JPH05222041A - Method for purifying adenine derivative - Google Patents
Method for purifying adenine derivativeInfo
- Publication number
- JPH05222041A JPH05222041A JP2675892A JP2675892A JPH05222041A JP H05222041 A JPH05222041 A JP H05222041A JP 2675892 A JP2675892 A JP 2675892A JP 2675892 A JP2675892 A JP 2675892A JP H05222041 A JPH05222041 A JP H05222041A
- Authority
- JP
- Japan
- Prior art keywords
- salt
- adenine derivative
- adenine
- solvent
- recrystallized
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明はアデニン誘導体、詳細に
はＮ6 −［２−（Ｎ−メトキシ−Ｎ−メチルアミノ）エ
チル］アデニンの精製方法に関する。本発明に係わるア
デニン誘導体はサイトカイニンは、サイトカイニン活性
を示し、植物の細胞分裂促進、側芽の生長促進、発芽促
進、花芽形成と開花の促進、着果促進、果実肥大、老化
抑制および貯蔵器官における物質蓄積促進等の植物生理
作用の促進に有効な物質であり、植物生長調節剤として
利用できる。The present invention is adenine derivatives BACKGROUND OF THE, N 6 and in particular - about [2-(N-methoxy -N- methyl-amino) ethyl] Purification methods adenine. The adenine derivative according to the present invention is a cytokinin, which exhibits cytokinin activity, and promotes cell division of plants, promotion of lateral bud growth, promotion of germination, promotion of flower bud formation and flowering, fruit setting promotion, fruit enlargement, aging suppression and substances in storage organs. It is a substance effective in promoting plant physiological actions such as accumulation promotion and can be used as a plant growth regulator.
【０００２】[0002]
【従来の技術、発明が解決しようとする課題】本発明に
係わるアデニン誘導体の製造方法については、特開平２
−２５５６８２号、特願平２−３０７０７７号、特願平
３- ３３５４２４号に、またその精製方法としては特願
平３−１３２０１２号、特願平３−２６９１３０号に記
載されている。しかし、その精製品の純度は高速液体ク
ロマト（ＨＰＬＣ）分析によると９９．７％以下であ
り、本剤のより安定的な使用に対して高い純度のものが
要求されている。本発明の目的は上記のアデニン誘導体
を効率良く高純度に製造する方法を提供することにあ
る。2. Description of the Related Art A method for producing an adenine derivative according to the present invention is described in JP-A-2
-255682, Japanese Patent Application No. 2-307077, Japanese Patent Application No. 3-335424, and its purification method are described in Japanese Patent Application Nos. 3-132012 and 3-269130. However, the purity of the purified product is 99.7% or less according to high performance liquid chromatography (HPLC) analysis, and a high purity is required for more stable use of this agent. An object of the present invention is to provide a method for efficiently producing the above adenine derivative with high purity.
【０００３】[0003]
【課題を解決するための手段】本発明者らは、前述の事
情に鑑み、アデニン誘導体の精製について特願平３−１
３２０１２号による昇華法、ないし、特願平３−２６９
１３０号による再結晶を繰り返し行うことを試みたが純
度の向上が見られないことがわかり、さらにこのアデニ
ン誘導体の精製方法を鋭意検討した結果、その鉱酸との
塩を再結晶した後、塩基処理して本の該アデニン誘導体
を遊離することにより高純度に精製されることを見い出
し、本発明を完成した。In view of the above-mentioned circumstances, the inventors of the present invention have proposed Japanese Patent Application No. 3-1 regarding purification of an adenine derivative.
Sublimation method according to No. 32012 or Japanese Patent Application No. 3-269
Attempts were made to repeat recrystallization according to No. 130, but it was found that the purity was not improved. Further, as a result of diligent examination of the purification method of this adenine derivative, after recrystallizing the salt with the mineral acid, a base was obtained. The present invention has been completed by discovering that it is purified to a high degree of purity by processing to release the adenine derivative of the book.
【０００４】すなわち、本発明は式That is, the present invention
【化２】 で示されるアデニン誘導体を鉱酸との塩に変換してから
再結晶した後、塩基と処理して該アデニン誘導体を遊離
することを特徴とするアデニン誘導体の精製法に関す
る。以下にさらに詳しく本発明について記載する。[Chemical 2] The present invention relates to a method for purifying an adenine derivative, which is characterized in that the adenine derivative represented by the formula (1) is converted to a salt with a mineral acid, recrystallized, and then treated with a base to release the adenine derivative. The present invention will be described in more detail below.
【０００５】Ｎ6 −［ｎ−（Ｎ−メトキシ−Ｎ−メチル
アミノ）エチル］アデニンは６−クロロプリンとＮ−メ
トキシ−Ｎ−メチルメチレンジアミンとを塩基存在下反
応させることによって合成される。反応混合物から上記
化合物を単離する方法は以下のように行われる。すなわ
ち、反応混合物を水または重曹水と混合した後、有機溶
媒にて抽出し、乾燥後濃縮して粗生成物が固体として得
られる。この粗生成物は原料の６−クロロプリン、加水
分解によって生成するハイポキサンチン等を含むもので
あり、ＨＰＬＣ分析（カラム；ＯＤＳ，溶離液；水／ア
セトニトリル＝２／８、検出；２６８ｎｍ）によると８
８〜９５％程度の純度である。特願平３−２６９１３０
号に記載の精製方法によると、この粗生成物を１回の再
結晶によって、その純度が９８．５〜９９．７％である
精製品を、８０％以上の回収率で得ることができる。し
かし、この方法を繰り返し行ってもその純度は向上しな
い。また、特願平３−１３２０１２号による昇華法を併
用しても同様に純度の向上は見られなかった。本発明に
おいては、一度再結晶ない昇華したものを鉱酸との塩に
変換してから再結晶した後、塩基処理して該アデニン誘
導体を遊離するこによってＨＰＬＣ純度９９．９％以上
（９９．９４〜９９．９９％）の高純度精製品が得られ
る。鉱酸としては塩酸、臭化水素酸、硫酸、燐酸、また
は硝酸などを用いることができる。特に、その結晶性、
ないし取扱いの容易さから塩酸が有効である。その生成
方法は水ないしはアルコ−ルなどの溶媒中で行い、溶媒
を留去して該アデニン誘導体と鉱酸との塩が固体として
定量的に得られる。N 6- [n- (N-methoxy-N-methylamino) ethyl] adenine is synthesized by reacting 6-chloropurine with N-methoxy-N-methylmethylenediamine in the presence of a base. The method for isolating the above compound from the reaction mixture is carried out as follows. That is, the reaction mixture is mixed with water or aqueous sodium hydrogen carbonate, extracted with an organic solvent, dried and concentrated to give a crude product as a solid. The crude product contains 6-chloropurine as a raw material, hypoxanthine produced by hydrolysis, and the like, and according to HPLC analysis (column; ODS, eluent; water / acetonitrile = 2/8, detection; 268 nm). 8
The purity is about 8 to 95%. Japanese Patent Application No. 3-269130
According to the purification method described in No. 1, a purified product having a purity of 98.5 to 99.7% can be obtained with a recovery rate of 80% or more by recrystallizing the crude product once. However, the purity is not improved even if this method is repeated. Further, even if the sublimation method according to Japanese Patent Application No. 3-132012 was used in combination, no improvement in purity was observed. In the present invention, the sublimated substance that has not been recrystallized once is converted into a salt with a mineral acid, recrystallized, and then treated with a base to release the adenine derivative, whereby the HPLC purity is 99.9% or more (99. A high-purity refined product of 94-99.99%) is obtained. As the mineral acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or the like can be used. Especially its crystallinity,
Or, hydrochloric acid is effective because it is easy to handle. The production method is performed in a solvent such as water or alcohol, and the solvent is distilled off to quantitatively obtain a salt of the adenine derivative and the mineral acid as a solid.
【０００６】再結晶の溶媒としては単一または混合溶媒
を用いることができるが、混合溶媒がより有効である。
混合溶媒の例としてはメタノ−ル、エタノ−ル、ｎ−プ
ロピルアルコ−ル、イソプロピルアルコ−ルまたはｎ−
ブタノ−ルなどのアルコ−ル類、エチルエ−テル、イソ
プロピルエ−テル、モノグライム、ジグライム、ジオキ
サンまたはテトラヒドロフランなどのエ−テル類、ジク
ロロエタン、クロロホルム、ジクロロエタンなどのハロ
ゲン化炭素類、アセトン、エチルメチルケトン、エチル
イソプロピルケトン、メチルブチルケトンなどのケトン
類、ニトロメタン、ニトロベンゼン等のニトロ炭化水
素、アセトニトリル、炭化水素溶媒、または水から選ば
れる２種以上の溶媒からなる均一な混合溶媒を挙げるこ
とができる。鉱酸との塩から該アデニン誘導体を遊離さ
せるには１モル等量以上のアルカリ金属の水酸化物また
は３級アミンなどを用いることができる。塩基と水を溶
媒として反応させ、有機溶媒にて該アデニン誘導体を抽
出し、乾燥後、溶媒を留去して高純度精製品が得られ
る。As a solvent for recrystallization, a single solvent or a mixed solvent can be used, but the mixed solvent is more effective.
Examples of the mixed solvent include methanol, ethanol, n-propyl alcohol, isopropyl alcohol or n-.
Alcohols such as butanol, ethyl ether, isopropyl ether, monoglyme, diglyme, dioxane or tetrahydrofuran and other ethers, dichloroethane, chloroform, dichloroethane and other halogenated carbons, acetone, ethyl methyl ketone Examples thereof include ketones such as ethyl isopropyl ketone and methyl butyl ketone, nitrohydrocarbons such as nitromethane and nitrobenzene, acetonitrile, a hydrocarbon solvent, and a uniform mixed solvent of two or more solvents selected from water. In order to release the adenine derivative from the salt with a mineral acid, 1 mol equivalent or more of an alkali metal hydroxide or a tertiary amine can be used. A base and water are reacted as a solvent, the adenine derivative is extracted with an organic solvent, dried and the solvent is distilled off to obtain a highly purified product.
【０００７】[0007]
【実施例】本発明を実施例によりさらに具体的に説明す
るが、本発明はこれらの実施例に限定されるものではな
い。 実施例 Ｎ6 −［２−（Ｎ−メトキシ−Ｎ−メチルアミノ）エチ
ル］アデニンの精製 開示された方法によって得られる粗生成物４．１２ｇ
（ＨＰＬＣ純度 ９１％）を活性炭にて脱色した後、４
０ｍｌのメタノ−ル／塩化メチレン混合溶媒（メタノ−
ル／塩化メチレン＝１／９）に加温して溶解せしめ、こ
れを半分の容量にまで濃縮した。この溶液に２０ｍｌの
イソプロピルエ−テルを加えて０℃に冷却し、析出した
結晶を濾別、乾燥して、精製品 ３．９８ｇ（回収率
９６％）を白色結晶として得た。このものＨＰＬＣ純度
は９９．６％であった。この化合物１．９５ｇを８．８
３ｍｌの１Ｎ塩酸と２０ｍｌのエタノ−ルに溶かした
後、溶媒をエバポレ−タ−で留去して、塩酸塩２．２０
ｇを得た。この固体を１３ｍｌのクロロホルム／エタノ
−ル（９：１）に加熱して溶解させ、これに１５ｍｌの
イロプロピルエ−テルを加えて０℃に５時間冷却し、析
出した結晶を濾別し、１．８４ｇの精製塩酸塩を得た。
次に、この結晶を２０ｍｌの５％水酸化ナトリウムに溶
かし、この溶液をクロロホルム１００ｍｌにて連続抽出
した。有機層を無水炭酸ナトリウムにて乾燥後、濃縮、
乾固し、得られた無色固体をエ−テルで洗浄した。減圧
下乾燥して標題化合物１．７７ｇ（回収率 ９１％）を
得た。このもののＨＰＬＣ純度は９９．９５％で、融点
は１７０〜１７２℃であった。EXAMPLES The present invention will be described more specifically by way of examples, but the present invention is not limited to these examples. Example N 6 - [2- (N- methoxy -N- methylamino) ethyl] crude product obtained by purification methods of the disclosed adenine 4.12g
After decolorizing (HPLC purity 91%) with activated carbon, 4
0 ml of methanol / methylene chloride mixed solvent (methanol
Solution / methylene chloride = 1/9) to dissolve it by heating, and this was concentrated to a half volume. 20 ml of isopropyl ether was added to this solution and cooled to 0 ° C., and the precipitated crystals were separated by filtration and dried to obtain 3.98 g of a purified product (recovery rate).
96%) as white crystals. Its HPLC purity was 99.6%. 8.8 g of this compound
After dissolving in 3 ml of 1N hydrochloric acid and 20 ml of ethanol, the solvent was distilled off with an evaporator to give a hydrochloride of 2.20.
g was obtained. This solid was heated and dissolved in 13 ml of chloroform / ethanol (9: 1), 15 ml of isopropyl ether was added thereto, and the mixture was cooled to 0 ° C. for 5 hours, and the precipitated crystal was separated by filtration. 84 g of purified hydrochloride salt was obtained.
Next, this crystal was dissolved in 20 ml of 5% sodium hydroxide, and this solution was continuously extracted with 100 ml of chloroform. The organic layer was dried over anhydrous sodium carbonate and then concentrated,
It was evaporated to dryness and the obtained colorless solid was washed with ether. The crystals were dried under reduced pressure to give the title compound (1.77 g, recovery rate 91%). This had an HPLC purity of 99.95% and a melting point of 170 to 172 ° C.
【０００８】[0008]
【発明の効果】本発明によれば、植物生長調節剤の有効
成分となるＮ6 −［２−（Ｎ−メトキシ−Ｎ−メチルア
ミノ）エチル］アデニン化合物を高純度に精製すること
ができる。INDUSTRIAL APPLICABILITY According to the present invention, the N 6- [2- (N-methoxy-N-methylamino) ethyl] adenine compound, which is an active ingredient of a plant growth regulator, can be purified with high purity.
Claims (1)
再結晶した後、塩基と処理して該アデニン誘導体を遊離
することを特徴とするアデニン誘導体の精製法。1. The formula: A method for purifying an adenine derivative, which comprises converting the adenine derivative represented by the formula (1) to a salt with a mineral acid, recrystallizing the salt, and treating the salt with a base to release the adenine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2675892A JPH05222041A (en) | 1992-02-13 | 1992-02-13 | Method for purifying adenine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2675892A JPH05222041A (en) | 1992-02-13 | 1992-02-13 | Method for purifying adenine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05222041A true JPH05222041A (en) | 1993-08-31 |
Family
ID=12202182
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2675892A Pending JPH05222041A (en) | 1992-02-13 | 1992-02-13 | Method for purifying adenine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05222041A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007115990A1 (en) * | 2006-04-07 | 2007-10-18 | Lek Pharmaceuticals D.D. | Process for the preparation of pure irbesartan |
| JP2009179634A (en) * | 2005-06-22 | 2009-08-13 | H Lundbeck As | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
-
1992
- 1992-02-13 JP JP2675892A patent/JPH05222041A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009179634A (en) * | 2005-06-22 | 2009-08-13 | H Lundbeck As | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base |
| WO2007115990A1 (en) * | 2006-04-07 | 2007-10-18 | Lek Pharmaceuticals D.D. | Process for the preparation of pure irbesartan |
| US8212051B2 (en) | 2006-04-07 | 2012-07-03 | Lek Pharmaceuticals, D.D. | Process for the preparation of pure irbesartan |
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