JP2008069123A - Manufacturing method of hydroxypyridine n-oxide derivative, bipyridine diol derivative and dihalobipyridine derivative - Google Patents
Manufacturing method of hydroxypyridine n-oxide derivative, bipyridine diol derivative and dihalobipyridine derivative Download PDFInfo
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本発明は、有機合成化合物の中間体及び有機エレクトロルミネッセンス用中間体として有用なヒドロキシピリジンＮ−オキサイド誘導体、ビピリジンジオール誘導体及びジハロビピリジン誘導体の製造方法に関する。 The present invention relates to a method for producing hydroxypyridine N-oxide derivatives, bipyridinediol derivatives, and dihalobipyridine derivatives useful as intermediates for organic synthetic compounds and intermediates for organic electroluminescence.
４−ヒドロキシピリジンＮ−オキサイド誘導体の合成法として、４−ニトロピリジンＮ−オキサイドと無水酢酸からジメチルアニリン存在下で４−ヒドロキシピリジンＮ−オキサイドを得る合成法が記載されている（非特許文献１）。しかしながら、原料として用いる４−ニトロピリジンＮ−オキサイドは、爆発性が高いこと、変異原性が強陽性であること等の安全性の問題があった。又、更なる収率の向上が望まれていた。 As a method for synthesizing 4-hydroxypyridine N-oxide derivatives, a method for synthesizing 4-hydroxypyridine N-oxide from 4-nitropyridine N-oxide and acetic anhydride in the presence of dimethylaniline is described (Non-patent Document 1). ). However, 4-nitropyridine N-oxide used as a raw material has safety problems such as high explosiveness and strong positive mutagenicity. In addition, further improvement in yield has been desired.
更に、ビピリジンジオール誘導体の合成法として、４−ニトロピリジンＮ−オキサイドと４−ニトロピリジンからピリジルオキシピロリドンを経由して３，３′−ビピリジン−４，４′−ジオールを得ることが記載されている（非特許文献２）。しかしながら、４−ニトロピリジンは爆発性が非常に高く、大量生産に不適であるという問題があった。
本発明は上記問題点を解決すべく為されたものであり、その目的は、安全性が高く、高収率で得られるヒドロキシピリジンＮ−オキサイド誘導体、ビピリジンジオール誘導体及びジハロビピリジン誘導体の製造方法を提供することにある。 The present invention has been made to solve the above problems, and its object is to produce a hydroxypyridine N-oxide derivative, a bipyridinediol derivative, and a dihalobipyridine derivative that are highly safe and can be obtained in a high yield. Is to provide.
上記本発明の目的は、以下の構成により解決することができた。 The object of the present invention can be solved by the following configuration.
１．
下記一般式［１］で表される化合物を用いることを特徴とする下記一般式［２］で表されるヒドロキシピリジンＮ−オキサイド誘導体の製造方法。
1.
A method for producing a hydroxypyridine N-oxide derivative represented by the following general formula [2], wherein a compound represented by the following general formula [1] is used.
〔式中、Ｒ1は置換基を表し、Ｘ1はハロゲン原子を表す。ｎ1は０〜３の整数を表す。Ｍ1は水素原子又は金属原子を表す。〕
２．
下記一般式［２］で表される化合物と下記一般式［３］で表される化合物を反応することを特徴とする下記一般式［４］で表されるビピリジンジオール誘導体の製造方法。
[Wherein, R 1 represents a substituent, and X 1 represents a halogen atom. n 1 represents an integer of 0 to 3. M 1 represents a hydrogen atom or a metal atom. ]
2.
A method for producing a bipyridinediol derivative represented by the following general formula [4], comprising reacting a compound represented by the following general formula [2] with a compound represented by the following general formula [3].
〔式中、Ｒ1及びＲ2は各々、置換基を表し、Ｘ2はハロゲン原子を表す。ｎ1及びｎ2は各々、０〜３の整数を表す。Ｍ1及びＭ2は各々、水素原子又は金属原子を表す。〕
３．
前記１又は２記載の製造方法により得られた下記一般式［４］で表される化合物とハロゲン化剤を反応することを特徴とする下記一般式［５］で表されるジハロビピリジン誘導体の製造方法。
[Wherein, R 1 and R 2 each represent a substituent, and X 2 represents a halogen atom. n 1 and n 2 each represent an integer of 0 to 3. M 1 and M 2 each represent a hydrogen atom or a metal atom. ]
3.
A dihalobipyridine derivative represented by the following general formula [5] obtained by reacting a compound represented by the following general formula [4] obtained by the production method according to the above 1 or 2 with a halogenating agent. Production method.
〔式中、Ｒ1及びＲ2は各々、置換基を表し、Ｘ3はハロゲン原子を表す。ｎ1及びｎ2は各々、０〜３の整数を表す。Ｍ2は水素原子又は金属原子を表す。〕 [Wherein, R 1 and R 2 each represent a substituent, and X 3 represents a halogen atom. n 1 and n 2 each represent an integer of 0 to 3. M 2 represents a hydrogen atom or a metal atom. ]
本発明の製造方法により、有機合成化合物の中間体及び有機エレクトロルミネッセンス用中間体として有用なヒドロキシピリジンＮ−オキサイド誘導体、ビピリジンジオール誘導体及びジハロビピリジン誘導体を、安全性上問題のある化合物を用いることなく、高収率で得ることが出来る。 Use of a compound having a safety problem as a hydroxypyridine N-oxide derivative, a bipyridinediol derivative and a dihalobipyridine derivative useful as an intermediate of an organic synthetic compound and an intermediate for organic electroluminescence by the production method of the present invention. And can be obtained in high yield.
以下、本発明を更に詳細に述べる。 Hereinafter, the present invention will be described in more detail.
前記一般式［１］、一般式［２］、一般式［３］、一般式［４］及び一般式［５］において、Ｒ1及びＲ2で表される置換基としては、例えばアルキル、シクロアルキル、アルケニル、アリール、アシルアミノ、スルホンアミド、アルキルチオ、アリールチオ、ハロゲン原子、複素環、スルホニル、スルフィニル、ホスホニル、アシル、カルバモイル、スルファモイル、シアノ、アルコキシ、アリールオキシ、複素環オキシ、シロキシ、アシルオキシ、カルバモイルオキシ、アミノ、アルキルアミノ、イミド、ウレイド、スルファモイルアミノ、アルコキシカルボニルアミノ、アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、アルコキシカルボニル、アリールオキシカルボニル、カルボキシル等の各基が挙げられる。 In the general formula [1], general formula [2], general formula [3], general formula [4] and general formula [5], examples of the substituent represented by R 1 and R 2 include alkyl, cyclo Alkyl, alkenyl, aryl, acylamino, sulfonamido, alkylthio, arylthio, halogen atom, heterocyclic, sulfonyl, sulfinyl, phosphonyl, acyl, carbamoyl, sulfamoyl, cyano, alkoxy, aryloxy, heterocyclic oxy, siloxy, acyloxy, carbamoyloxy , Amino, alkylamino, imide, ureido, sulfamoylamino, alkoxycarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, carboxyl and the like.
Ｘ1、Ｘ2及びＸ3で表されるハロゲン原子としては、弗素、塩素、臭素及び沃素原子が挙げられる。これらの内、好ましいものは塩素原子である。 Examples of the halogen atom represented by X 1 , X 2 and X 3 include fluorine, chlorine, bromine and iodine atoms. Of these, preferred is a chlorine atom.
Ｍ1及びＭ2で表される金属原子としては、例えばアルカリ金属原子、アルカリ土類金属原子が挙げられる。これ等の内で好ましいものは、水素原子、ナトリウム原子及びカリウム原子である。 Examples of the metal atom represented by M 1 and M 2 include an alkali metal atom and an alkaline earth metal atom. Of these, preferred are a hydrogen atom, a sodium atom and a potassium atom.
上記の基は、何れも更に置換基によって置換されてもよく、該置換基として、例えばアルキル、シクロアルキル、アルケニル、アリール、アシルアミノ、スルホンアミド、アルキルチオ、アリールチオ、ハロゲン原子、複素環、スルホニル、スルフィニル、ホスホニル、アシル、カルバモイル、スルファモイル、シアノ、アルコキシ、アリールオキシ、複素環オキシ、シロキシ、アシルオキシ、カルバモイルオキシ、アミノ、アルキルアミノ、イミド、ウレイド、スルファモイルアミノ、アルコキシカルボニルアミノ、アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、アルコキシカルボニル、アリールオキシカルボニル、カルボキシル等の各基が挙げられる。 Any of the above groups may be further substituted with a substituent, such as alkyl, cycloalkyl, alkenyl, aryl, acylamino, sulfonamido, alkylthio, arylthio, halogen atom, heterocycle, sulfonyl, sulfinyl. , Phosphonyl, acyl, carbamoyl, sulfamoyl, cyano, alkoxy, aryloxy, heterocyclic oxy, siloxy, acyloxy, carbamoyloxy, amino, alkylamino, imide, ureido, sulfamoylamino, alkoxycarbonylamino, alkoxycarbonylamino, aryl Examples include oxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, carboxyl and the like.
以下に、本発明の一般式［１］、一般式［２］、一般式［３］、一般式［４］及び一般式［５］で表される化合物の代表的具体例を示すが、本発明はこれらに限定されものではない。 The typical examples of the compounds represented by the general formula [1], general formula [2], general formula [3], general formula [4] and general formula [5] of the present invention are shown below. The invention is not limited to these.
一般式［２］で表される化合物は、一般式［１］で表される化合物と金属水酸化物との反応で得られる。又、アルコール（例えばベンジルアルコール）との反応で得られたエーテル体を還元することで得ることもできる。金属水酸化物としては、例えばアルカリ金属水酸化物、アルカリ土類金属水酸化物が挙げられる。これ等の内で好ましいものはアルカリ金属水酸化物であり、更に好ましくは水酸ナトリウムである。 The compound represented by the general formula [2] can be obtained by a reaction between the compound represented by the general formula [1] and a metal hydroxide. Moreover, it can also obtain by reducing the ether body obtained by reaction with alcohol (for example, benzyl alcohol). Examples of the metal hydroxide include alkali metal hydroxide and alkaline earth metal hydroxide. Of these, preferred are alkali metal hydroxides, and more preferred is sodium hydroxide.
金属水酸化物の添加量は、一般式［１］で表される化合物１モルに対して１〜１０モルの範囲で用いることが好ましいが、３〜５モルの範囲が特に好ましい。用いられる反応溶媒としては、例えばアルコール、非プロトン性溶媒及び水等が挙げられるが、これ等の内で好ましいものは水である。反応温度は、通常、８０〜１３０℃で行われるのが好ましく、１００〜１１０℃が特に好ましい。 The addition amount of the metal hydroxide is preferably in the range of 1 to 10 mol, particularly preferably in the range of 3 to 5 mol, with respect to 1 mol of the compound represented by the general formula [1]. Examples of the reaction solvent used include alcohols, aprotic solvents, and water. Among these, water is preferable. The reaction temperature is usually preferably 80 to 130 ° C, particularly preferably 100 to 110 ° C.
本発明で用いられる一般式［３］で表される化合物は塩の形態で使用してもよく、例えば塩酸塩、硫酸等の鉱酸塩、メタンスルホン酸、トシル酸等のスルホン酸塩等が挙げられる。それらの塩の内、好ましいものは塩酸塩である。 The compound represented by the general formula [3] used in the present invention may be used in the form of a salt, for example, a hydrochloride, a mineral salt such as sulfuric acid, a sulfonate such as methanesulfonic acid, tosylic acid, etc. Can be mentioned. Of those salts, the hydrochloride is preferred.
一般式［２］で表される化合物と一般式［３］で表される化合物から、一般式［４］で表される化合物を得る反応は２段階で進行し、下記一般式［６］で表される中間体を経由する。第一の反応は反応系内のｐＨの影響を非常に受け易く、塩基性では反応が遅いのに対して、酸性となるにつれて反応が早くなるが、一般式［６］で表される中間体が経時で分解し易くなるという問題があった。これを改良する方法として、弱酸（例えば燐酸、カルボン酸等）の添加が有効であり、特に酢酸の添加が好ましいことが判った。 The reaction for obtaining the compound represented by the general formula [4] from the compound represented by the general formula [2] and the compound represented by the general formula [3] proceeds in two stages. Via the represented intermediate. The first reaction is very susceptible to the pH in the reaction system, and the reaction is slow when it is basic, whereas the reaction becomes faster as it becomes acidic, but the intermediate represented by the general formula [6] However, there was a problem that it became easy to decompose over time. As a method for improving this, it has been found that the addition of a weak acid (for example, phosphoric acid, carboxylic acid, etc.) is effective, and the addition of acetic acid is particularly preferable.
添加量は、一般式［２］で表される化合物１モルに対して０．１〜２．０モルの範囲で用いることが好ましいが、０．２〜０．７モルの範囲が特に好ましい。 The addition amount is preferably used in the range of 0.1 to 2.0 mol with respect to 1 mol of the compound represented by the general formula [2], but the range of 0.2 to 0.7 mol is particularly preferable.
一般式［６］で表される中間体から一般式［３］で表される化合物を得る反応は、熱による転位反応であり、用いられる溶媒として特に制限はないが、芳香族炭化水素類、エーテル類が好ましく、特にエチレングリコールジメチルエーテル、トルエンが好ましい。 The reaction for obtaining the compound represented by the general formula [3] from the intermediate represented by the general formula [6] is a rearrangement reaction by heat and is not particularly limited as a solvent to be used. Ethers are preferable, and ethylene glycol dimethyl ether and toluene are particularly preferable.
一般式［５］で表される化合物は、一般式［４］で表される化合物とハロゲン化剤との反応で得られる。該ハロゲン化剤としては、例えば塩化チオニル、三塩化燐、五塩化燐、オキシ塩化燐、三臭化燐等が挙げられる。これらの内で好ましいものはオキシ塩化燐である。 The compound represented by the general formula [5] is obtained by reacting the compound represented by the general formula [4] with a halogenating agent. Examples of the halogenating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide and the like. Of these, phosphorus oxychloride is preferred.
以下に実施例を挙げて本発明を具体的に説明するが、本発明の実施態様はこれらに限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the embodiments of the present invention are not limited to these examples.
実施例１（比較例）
《例示化合物２−１の合成》
Example 1 (comparative example)
<< Synthesis of Exemplary Compound 2-1 >>
無水酢酸７０ｍｌ、ジメチルアニリン１２ｇを混合し、約１００℃に加熱し、ニトロピリジン−Ｎ−オキシド１４ｇを４０分かけて添加した。更に、１００℃で２０分加熱・撹拌した。冷却後、撹拌しながらメタノール２０ｍｌを添加し、析出した結晶を減圧濾過により単離、乾燥することにより、例示化合物２−１を５．６ｇ得た（収率５０％）。 70 ml of acetic anhydride and 12 g of dimethylaniline were mixed and heated to about 100 ° C., and 14 g of nitropyridine-N-oxide was added over 40 minutes. Furthermore, it heated and stirred at 100 degreeC for 20 minutes. After cooling, 20 ml of methanol was added with stirring, and the precipitated crystals were isolated by filtration under reduced pressure and dried to obtain 5.6 g of Exemplified Compound 2-1 (yield 50%).
実施例２（本発明）
《例示化合物２−４の合成》
Example 2 (Invention)
<< Synthesis of Exemplary Compound 2-4 >>
水酸化ナトリウム７．７ｇを純水４６ｍｌに溶解し、この溶液に４−クロロピリジン−Ｎ−オキサイド５ｇを添加し、加熱・還流を３．５時間行った。反応液から水を減圧蒸溜により２０ｍｌ回収した後、更に室温で３時間攪拌した。その後、析出した結晶を濾取、乾燥することにより、例示化合物２−４を４．５ｇ得た（収率８７％）。 7.7 g of sodium hydroxide was dissolved in 46 ml of pure water, 5 g of 4-chloropyridine-N-oxide was added to this solution, and heating and refluxing were performed for 3.5 hours. After 20 ml of water was recovered from the reaction solution by distillation under reduced pressure, the mixture was further stirred at room temperature for 3 hours. Thereafter, the precipitated crystals were collected by filtration and dried to obtain 4.5 g of Exemplified Compound 2-4 (yield 87%).
実施例３（比較例）
《例示化合物４−１の合成》
Example 3 (comparative example)
<< Synthesis of Exemplary Compound 4-1 >>
４−ヒドロキシピリジン−Ｎ−オキサイド５．５５ｇ、４−ニトロピリジン６．２１ｇをメタノール１００ｍｌに投入し、１０時間加熱・還流した。メタノールを減圧溜去後、トルエン１５０ｍｌを加え、懸濁状態のまま１５時間加熱・還流した。冷却後、固体を減圧濾過により単離、乾燥することにより、例示化合物４−１を４．５ｇ得た（収率４８％）。 4-Hydroxypyridine-N-oxide 5.55 g and 4-nitropyridine 6.21 g were added to 100 ml of methanol, and heated and refluxed for 10 hours. Methanol was distilled off under reduced pressure, 150 ml of toluene was added, and the mixture was heated and refluxed for 15 hours while being suspended. After cooling, the solid was isolated by vacuum filtration and dried to obtain 4.5 g of Exemplified Compound 4-1 (yield 48%).
実施例４（本発明）
《例示化合物４−１の合成》
Example 4 (Invention)
<< Synthesis of Exemplary Compound 4-1 >>
４−クロロピリジン塩酸塩５．６ｇをメタノール３３ｍｌに溶解し、氷水冷下にＳＭ−２８を７．３ｇ加えた。もう一つの容器に４−クロロピリジン−Ｎ−オキサイド５．０ｇとメタノール３３ｍｌを入れ、更に、前記混合液及び酢酸１．２ｇを加えた。次に８時間加熱・攪拌した。不溶分を除去後、溶媒を溜去した。更にメタノール／アセトニトリル（１／４）を加え不溶分を再度除去した後、溶媒を溜去した。その後、エチレングリコールジメチルエーテル６６ｍｌを加え４時間加熱・還流した。減圧蒸溜にて溶媒を溜去し、メタノールを加え、析出した結晶を濾取、乾燥し、例示化合物４−１を４．３ｇ得た（収率６１％）。 5.6 g of 4-chloropyridine hydrochloride was dissolved in 33 ml of methanol, and 7.3 g of SM-28 was added under ice water cooling. In another container, 5.0 g of 4-chloropyridine-N-oxide and 33 ml of methanol were added, and the mixture and 1.2 g of acetic acid were further added. Next, the mixture was heated and stirred for 8 hours. After removing insoluble matter, the solvent was distilled off. Further, methanol / acetonitrile (1/4) was added to remove insoluble matters again, and then the solvent was distilled off. Thereafter, 66 ml of ethylene glycol dimethyl ether was added and heated and refluxed for 4 hours. The solvent was distilled off under reduced pressure, methanol was added, and the precipitated crystals were collected by filtration and dried to obtain 4.3 g of Exemplified Compound 4-1 (61% yield).
実施例５（本発明）
《例示化合物５−１の合成》
Example 5 (Invention)
<< Synthesis of Exemplary Compound 5-1 >>
例示化合物４−１を４．０ｇとオキシ塩化燐２０ｇを混合し、１時間加熱・還流を行った。過剰のＰＯＣｌ3を減圧溜去し、氷水をゆっくりと加え、更にｐＨが８程度になるまで炭酸カリウムを添加した。酢酸エチル抽出、水洗後、減圧蒸溜にて酢酸エチルを溜去した。酢酸エチル／トルエン（３／７）に溶解し、これに塩基性アルミナ９ｇを加え３０分間攪拌した。アルミナを除去後、減圧蒸溜にて溶媒を溜去した。更にヘキサンを加えて加熱後、冷却、攪拌し、析出した結晶を濾取、乾燥し、例示化合物５−１を３．５ｇ得た（収率７３％）。 4.0 g of Exemplified Compound 4-1 and 20 g of phosphorus oxychloride were mixed and heated and refluxed for 1 hour. Excess POCl 3 was distilled off under reduced pressure, ice water was slowly added, and potassium carbonate was further added until the pH reached about 8. After extraction with ethyl acetate and washing with water, ethyl acetate was distilled off under reduced pressure. It melt | dissolved in ethyl acetate / toluene (3/7), 9 g of basic aluminas were added to this, and it stirred for 30 minutes. After removing the alumina, the solvent was distilled off under reduced pressure. Further, hexane was added and heated, followed by cooling and stirring. The precipitated crystals were collected by filtration and dried to obtain 3.5 g of Exemplified Compound 5-1 (yield 73%).
実施例中の各化合物の同定はＭＡＳＳ及びＮＭＲスペクトルで行い、それぞれ目的化合物であることを確認した。その他の例示化合物も、上記の方法に準じて合成することが出来る。 Each compound in the examples was identified by MASS and NMR spectra to confirm that it was the target compound. Other exemplary compounds can also be synthesized according to the above method.
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