JP5082341B2 - Method for producing imidazo [1,2-b] pyridazine compound - Google Patents
Method for producing imidazo [1,2-b] pyridazine compound Download PDFInfo
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Description
本発明は、イミダゾ［１，２−ｂ］ピリダジン化合物の製造方法に関する。 The present invention relates to a method for producing an imidazo [1,2-b] pyridazine compound.
イミダゾ［１，２−ｂ］ピリダジン化合物は、医農薬中間体として有用である。例えば、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンはスルホニル尿素系除草剤の中間体として重要な化合物である（例えば、特許文献１および２参照。）。該化合物の製造方法としては、例えば、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸とオキシ塩化リンとを反応させる方法が知られている（例えば、特許文献３参照。）。しかしながら、かかる方法では高温高圧の反応条件が必要であるため、工業的製法としては満足できるものではなかった。 The imidazo [1,2-b] pyridazine compound is useful as an intermediate for medicines and agricultural chemicals. For example, 2,6-dichloroimidazo [1,2-b] pyridazine is an important compound as an intermediate of a sulfonylurea herbicide (see, for example, Patent Documents 1 and 2). As a method for producing the compound, for example, a method of reacting 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid and phosphorus oxychloride is known (see, for example, Patent Document 3). ). However, such a method requires high-temperature and high-pressure reaction conditions, which is not satisfactory as an industrial production method.
このような状況のもと、本発明者らは、工業的に有利なイミダゾ［１，２−ｂ］ピリダジン化合物の製造方法について鋭意検討した結果、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物とオキシハロゲン化リンとの反応において、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物に対し０．５モル倍以上、かつ、オキシハロゲン化リンに対して１モル倍以下の範囲の量で有機塩基を存在させて実施することにより、常圧条件下においても効率よく反応が進行することを見出し、本発明に至った。 Under such circumstances, the present inventors have conducted extensive studies on a method for producing an industrially advantageous imidazo [1,2-b] pyridazine compound, and as a result, 3-imino-2,3-dihydropyridazine-2. -In reaction of an acetic acid compound and phosphorus oxyhalide, 0.5 mol times or more with respect to 3-imino-2,3-dihydropyridazine-2-acetic acid compound and 1 mol times or less with respect to phosphorus oxyhalide It was found that the reaction proceeds efficiently even under normal pressure conditions by carrying out the reaction in the presence of an organic base in an amount within the range of the present invention, and the present invention has been achieved.
すなわち本発明は、式（１）
で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物とオキシハロゲン化リンとを反応させることによる式（２）
で示されるイミダゾ［１，２−ｂ］ピリダジン化合物の製造方法において、式（１）で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物に対し０．５モル倍以上、かつ、オキシハロゲン化リンに対して１モル倍以下の範囲の量で有機塩基を存在させて実施することを特徴とするイミダゾ［１，２−ｂ］ピリダジン化合物の製造方法を提供するものである。
That is, the present invention provides the formula (1)
Formula (2) by reacting 3-imino-2,3-dihydropyridazine-2-acetic acid compound represented by the formula (2) with phosphorus oxyhalide
In the process for producing the imidazo [1,2-b] pyridazine compound represented by formula (1), the molar ratio is 0.5 mol times or more with respect to the 3-imino-2,3-dihydropyridazine-2-acetic acid compound represented by formula (1), and The present invention provides a method for producing an imidazo [1,2-b] pyridazine compound, which is carried out in the presence of an organic base in an amount in the range of 1 mol times or less with respect to phosphorus oxyhalide.
本発明によれば、医農薬中間体として有用なイミダゾ［１，２−ｂ］ピリダジン化合物を比較的低温かつ常圧の条件下で製造できるため、工業的に有利である。また、上記の量で有機塩基を存在させることにより、従来よりもオキシハロゲン化リンの使用量が削減できるという効果もある。 According to the present invention, an imidazo [1,2-b] pyridazine compound useful as an intermediate for medicines and agricultural chemicals can be produced under relatively low temperature and normal pressure conditions, which is industrially advantageous. In addition, the presence of the organic base in the above amount has an effect that the amount of phosphorus oxyhalide used can be reduced as compared with the conventional amount.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
式（１）で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（以下、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）と略記する。）の式中、Ｒ１、Ｒ２およびＲ３はそれぞれ同一または相異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されていてもよいアルキル基、ハロゲン原子で置換されていてもよいアルケニル基またはハロゲン原子で置換されていてもよいアルコキシ基を表す。 Formula of 3-imino-2,3-dihydropyridazine-2-acetic acid compound represented by formula (1) (hereinafter abbreviated as 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1)). R 1 , R 2 and R 3 are the same or different and are each a hydrogen atom, a halogen atom, an alkyl group which may be substituted with a halogen atom, an alkenyl group which may be substituted with a halogen atom or a halogen atom. Represents an alkoxy group which may be substituted with
ハロゲン原子としては、例えばフッ素原子、塩素原子、臭素原子が挙げられる。 Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
アルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘキシル基、シクロペンチル基、シクロヘキシル基等の炭素数１〜６の直鎖状、分岐状または環状のアルキル基が挙げられる。また、ハロゲン原子で置換されたアルキル基とは、前記アルキル基の炭素原子上に前記ハロゲン原子が１以上置換したものであり、例えばフルオロメチル基、クロロメチル基、ブロモメチル基、トリフルオロメチル基、１−クロロエチル基、１−ブロモエチル基、１，１，１−トリフルオロエチル基、１−クロロプロピル基、１−ブロモプロピル基、１，１，１−トリフルオプロピル基等が挙げられる。 Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclopentyl group, and a cyclohexyl group. -6 linear, branched or cyclic alkyl groups. In addition, the alkyl group substituted with a halogen atom is a group in which one or more halogen atoms are substituted on a carbon atom of the alkyl group, such as a fluoromethyl group, a chloromethyl group, a bromomethyl group, a trifluoromethyl group, Examples include 1-chloroethyl group, 1-bromoethyl group, 1,1,1-trifluoroethyl group, 1-chloropropyl group, 1-bromopropyl group, 1,1,1-trifluoropropyl group, and the like.
アルケニル基としては、例えばエテニル基、１−プロペニル基、２−プロペニル基、２−メチル−１−プロペニル基、１，２−プロパジエニル基、１−ブテニル基、２−ブテニル基、１，３−ブタジエニル基、１−ペンテニル基、１−ヘキセニル基、１−シクロヘキセニル基等の炭素数２〜６の直鎖状、分岐状および環状のアルケニル基が挙げられる。また、ハロゲン原子で置換されたアルケニル基とは、前記アルケニル基の炭素原子上に前記ハロゲン原子が１以上置換したものであり、例えば２−クロロー１−プロペニル基、２，２−ジクロロエテニル基、２−クロロー２−フルオロエテニル基、３−ブロモ−１−メチル−１−プロペニル基等が挙げられる。 Examples of the alkenyl group include ethenyl group, 1-propenyl group, 2-propenyl group, 2-methyl-1-propenyl group, 1,2-propadienyl group, 1-butenyl group, 2-butenyl group and 1,3-butadienyl. And straight-chain, branched and cyclic alkenyl groups having 2 to 6 carbon atoms such as a group, 1-pentenyl group, 1-hexenyl group and 1-cyclohexenyl group. The alkenyl group substituted with a halogen atom is a group in which one or more halogen atoms are substituted on the carbon atom of the alkenyl group, such as a 2-chloro-1-propenyl group, a 2,2-dichloroethenyl group, A 2-chloro-2-fluoroethenyl group, a 3-bromo-1-methyl-1-propenyl group and the like can be mentioned.
アルコキシ基としては、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、シクロプロピルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基等の炭素数１〜６の直鎖状または分岐状のアルコキシ基が挙げられる。ハロゲン原子で置換されたアルコキル基とは、前記アルコキシ基の炭素原子上に前記ハロゲン原子が１以上置換したものであり、例えばフルオロメトキシ基、クロロメトキシ基、ブロモメトキシ基、トリフルオロメトキシ基、１−クロロエトキシ基、１−ブロモエトキシ基、１，１，１−トリフルオロエトキシ基、１−クロロプロポキシ基、１−ブロモプロポキシ基、１，１，１−トリフルオプロポキシ基等が挙げられる。 As the alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, cyclopropyloxy group, cyclopentyloxy group, cyclohexyl C1-C6 linear or branched alkoxy groups, such as an oxy group, are mentioned. The alkoxy group substituted with a halogen atom is a group in which one or more halogen atoms are substituted on a carbon atom of the alkoxy group, such as a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, a trifluoromethoxy group, 1 -Chloroethoxy group, 1-bromoethoxy group, 1,1,1-trifluoroethoxy group, 1-chloropropoxy group, 1-bromopropoxy group, 1,1,1-trifluoropropoxy group and the like.
３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）としては、例えば、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−６−メチル−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−６−メトキシ−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−６−エトキシ−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−６−トリフルオロメチル−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−４−メチル−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−４，６−ジメチル−２，３−ジヒドロピリダジン−２−酢酸等が挙げられる。 Examples of the 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1) include 3-imino-2,3-dihydropyridazine-2-acetic acid, 3-imino-6-chloro-2,3- Dihydropyridazine-2-acetic acid, 3-imino-6-methyl-2,3-dihydropyridazine-2-acetic acid, 3-imino-6-methoxy-2,3-dihydropyridazine-2-acetic acid, 3-imino-6 -Ethoxy-2,3-dihydropyridazine-2-acetic acid, 3-imino-6-trifluoromethyl-2,3-dihydropyridazine-2-acetic acid, 3-imino-4-methyl-2,3-dihydropyridazine- Examples include 2-acetic acid and 3-imino-4,6-dimethyl-2,3-dihydropyridazine-2-acetic acid.
かかる３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）は、市販のものを用いてもよいし、例えば、特許第２８６３８５７号公報に記載の方法に準じて製造したものを用いてもよい。 As the 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1), a commercially available product may be used, for example, a product prepared according to the method described in Japanese Patent No. 2863857. May be.
反応に用いるオキシハロゲン化リンとしては、オキシ塩化リン、オキシ臭化リンが挙げられる。これらのオキシハロゲン化リンは、通常市販のものを用いることができる。その使用量は、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）に対して１モル倍以上あれば本発明の目的を達することができ、その上限は特にないが、通常１〜１０モル倍、好ましくは１．５〜６モル倍の範囲である。 Examples of the phosphorus oxyhalide used for the reaction include phosphorus oxychloride and phosphorus oxybromide. As these phosphorus oxyhalides, commercially available products can be used. If the amount used is 1 mole or more with respect to the 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1), the object of the present invention can be achieved, and there is no particular upper limit. It is 1-10 mol times, Preferably it is the range of 1.5-6 mol times.
有機塩基としては、例えば、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン等のトリアルキルアミン；ジメチルアニリン等のジアルキルアリールアミン；２−メチル−５−エチルピリジン、ピリジン等の複素芳香族アミン；などが挙げられる。かかる有機塩基は、通常、市販のものを用いることができる。また、有機塩基は、塩酸、臭化水素酸等のハロゲン化水素酸との塩であってもよい。有機塩基のハロゲン化水素酸塩は、市販のものを用いてもよいし、有機塩基とハロゲン化水素とから調整したものを用いてもよい。有機塩基をハロゲン化水素酸塩として用いる場合は、ハロゲン化水素酸におけるハロゲン原子が、オキシハロゲン化リンにおけるハロゲン原子と同一であることが好ましい。有機塩基の使用量は、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）に対して０．５モル倍以上、かつ、オキシハロゲン化リンに対して１モル倍以下の範囲であれば、本発明の目的を達することができる。 Examples of the organic base include trialkylamines such as trimethylamine, triethylamine and diisopropylethylamine; dialkylarylamines such as dimethylaniline; heteroaromatic amines such as 2-methyl-5-ethylpyridine and pyridine; As the organic base, a commercially available one can be usually used. The organic base may be a salt with a hydrohalic acid such as hydrochloric acid or hydrobromic acid. The organic base hydrohalide may be a commercially available one, or one prepared from an organic base and a hydrogen halide. When an organic base is used as the hydrohalide, it is preferable that the halogen atom in the hydrohalic acid is the same as the halogen atom in the phosphorus oxyhalide. The amount of the organic base used is in the range of 0.5 mol times or more with respect to the 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1) and 1 mol times or less with respect to phosphorus oxyhalide. If so, the object of the present invention can be achieved.
本反応は、溶媒を用いることなく実施することもできるが、反応に不活性な溶媒の存在下に実施することもできる。かかる溶媒としては、例えば、トルエン、キシレン等の芳香族炭化水素溶媒；デカン等の脂肪族炭化水素溶媒；モノクロロベンゼン等のハロゲン化芳香族炭化水素溶媒；テトラクロロエタン等のハロゲン化脂肪族炭化水素溶媒；等が挙げられ、その使用量は特に制限されない。 This reaction can be carried out without using a solvent, but can also be carried out in the presence of a solvent inert to the reaction. Examples of the solvent include aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as decane; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; halogenated aliphatic hydrocarbon solvents such as tetrachloroethane. Etc., and the amount used is not particularly limited.
反応温度は、６０℃以上であれば本発明の目的を達することができ、通常６０〜１８０℃、好ましくは８０〜１３０℃の範囲である。また本反応は、溶媒を使用する場合にはその沸点以下、溶媒を使用しない場合には有機塩基の沸点以下の温度で、それぞれ実施することが好ましい。したがって、より好ましい実施態様としては、沸点１３０℃以上の溶媒の存在下であるか、または、溶媒の非存在下であって用いる有機塩基の沸点が１３０℃以上であるか、いずれかの条件において、８０〜１３０℃の範囲で実施することがより好ましい。 If the reaction temperature is 60 ° C. or higher, the object of the present invention can be achieved, and it is usually in the range of 60 to 180 ° C., preferably 80 to 130 ° C. Further, this reaction is preferably carried out at a temperature not higher than the boiling point when a solvent is used and at a temperature not higher than the boiling point of the organic base when a solvent is not used. Therefore, in a more preferred embodiment, in the presence of a solvent having a boiling point of 130 ° C. or higher, or in the absence of a solvent, the boiling point of the organic base used is 130 ° C. or higher. More preferably, it is carried out in the range of 80 to 130 ° C.
本発明の反応は、通常、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）とオキシハロゲン化リンと有機塩基を混合した後、反応温度まで昇温することにより実施される。混合の順序は特に限定されないが、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）と接触するより前にオキシハロゲン化リンが有機塩基と接触することのないように混合することが好ましい。好ましい実施態様の具体例としては、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）と有機塩基と必要により溶媒との混合物中にオキシハロゲン化リンを加えていく方法；３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（１）と必要により溶媒との混合物中にオキシハロゲン化リンを加えていき、次いで有機塩基を加えていく方法；等が挙げられる。 The reaction of the present invention is usually carried out by mixing 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1), phosphorus oxyhalide and an organic base, and then raising the temperature to the reaction temperature. . The order of mixing is not particularly limited, but the mixing is performed so that the phosphorus oxyhalide does not come into contact with the organic base before contacting with the 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1). It is preferable. Specific examples of preferred embodiments include a method of adding phosphorus oxyhalide into a mixture of 3-imino-2,3-dihydropyridazine-2-acetic acid compound (1), an organic base, and optionally a solvent; 3 -A method of adding phosphorus oxyhalide into a mixture of imino-2,3-dihydropyridazine-2-acetic acid compound (1) and, if necessary, a solvent, and then adding an organic base.
副反応を抑制するため、上記の混合は６０℃未満に温度を保ちながら実施することが好ましく、０〜４０℃の範囲で混合することがより好ましい。また、上記の混合は、通常、発熱を伴うため、例えば滴下等の操作により、ゆっくりと試剤を加えていきながら混合することがさらに好ましい。 In order to suppress side reactions, the above mixing is preferably performed while maintaining the temperature below 60 ° C, and more preferably in the range of 0 to 40 ° C. In addition, since the above-mentioned mixing usually involves heat generation, it is more preferable to mix while slowly adding the reagent by an operation such as dropping.
上記混合操作の後、通常、上記の反応温度まで昇温することにより、反応が進行する。その際、急激に昇温すると、ハロゲン化水素ガスが一斉に発生し、操作面および収率面において悪影響が生じるおそれがあるため、ゆっくりと昇温することが好ましい。 After the mixing operation, the reaction proceeds usually by raising the temperature to the above reaction temperature. At that time, if the temperature is rapidly increased, hydrogen halide gas is generated all at once, which may cause adverse effects on the operation surface and the yield.
本発明の反応は、加圧条件下で実施してもよいが、通常は常圧条件下で実施する。 The reaction of the present invention may be carried out under pressurized conditions, but is usually carried out under normal pressure conditions.
昇温後の反応時間は、用いる溶媒や反応温度等の条件によって異なるが、通常１〜２４時間程度の範囲である。また、反応の進行は、例えばガスクロマトグラフィ、高速液体クロマトグラフィ、薄層クロマトグラフィ、ＮＭＲ、ＩＲ等の通常の分析手段により確認することができる。 The reaction time after the temperature rise varies depending on conditions such as the solvent used and the reaction temperature, but is usually in the range of about 1 to 24 hours. In addition, the progress of the reaction can be confirmed by ordinary analysis means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, NMR, IR and the like.
反応終了後、例えば、反応混合物と水もしくはアルカリ水溶液を混合し、必要に応じて水に不溶の有機溶媒を加えて抽出処理することにより、式（２）で示されるイミダゾ［１，２−ｂ］ピリダジン化合物（以下、イミダゾ［１，２−ｂ］ピリダジン化合物（２）と略記する。）を含む有機層を得ることができ、得られた有機層を濃縮することにより、イミダゾ［１，２−ｂ］ピリダジン化合物（２）を取り出すことができる。取り出したイミダゾ［１，２−ｂ］ピリダジン化合物（２）は、例えば再結晶やカラムクロマトグラフィ等の処理を施すことにより、さらに精製してもよい。水に不溶の有機溶媒としては、例えば、トルエン、キシレン、メシチレン等の芳香族炭化水素溶媒；デカン等の脂肪族炭化水素溶媒；モノクロロベンゼン等のハロゲン化芳香族炭化水素溶媒；テトラクロロエタン等のハロゲン化脂肪族炭化水素溶媒；酢酸エチル等のエステル溶媒；ジエチルエーテル、メチルｔｅｒｔ−ブチルエーテル等のエーテル溶媒；メチルエチルケトン、メチルイソブチルケトン等のケトン溶媒などが挙げられ、その使用量は特に制限されない。 After completion of the reaction, for example, the reaction mixture is mixed with water or an aqueous alkali solution, and if necessary, an insoluble organic solvent is added to water and extraction treatment is performed, whereby imidazo [1,2-b represented by the formula (2) is represented. ] An organic layer containing a pyridazine compound (hereinafter abbreviated as imidazo [1,2-b] pyridazine compound (2)) can be obtained, and by concentrating the obtained organic layer, imidazo [1,2 -B] The pyridazine compound (2) can be taken out. The extracted imidazo [1,2-b] pyridazine compound (2) may be further purified, for example, by subjecting it to treatment such as recrystallization or column chromatography. Examples of the water-insoluble organic solvent include aromatic hydrocarbon solvents such as toluene, xylene and mesitylene; aliphatic hydrocarbon solvents such as decane; halogenated aromatic hydrocarbon solvents such as monochlorobenzene; halogens such as tetrachloroethane An aliphatic hydrocarbon solvent; an ester solvent such as ethyl acetate; an ether solvent such as diethyl ether and methyl tert-butyl ether; a ketone solvent such as methyl ethyl ketone and methyl isobutyl ketone; and the amount used is not particularly limited.
本発明の反応により得られるイミダゾ［１，２−ｂ］ピリダジン化合物（２）としては、例えば、２−クロロイミダゾ［１，２−ｂ］ピリダジン、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン、６−メチル−２−クロロイミダゾ［１，２−ｂ］ピリダジン、６−メトキシ−２−クロロイミダゾ［１，２−ｂ］ピリダジン、６−エトキシ−２−クロロイミダゾ［１，２−ｂ］ピリダジン、６−トリフルオロメチル−２−クロロイミダゾ［１，２−ｂ］ピリダジン、４−メチル−２−クロロイミダゾ［１，２−ｂ］ピリダジン、４，６−ジメチル−２−クロロイミダゾ［１，２−ｂ］ピリダジン等が挙げられる。 Examples of the imidazo [1,2-b] pyridazine compound (2) obtained by the reaction of the present invention include 2-chloroimidazo [1,2-b] pyridazine, 2,6-dichloroimidazo [1,2-b]. Pyridazine, 6-methyl-2-chloroimidazo [1,2-b] pyridazine, 6-methoxy-2-chloroimidazo [1,2-b] pyridazine, 6-ethoxy-2-chloroimidazo [1,2- b] pyridazine, 6-trifluoromethyl-2-chloroimidazo [1,2-b] pyridazine, 4-methyl-2-chloroimidazo [1,2-b] pyridazine, 4,6-dimethyl-2-chloroimidazo [1,2-b] pyridazine and the like.
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれら実施例に限定されない。なお、以下の実施例における含量分析は、いずれも高速液体クロマトグラフィ内部基準法（以下、ＬＣ−ＩＳ法と略記する。）を用いて実施した。 EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples. In addition, all the content analysis in the following Examples was implemented using the high performance liquid chromatography internal reference method (henceforth abbreviated as LC-IS method).
実施例１
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９６．５重量％）４１．５ｇと混合キシレン２６０．０ｇとを混合し、該混合物を攪拌しながらオキシ塩化リン９８．１ｇを１時間かけて加えた。このときの内温は、２０〜２５℃の範囲であった。次いで内温を１０〜４０℃の範囲に保ちながら、トリエチルアミン３２．４ｇを２時間かけて加え、その後３時間かけて内温１２０℃まで昇温した。同温度で１２時間反応させた後、８０℃まで冷却した反応混合液を、８５℃に加温した水１８４．８ｇの中に１時間かけて滴下した。混合キシレン１２０．０ｇを加えた後、４８重量％水酸化ナトリウム水溶液を加えて、水層のｐＨを４．５に調整した。分液操作により有機層を分取した後、有機層を１重量％水酸化ナトリウム水溶液８３ｇを用いて洗浄し、さらに水８３ｇを用いて洗浄後、濃縮して２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジン３９．６ｇ（含量：９７．０重量％）を得た。
収率：９６％
Example 1
41.5 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 96.5% by weight) and 260.0 g of mixed xylene were mixed, and the mixture was stirred with phosphorus oxychloride. 98.1 g was added over 1 hour. The internal temperature at this time was in the range of 20 to 25 ° C. Next, 32.4 g of triethylamine was added over 2 hours while maintaining the internal temperature in the range of 10 to 40 ° C., and then the temperature was raised to 120 ° C. over 3 hours. After reacting at the same temperature for 12 hours, the reaction mixture cooled to 80 ° C. was dropped into 184.8 g of water heated to 85 ° C. over 1 hour. After adding 120.0 g of mixed xylene, a 48 wt% aqueous sodium hydroxide solution was added to adjust the pH of the aqueous layer to 4.5. After separating the organic layer by a liquid separation operation, the organic layer is washed with 83 g of a 1% by weight aqueous sodium hydroxide solution, further washed with 83 g of water, and concentrated to 2,6-dichloroimidazo [1, 2-b] pyridazine (39.6 g, content: 97.0% by weight) was obtained.
Yield: 96%
実施例２
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９９．５重量％）１．８８ｇと２−メチル−５−エチルピリジン３．６４ｇとを混合し、該混合物を攪拌しながらオキシ塩化リン９．２２ｇを３分間かけて滴下した。このときの内温は２０〜４０℃の範囲であった。次いで、２０分かけて内温１２０℃まで昇温した。同温度で６時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：９５％
Example 2
1.88 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 99.5% by weight) and 3.64 g of 2-methyl-5-ethylpyridine were mixed, and the mixture was While stirring, 9.22 g of phosphorus oxychloride was added dropwise over 3 minutes. The internal temperature at this time was in the range of 20 to 40 ° C. Subsequently, it heated up to 120 degreeC of internal temperature over 20 minutes. After reacting at the same temperature for 6 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 95%
実施例３
実施例２において、２−メチル−５−エチルピリジン３．６４ｇに代えて、ジメチルアニリン塩酸塩４．７０ｇを用いた以外は、実施例２と同様に実施したところ、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの収率は９０％であった。
Example 3
The same procedure as in Example 2 was performed except that 4.70 g of dimethylaniline hydrochloride was used instead of 3.64 g of 2-methyl-5-ethylpyridine in Example 2, and 2,6-dichloroimidazo [ The yield of 1,2-b] pyridazine was 90%.
実施例４
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９９．５重量％）１．８８ｇとモノクロロベンゼン７．５２ｇとピリジン０．７９ｇとを混合し、該混合物を攪拌しながらオキシ塩化リン３．８４ｇを３分間かけて滴下した。このときの内温は２０〜４０℃の範囲であった。次いで、２０分かけて内温１２０℃まで昇温した。その温度で６時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：９９％
Example 4
1.88 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 99.5 wt%), 7.52 g of monochlorobenzene and 0.79 g of pyridine are mixed, and the mixture is stirred. Then, 3.84 g of phosphorus oxychloride was added dropwise over 3 minutes. The internal temperature at this time was in the range of 20 to 40 ° C. Subsequently, it heated up to 120 degreeC of internal temperature over 20 minutes. After reacting at that temperature for 6 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 99%
実施例５
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９８重量％）１０．００ｇとキシレン６２．７２ｇの混合物を攪拌しながら、オキシ塩化リン２４．０３ｇを内温１０〜３０℃で滴下し、さらに該混合物を攪拌しながらトリエチルアミン１５．８４ｇを内温１０〜５０℃の範囲で滴下した。次いで、該混合物を内温１２０℃まで昇温した。その温度で２１時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：６１％
Example 5
While stirring a mixture of 10.00 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 98% by weight) and 62.72 g of xylene, 24.03 g of phosphorus oxychloride was added at an internal temperature of 10 The mixture was added dropwise at ˜30 ° C., and further, 15.84 g of triethylamine was added dropwise within the range of 10 to 50 ° C. while stirring the mixture. Next, the mixture was heated to an internal temperature of 120 ° C. After reacting at that temperature for 21 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 61%
実施例６
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９８重量％）１０．００ｇとキシレン６２．７２ｇの混合物を攪拌しながら、オキシ塩化リン１２．０１ｇを内温１０〜３０℃で滴下し、さらに該混合物を攪拌しながらトリエチルアミン２．６４ｇを内温１０〜５０℃の範囲で滴下した。次いで、該混合物を内温１２０℃まで昇温した。その温度で２４時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：６２％
Example 6
While stirring a mixture of 10.00 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 98 wt%) and 62.72 g of xylene, 120.1 g of phosphorus oxychloride was added at an internal temperature of 10 The mixture was added dropwise at -30 ° C, and 2.64 g of triethylamine was added dropwise in the range of 10-50 ° C while stirring the mixture. Next, the mixture was heated to an internal temperature of 120 ° C. After reacting at that temperature for 24 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 62%
実施例７
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９８重量％）１０．００ｇとキシレン６２．７２ｇの混合物を攪拌しながら、オキシ塩化リン２４．０３ｇを内温１０〜３０℃で滴下し、さらに該混合物を攪拌しながらジイソプロピルエチルアミン１０．１３ｇを内温１０〜５０℃の範囲で滴下した。次いで、該混合物を内温１２０℃まで昇温した。その温度で１５時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：７３％
Example 7
While stirring a mixture of 10.00 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 98% by weight) and 62.72 g of xylene, 24.03 g of phosphorus oxychloride was added at an internal temperature of 10 The mixture was added dropwise at -30 ° C, and 10.13 g of diisopropylethylamine was added dropwise at an internal temperature of 10-50 ° C while stirring the mixture. Next, the mixture was heated to an internal temperature of 120 ° C. After reacting at that temperature for 15 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 73%
比較例１
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９９．５重量％）１．８８ｇを攪拌しながらオキシ塩化リン９．２２ｇを３分間かけて滴下した。このときの内温は２０〜４０℃の範囲であった。次いで、３０分かけて内温１２０℃まで昇温した。同温度で６時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：２２％
Comparative Example 1
While stirring 1.88 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 99.5 wt%), 9.22 g of phosphorus oxychloride was added dropwise over 3 minutes. The internal temperature at this time was in the range of 20 to 40 ° C. Subsequently, it heated up to 120 degreeC of internal temperature over 30 minutes. After reacting at the same temperature for 6 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 22%
比較例２
３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸（含量：９９．５重量％）１．８８ｇと２−メチル−５−エチル−ピリジン７．２９ｇの混合物を攪拌しながら、オキシ塩化リン４．６１ｇを内温４０℃以下になるよう滴下し、次いで、該混合物を内温１２０℃まで昇温した。その温度で６時間反応させた後、冷却して反応混合液をＬＣ−ＩＳ法にて分析し、２，６−ジクロロイミダゾ［１，２−ｂ］ピリダジンの生成を確認した。
収率：０．４％
Comparative Example 2
While stirring a mixture of 1.88 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 99.5 wt%) and 7.29 g of 2-methyl-5-ethyl-pyridine, 4.61 g of phosphorus oxychloride was added dropwise so that the internal temperature was 40 ° C. or lower, and then the mixture was heated to an internal temperature of 120 ° C. After reacting at that temperature for 6 hours, the reaction mixture was cooled and analyzed by LC-IS method to confirm the formation of 2,6-dichloroimidazo [1,2-b] pyridazine.
Yield: 0.4%
Claims (4)
で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物とオキシハロゲン化リンとを反応させることによる式（２）
で示されるイミダゾ［１，２−ｂ］ピリダジン化合物の製造方法において、式（１）で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物に対し０．５モル倍以上、かつ、オキシハロゲン化リンに対して１モル倍以下の範囲の量で有機塩基を存在させて前記反応を実施することを特徴とするイミダゾ［１，２−ｂ］ピリダジン化合物の製造方法。 Formula (1)
Formula (2) by reacting 3-imino-2,3-dihydropyridazine-2-acetic acid compound represented by the formula (2) with phosphorus oxyhalide
In the process for producing the imidazo [1,2-b] pyridazine compound represented by formula (1), the molar ratio is 0.5 mol times or more with respect to the 3-imino-2,3-dihydropyridazine-2-acetic acid compound represented by formula (1), and A method for producing an imidazo [1,2-b] pyridazine compound, wherein the reaction is carried out in the presence of an organic base in an amount in the range of 1 mole or less relative to phosphorus oxyhalide.
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