル、アルミナ、デキストランゲル、イオン交換樹脂、合成吸着剤、分子ふるい、C8H17,C18H37,C6H5などの化学結合型シリカゲルなどの担体を用いたクロマトグラフィーに付し、得られた目的の化合物を含む画分を濃縮乾固する方法が知られている（例えば、特許文献１、特許文献２、特許文献３又は特許文献４参照。）。しかしながら、これらのクロマトグラフィーを用いる方法では、担体の負荷量が低いため、大量のクロマト担体及び有機溶媒等の溶出溶媒を用いねばならず、生産性も低く、得られた精製品は高価なものとなり、工業的には必ずしも満足できる精製法ではない。
【０００６】
【特許文献１】
特開昭５０−２９７４２号公報
【特許文献２】
特開昭５５−１３１３９８号公報
【特許文献３】
特開昭５６−３２４８１号公報
【特許文献４】
特開平１−１９３２７０号公報
【０００７】
【発明が解決しようとする課題】
本発明の目的は、工業的に煩雑な精製法、例えばクロマトグラフィーを用いずに、簡便に不要物を除去することができるミルベマイシン類の精製法を提供することにある。
【０００８】
【課題を解決するための手段】
本発明者らは、前記した課題の解決のため鋭意努力を重ねた結果、ミルベマイシン類を塩基で洗浄することにより、簡便に不要物を除去できることを見出し、本発明を完成した。
本発明は、
（１）ミルベマイシン類を塩基で洗浄することによるミルベマイシン類の精製法、
（２）ミルベマイシン類が、ミルベマイシンＡ3、ミルベマイシンＡ4、ミルベマイシンＤ、ミルベマイシンα11又はミルべマイシンα14から選択される化合物の一つ又は二つ以上の混合物である（１）記載の精製法、
（３）ミルベマイシン類が、ミルベマイシンＡ3、ミルベマイシンＡ4又はこれらの混合物である（１）又は（２）記載の精製法、
（４）溶剤中で行うことを特徴とする（１）乃至（３）から選ばれるいずれか一つに記載の精製法。
（５）ミルベマイシン類の酢酸エチル溶液を塩基で洗浄することを特徴とする、（１）乃至（４）から選ばれるいずれか一つに記載の精製法。
（６）塩基が、アミン類の溶液である、（１）乃至（５）から選ばれるいずれか一つに記載の精製法。
（７）塩基が、アンモニア水溶液である、（１）乃至（６）から選ばれるいずれか一つに記載の精製法である。
【０００９】
本発明における「ミルベマイシン類」としては、例えばミルベマイシンＡ3、ミルベマイシンＡ4、ミルベマイシンＤ、ミルベマイシンα11又はミルベマイシンα14から選択される化合物の１つ又は２つ以上の混合物を挙げることができ、好適には、ミルベマイシンＡ3、ミルベマイシンＡ4又はミルベマイシンＤから選択される化合物の１つ又は２つ以上の混合物を挙げることができ、さらに好適には、ミルベマイシンＡ3、ミルベマイシンＡ4又はこれらの混合物を挙げることが出来る。
【００１０】
本発明における「溶剤」としては、例えば、水；メタノール、エタノールもしくはｔ−ブタノールのようなアルコール類；アセトンもしくはメチルイソブチルケトンのようなケトン類；アセトニトリルのようなニトリル類；酢酸エチルのようなエステル類；塩化メチレン、クロロホルムもしくはジクロルエタンのようなハロゲン化炭化水素類；ジエチルエーテル、テトラヒドロフランもしくはジオキサンのようなエーテル類；ベンゼンもしくはトルエンのような芳香族炭化水素類；ジメチルホルムアミドもしくはジメチルアセトア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又はヘキサンもしくはオクタン等の脂肪族炭化水素類、及びこれらの混合溶媒があげられる。
【００１１】
本発明における「塩基」とは、ミルベマイシン類を分解させるものでなければ特に限定はないが、例えば、水酸化ナトリウム、水酸化カリウムもしくは水酸化リチウム等のようなアルカリ金属水酸化物；水酸化カルシウムもしくは水酸化マグネシウム等のようなアルカリ土類金属水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウムもしくは炭酸セシウム等のようなアルカリ金属炭酸塩又は炭酸カルシウム等のようなアルカリ土類金属炭酸塩のような無機の塩基類、あるいは、アンモニア、メチルアミン、ジメチルアミン、トリメチルアミン、エチルアミン、ジエチルアミン、トリエチルアミン、トリｎ−ブチルアミン、ジイソプロピルエチルアミン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８−ジアザビシクロ［５．４．０］ウンデセ−７−エン（ＤＢＵ）、ピリジン、コリジン又は４−（Ｎ，Ｎ−ジメチルアミノ）ピリジンなどのアミン類等が挙げられ、好適には、アミン類が挙げられ、さらに好適には、アンモニアが挙げられる。
【００１２】
【発明の実施の形態】
本発明は、ミルベマイシン類を塩基で洗浄することによるミルベマイシン類の精製法である。
ここで、「ミルベマイシン類を塩基で洗浄する」とは、
（Ａ）ミルベマイシン類を溶剤に溶かし、その溶剤に溶けない塩基を加え攪拌等をおこなうこと、
（Ｂ）ミルベマイシン類を溶剤に溶かし、その溶剤と混ざらない溶剤に塩基を溶かし攪拌等をおこなうこと、
（Ｃ）塩基をミルベマイシン類の溶けない溶剤に溶かし、ミルベマイシン類を加え攪拌等をおこなうこと、
（Ｄ）ミルベマイシン類を、洗浄を行う温度で液体である塩基に加え攪拌等をおこなうこと等を示す。
これらのうち、好適には、
（１）上記（Ａ）乃至（Ｃ）があげられ、さらに好適には、
（２）上記（Ａ）又は（Ｂ）が挙げられ、さらにより好適には、
（３）上記（Ａ）又は（Ｂ）において、ミルベマイシン類を溶かす溶剤が酢酸エチルである場合が挙げられ、特に好適には、
（４）上記（Ａ）又は（Ｂ）において、ミルベマイシン類を溶かす溶剤が酢酸エチルで、塩基がアミン類である場合が挙げられ、最も好適には、
（５）上記（Ｂ）において、ミルベマイシン類を溶かす溶剤が酢酸エチルで、塩基がアンモニアでその溶剤が水である場合が挙げられる。
【００１３】
ミルベマイシン類は、前記したようにいずれも殺虫、殺ダニ活性又は駆虫活性を有することが知られている公知の化合物であり、ミルベマイシンＡ3及びミルベマイシンＡ4は特開昭５５−１３１３９８号公報に、ミルベマイシンＤは特開昭５６−３２４８１号公報に、ミルベマイシンα11及びミルベマイシンα14は特開平１−１９３２７０号公報にそれぞれ記載されている方法により、製造することが出来る。
【００１４】
ミルベマイシン類を塩基で洗浄する際の時間は、特に限定はないが、通常１５分乃至２日間であり、好適には３０分乃至３時間である。その際の温度は、通常０乃至８０℃であり、好適には２０乃至４０℃である。
【００１５】
使用される塩基の使用量は、ミルベマイシン類の純度により大巾に変わりうるが、通常、ミルベマイシン類に対して重量比で２０％乃至１０倍量であり、好適には５０％乃至５倍量である。
【００１６】
洗浄工程終了後は、上記
（Ａ）の場合は、常法に従い塩基をろ過後、ろ液を、必要に応じて、例えば硫酸水溶液等の酸性の溶液で洗浄後、減圧下又は常圧で濃縮することにより、純度の改善されたミルベマイシン類を得ることができ、
（Ｂ）の場合は、ミルベマイシン類の溶けている溶液を抽出し、必要に応じて、例えば硫酸水溶液等の酸性の溶液で洗浄後、減圧下又は常圧で濃縮することにより、純度の改善されたミルベマイシン類を得ることができ、
（Ｃ）及び（Ｄ）の場合は、ミルベマイシン類をろ過し、適当な溶剤で洗浄することにより、純度の改善されたミルベマイシン類を得ることができる。
【００１７】
さらに必要に応じて、より高い純度の化合物を必要とする場合には、再結晶化法や液−液分配法、誘導化法などの方法を組み合わせることもできる。
【００１８】
【実施例】
本発明をさらに具体的に説明するために、以下に実施例等を示すが、本発明はこれに限定されるものではない。
（実施例１）
ミルベマイシンA3とミルベマイシンA4の発酵培養液由来のケーキから酢酸エチル溶液を調製した。一部を減圧下で濃縮した結果、その濃縮残渣の純度は28%（ミルベマイシンA3:4.2％；ミルベマイシンA4:23.8％）であった。当該酢酸エチル溶液（130ml）を、5%アンモニア水63ml、5%硫酸水溶液39mlで順次洗浄した。この酢酸エチル溶液を濃縮して得られた残渣にメタノール300mlと水300mlを順次添加し、その後、アイソパーE（エクソンモービル社製炭化水素系溶媒：オクタン60-70%、ノナン30-40%混合物）で抽出した。得られたアイソパーE溶液を減圧下で濃縮することにより再結晶化、ついで濾取を行うことにより、ミルベマイシンA3とミルベマイシンA4の結晶3.06g (収率75%)を得た。その純度は95%（ミルベマイシンA3:15.2％；ミルベマイシンA4:79.8％）であった。
【００１９】
ミルベマイシンA3とミルベマイシンA4の含有量、純度は下記の条件で高速液体クロマトグラフィーを用いて決定した。参考例１においても同様に決定した。
高速液体クロマトグラフィー条件
カラム：Wakosil-II 5C18 HG φ4.6×250mm
溶媒：アセトニトリル/水＝80/20
流速：1.0ml/min
検出：UV240nm
（参考例１）
ミルベマイシンA3とミルベマイシンA4の発酵培養液由来のケーキより調製したメタノール溶液１Lを濃縮し、得られた残渣をシリカゲル（ワコーゲルC-100、４００g使用）カラムクロマトグラフィーに付した。酢酸エチル-ヘキサン混合溶媒で展開し、得られたミルベマイシンA3とミルベマイシンA4含有画分を濃縮した。得られた残渣を再結晶に付した後、濾取することによりミルベメクチンの結晶２.６９g（収率78％）を得た。その純度は95%（ミルベマイシンA3:14.3％；ミルベマイシンA4:80.7％）であった。
【００２０】
【発明の効果】
本発明により、クロマトグラフィーを用いない簡便、安価、かつ精製効果の高いミルベマイシン類の精製法が提供される。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for purifying milbemycins on an industrial scale.
[0002]
[Prior art]
Milbemycins, which are 16-membered ring macrolide compounds obtained from microbial metabolites, are known to have insecticidal, acaricidal or anthelmintic activity, and include, for example, the compounds shown in Table 1 below.
[0003]
[Table 1]
In preparing these compounds, analogs and impurities are usually high, as are all microbial metabolites. Therefore, when these compounds are produced industrially, it is necessary to carry out purification by a method usable as an industrial production method.
[0005]
As a general method for purifying the above compound, after extracting the above compound with an organic solvent from a fermentation culture, silica gel, alumina, dextran gel, ion exchange resin, synthetic adsorbent, molecular sieve, C 8 H 17 , C 8 A method is known in which the fraction containing the target compound obtained is subjected to chromatography using a carrier such as a chemically bonded silica gel such as 18 H 37 and C 6 H 5 and concentrated to dryness (for example, See Patent Literature 1, Patent Literature 2, Patent Literature 3, or Patent Literature 4.) However, in these methods using chromatography, since the loading amount of the carrier is low, a large amount of a chromatographic carrier and an elution solvent such as an organic solvent must be used, the productivity is low, and the purified product obtained is expensive. This is not necessarily an industrially satisfactory purification method.
[0006]
[Patent Document 1]
Japanese Patent Application Laid-Open No. Sho 50-29742 [Patent Document 2]
JP-A-55-131398 [Patent Document 3]
JP-A-56-32481 [Patent Document 4]
JP-A-1-193270
[Problems to be solved by the invention]
An object of the present invention is to provide a method for purifying milbemycins that can easily remove unnecessary substances without using an industrially complicated purification method, for example, chromatography.
[0008]
[Means for Solving the Problems]
The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, have found that unnecessary substances can be easily removed by washing milbemycins with a base, thereby completing the present invention.
The present invention
(1) a method for purifying milbemycins by washing the milbemycins with a base,
(2) milbemycins are milbemycin A 3, milbemycin A 4, milbemycin D, which is one or a mixture of two or more compounds selected from milbemycin alpha 11 or mill base hygromycin alpha 14 (1) Purification Method according ,
(3) The purification method according to (1) or (2), wherein the milbemycins is milbemycin A 3 , milbemycin A 4 or a mixture thereof.
(4) The purification method according to any one of (1) to (3), which is performed in a solvent.
(5) The purification method according to any one of (1) to (4), wherein the ethyl acetate solution of milbemycins is washed with a base.
(6) The purification method according to any one of (1) to (5), wherein the base is a solution of amines.
(7) The purification method according to any one of (1) to (6), wherein the base is an aqueous ammonia solution.
[0009]
As the "milbemycins" in the present invention, for example milbemycin A 3, milbemycin A 4, milbemycin D, mention may be made of one or a mixture of two or more milbemycin alpha 11 or milbemycin alpha 14 compounds selected from, preferably May include one or a mixture of two or more compounds selected from milbemycin A 3 , milbemycin A 4 or milbemycin D. More preferably, milbemycin A 3 , milbemycin A 4 or a mixture thereof is used. Can be mentioned.
[0010]
Examples of the "solvent" in the present invention include water; alcohols such as methanol, ethanol or t-butanol; ketones such as acetone or methyl isobutyl ketone; nitriles such as acetonitrile; esters such as ethyl acetate. Halogenated hydrocarbons such as methylene chloride, chloroform or dichloroethane; ethers such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene or toluene; amides such as dimethylformamide or dimethylacetamide And sulfoxides such as dimethyl sulfoxide; aliphatic hydrocarbons such as hexane and octane; and mixed solvents thereof.
[0011]
The “base” in the present invention is not particularly limited as long as it does not decompose milbemycins. Examples thereof include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; calcium hydroxide Or alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate or cesium carbonate or alkaline earth metal carbonates such as calcium carbonate. Such inorganic bases, or ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-di Examples include amines such as zabicyclo [5.4.0] undec-7-ene (DBU), pyridine, collidine, and 4- (N, N-dimethylamino) pyridine, and preferably, amines. And more preferably ammonia.
[0012]
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is a method for purifying milbemycins by washing the milbemycins with a base.
Here, “washing milbemycins with a base” means
(A) dissolving milbemycins in a solvent, adding a base that is insoluble in the solvent, and stirring the mixture;
(B) dissolving the milbemycins in a solvent, dissolving the base in a solvent that does not mix with the solvent, and stirring the mixture;
(C) dissolving the base in a solvent in which milbemycins are insoluble, adding milbemycins and performing stirring, etc .;
(D) shows that milbemycins are added to a liquid base at a temperature at which washing is performed and stirring is performed.
Of these, preferably,
(1) The above (A) to (C) are mentioned, and more preferably,
(2) The above (A) or (B) is mentioned, and even more preferably,
(3) In the above (A) or (B), a case where the solvent for dissolving the milbemycins is ethyl acetate, and particularly preferably,
(4) In the above (A) or (B), a case in which the solvent for dissolving the milbemycins is ethyl acetate and the base is an amine, and most preferably,
(5) In the above (B), the case where the solvent for dissolving the milbemycins is ethyl acetate, the base is ammonia, and the solvent is water.
[0013]
Milbemycins are known compounds that are all known to have insecticidal, acaricidal or anthelmintic activity, as described above.Milbemycin A 3 and milbemycin A 4 are described in JP-A-55-131398. milbemycin D is in JP 56-32481, milbemycin alpha 11 and milbemycin alpha 14 by methods described respectively in JP-a-1-193270, can be produced.
[0014]
The time for washing the milbemycins with a base is not particularly limited, but is usually 15 minutes to 2 days, preferably 30 minutes to 3 hours. The temperature at that time is usually 0 to 80 ° C, preferably 20 to 40 ° C.
[0015]
The amount of the base used can vary widely depending on the purity of the milbemycins, but is usually 20% to 10 times by weight, preferably 50% to 5 times the weight of milbemycins. is there.
[0016]
After the washing step, in the case of the above (A), after filtering the base according to a conventional method, the filtrate is optionally washed with an acidic solution such as an aqueous sulfuric acid solution, and then concentrated under reduced pressure or normal pressure. By doing, it is possible to obtain milbemycins with improved purity,
In the case of (B), the purity of the solution is improved by extracting the solution in which the milbemycins are dissolved, washing with an acidic solution such as an aqueous solution of sulfuric acid as necessary, and concentrating under reduced pressure or normal pressure. Milbemycins can be obtained,
In the cases (C) and (D), milbemycins having improved purity can be obtained by filtering the milbemycins and washing them with a suitable solvent.
[0017]
Furthermore, if a higher purity compound is required, a method such as a recrystallization method, a liquid-liquid partition method, or a derivatization method can be used as needed.
[0018]
【Example】
EXAMPLES Examples and the like will be shown below to describe the present invention more specifically, but the present invention is not limited thereto.
(Example 1)
The ethyl acetate solution was prepared from milbemycin A 3 and cake from the fermentation broth of milbemycin A 4. Some results obtained by concentration under reduced pressure, purity of 28% of the concentrated residue:;: was (milbemycin A 3 4.2% milbemycin A 4 23.8%). The ethyl acetate solution (130 ml) was washed sequentially with 63 ml of 5% aqueous ammonia and 39 ml of 5% aqueous sulfuric acid. 300 ml of methanol and 300 ml of water are sequentially added to the residue obtained by concentrating the ethyl acetate solution, and then Isopar E (a mixture of hydrocarbons from ExxonMobil: 60-70% octane, 30-40% nonane). Extracted. Recrystallization resulting Isopar E solution by concentration under reduced pressure, followed by performing filtration to give crystals 3.06g of milbemycin A 3 and milbemycin A 4 (75% yield). Its purity 95%:;: was (milbemycin A 3 15.2% milbemycin A 4 79.8%).
[0019]
The content of milbemycin A 3 and milbemycin A 4, purity was determined by high performance liquid chromatography under the following conditions. Reference Example 1 was similarly determined.
High-performance liquid chromatography condition column: Wakosil-II 5C18 HG φ4.6 × 250mm
Solvent: acetonitrile / water = 80/20
Flow rate: 1.0ml / min
Detection: UV240nm
(Reference Example 1)
Concentration of the milbemycin A 3 and milbemycin A methanol solution 1L prepared from the cake from the fermentation broth of 4, the residue obtained was subjected to silica gel (Wako gel C-100,400g used) column chromatography. Ethyl acetate - developed with hexane mixed solvent, and concentrated milbemycin A 3 and milbemycin A 4 containing fraction obtained. The obtained residue was recrystallized and collected by filtration to obtain 2.69 g (yield 78%) of milbemectin crystals. Its purity 95%:;: was (milbemycin A 3 14.3% milbemycin A 4 80.7%).
[0020]
【The invention's effect】
According to the present invention, a simple, inexpensive, and highly effective purification method of milbemycins without using chromatography is provided.
Claims (7)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002371866A JP4373080B2 (en) | 2002-12-24 | 2002-12-24 | Purification of milbemycins |
| PCT/JP2003/016438 WO2004058771A1 (en) | 2002-12-24 | 2003-12-22 | Method for purification of milbemycins |
| KR1020057011825A KR101090047B1 (en) | 2002-12-24 | 2003-12-22 | Method for purification of milbemycins |
| CN200380107520.2A CN1732174B (en) | 2002-12-24 | 2003-12-22 | Method for purification of milbemycins |
| AU2003296180A AU2003296180A1 (en) | 2002-12-24 | 2003-12-22 | Method for purification of milbemycins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002371866A JP4373080B2 (en) | 2002-12-24 | 2002-12-24 | Purification of milbemycins |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2004203757A true JP2004203757A (en) | 2004-07-22 |
| JP2004203757A5 JP2004203757A5 (en) | 2006-02-16 |
| JP4373080B2 JP4373080B2 (en) | 2009-11-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002371866A Expired - Lifetime JP4373080B2 (en) | 2002-12-24 | 2002-12-24 | Purification of milbemycins |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP4373080B2 (en) |
| KR (1) | KR101090047B1 (en) |
| CN (1) | CN1732174B (en) |
| AU (1) | AU2003296180A1 (en) |
| WO (1) | WO2004058771A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2886640A1 (en) | 2013-12-18 | 2015-06-24 | Riga Technical University | Process for isolation of milbemycins A3 and A4 |
| CN106946905B (en) * | 2017-04-19 | 2019-09-20 | 丽珠集团福州福兴医药有限公司 | A kind of production method of mibemycin |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4582852A (en) * | 1983-11-02 | 1986-04-15 | Ciba-Geigy Corporation | 14- and 15-hydroxy milbemycin derivatives for controlling plant and animal parasites |
| GB2168345B (en) * | 1984-12-14 | 1988-05-25 | Ciba Geigy Ag | Pesticidal 13b-substituted milbemycin derivatives |
| FI860233A (en) * | 1985-01-22 | 1986-07-23 | Ciba Geigy Ag | 13 -ALKYL-MILBEMYCINDERIVAT FOER BEKAEMPNING AV PARASITER HOS DJUR OCH VAEXTER. |
| JPH0678342B2 (en) * | 1986-01-07 | 1994-10-05 | 三共株式会社 | New macrolide compound |
| AR243528A1 (en) * | 1986-12-11 | 1993-08-31 | Sankyo Co | A procedure for preparing macrolide compounds, and a procedure producing a pesticide compound with them. |
| US4855317A (en) * | 1987-03-06 | 1989-08-08 | Ciba-Geigy Corporation | Insecticides and parasiticides |
| JP2849389B2 (en) * | 1988-07-05 | 1999-01-20 | 三共株式会社 | New macrolide compound |
| NZ233680A (en) * | 1989-05-17 | 1995-02-24 | Beecham Group Plc | Avermectins and milbemycins and compositions thereof |
| NZ242592A (en) * | 1991-05-13 | 1993-12-23 | Merck & Co Inc | PROCESS FOR CONVERTING 13#a# HYDROXY AVERMECTIN AGLYCONES TO THE 13#B# |
| US5262400A (en) * | 1991-06-20 | 1993-11-16 | Merck & Co., Inc. | 4α-substituted avermectin derivatives |
| JPH0717979A (en) * | 1993-06-30 | 1995-01-20 | Takeda Chem Ind Ltd | Physiologically active substance ad-24-1b |
| DK0710290T3 (en) * | 1993-07-23 | 1999-08-30 | Pfizer | Process for precipitating natural avermectins and fermentative preparation of same |
| JPH08134071A (en) * | 1994-11-04 | 1996-05-28 | Sankyo Co Ltd | New 13-site-substituted milbemycin derivative |
| JP3499097B2 (en) * | 1995-09-22 | 2004-02-23 | 三共アグロ株式会社 | Insecticidal milbemycin derivatives having a substituent containing an oxime group at position 13 |
| HU225226B1 (en) * | 1995-09-29 | 2006-08-28 | Sankyo Lifetech Company Ltd | 13-substituted milbemycin 5-oxime derivatives, their use, and anthelmintic, acaricide and insecticide compositions containing these compounds |
-
2002
- 2002-12-24 JP JP2002371866A patent/JP4373080B2/en not_active Expired - Lifetime
-
2003
- 2003-12-22 CN CN200380107520.2A patent/CN1732174B/en not_active Expired - Lifetime
- 2003-12-22 WO PCT/JP2003/016438 patent/WO2004058771A1/en active Application Filing
- 2003-12-22 KR KR1020057011825A patent/KR101090047B1/en active IP Right Grant
- 2003-12-22 AU AU2003296180A patent/AU2003296180A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR101090047B1 (en) | 2011-12-07 |
| WO2004058771A1 (en) | 2004-07-15 |
| CN1732174A (en) | 2006-02-08 |
| AU2003296180A1 (en) | 2004-07-22 |
| JP4373080B2 (en) | 2009-11-25 |
| KR20050085876A (en) | 2005-08-29 |
| CN1732174B (en) | 2015-05-20 |
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