JP5092317B2 - Method for producing 3-imino-2,3-dihydropyridazine-2-acetic acid compound - Google Patents
Method for producing 3-imino-2,3-dihydropyridazine-2-acetic acid compound Download PDFInfo
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本発明は、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物の製造方法に関する。 The present invention relates to a method for producing a 3-imino-2,3-dihydropyridazine-2-acetic acid compound.
３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物は、医農薬中間体として有用である。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、クロロ酢酸とトリエチルアミンとからなる塩と３−アミノ−６−クロロピリダジ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、収率の点において工業的に満足できるものではなく、さらなる改善が求められていた。 3-Imino-2,3-dihydropyridazine-2-acetic acid compounds are useful as intermediates for medicines and agrochemicals. For example, 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid 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 a salt composed of chloroacetic acid and triethylamine with 3-amino-6-chloropyridazine is known (for example, see Patent Document 3). However, it is not industrially satisfactory in terms of yield, and further improvement has been demanded.
このような状況のもと、本発明者らは、工業的に有利な３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物の製造方法について鋭意検討した結果、ブロモ酢酸とアミン化合物とからなる塩を用いることにより、３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物が収率よく製造できることを見出し、本発明に至った。 Under such circumstances, the present inventors have intensively studied a method for producing an industrially advantageous 3-imino-2,3-dihydropyridazine-2-acetic acid compound, and as a result, from bromoacetic acid and an amine compound. It was found that a 3-imino-2,3-dihydropyridazine-2-acetic acid compound can be produced with good yield by using the resulting salt, and the present invention has been achieved.
すなわち本発明は、ブロモ酢酸とアミン化合物とからなる塩と式（１）
で示される３−アミノピリダジン化合物とを反応させることを特徴とする式（２）
で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物の製造方法を提供するものである。
That is, the present invention relates to a salt composed of bromoacetic acid and an amine compound and the formula (1)
And a 3-aminopyridazine compound represented by the formula (2)
The manufacturing method of 3-imino-2,3-dihydropyridazine-2-acetic acid compound shown by these is provided.
本発明によれば、医農薬中間体として有用な３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物を効率よく製造できるため、工業的に有利である。 According to the present invention, a 3-imino-2,3-dihydropyridazine-2-acetic acid compound useful as a pharmaceutical and agrochemical intermediate can be efficiently produced, which is industrially advantageous.
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−アミノピリダジン化合物（以下、３−アミノピリダジン化合物（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、アルキルチオ基、アルキルスルフェニル基、アルキルスルホニル基、ジアルキルアミノ基、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。 In the formula of the 3-aminopyridazine compound represented by the formula (1) (hereinafter abbreviated as 3-aminopyridazine compound (1)), R 1 , R 2 and R 3 are the same or different and are each a hydrogen atom , A halogen atom, an alkylthio group, an alkylsulfenyl group, an alkylsulfonyl group, a dialkylamino group, an alkyl group that may be substituted with a halogen atom, an alkenyl group that may be substituted with a halogen atom, or a halogen atom Represents an optionally substituted alkoxy group.
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.
無置換の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、前記無置換の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 unsubstituted 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. Examples thereof include a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. An alkyl group substituted with a halogen atom is one in which one or more halogen atoms are substituted on a carbon atom of the unsubstituted alkyl group. For example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, trifluoro Examples thereof include a methyl group, 1-chloroethyl group, 1-bromoethyl group, 1,1,1-trifluoroethyl group, 1-chloropropyl group, 1-bromopropyl group, 1,1,1-trifluoropropyl group.
無置換の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−プロペニル基等の炭素数２〜６の直鎖状、分岐状または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、前記無置換の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 unsubstituted 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, 1, C2-C6 straight chain such as 3-butadienyl group, 1-pentenyl group, 1-hexenyl group, 1-cyclohexenyl group ethenyl group, 1-propenyl group, 2-propenyl group, 2-methyl-1-propenyl group, etc. A chain, branched or cyclic alkenyl group may be mentioned. An alkenyl group substituted with a halogen atom is a group in which one or more halogen atoms are substituted on a carbon atom of the unsubstituted alkenyl group, such as a 2-chloro-1-propenyl group, 2,2-dichloroethyl, and the like. Examples thereof include a tenenyl group, a 2-chloro-2-fluoroethenyl group, and a 3-bromo-1-methyl-1-propenyl group.
無置換の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、前記無置換の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。 Examples of the unsubstituted alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, a cyclopropyloxy group, and a cyclopentyloxy group. And straight-chain or branched alkoxy groups having 1 to 6 carbon atoms such as a cyclohexyloxy group. 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 unsubstituted alkoxy group, such as a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, a trifluoromethoxy group. 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. .
アルキルチオ基、アルキルスルフェニル基、アルキルスルホニル基およびジアルキルアミノ基におけるアルキル基としては、前記した無置換のアルキル基が挙げられる。かかるアルキルチオ基としては、例えばメチルチオ基、エチルチオ基、プロピルチオ基、イソプロピルチオ基、ブチルチオ基、ｓｅｃ−ブチルチオ基、ｔｅｒｔ−ブチルチオ基、ペンチルチオ基、ヘキシルチオ基、シクロプロピルチオ基、シクロペンチルチオ基、シクロヘキシルチオ基等が挙げられ、アルキルスルフェニル基としては、例えばメチルスルフェニル基、エチルスルフェニル基、プロピルスルフェニル基、イソプロピルスルフェニル基、ブチルスルフェニル基、ｓｅｃ−ブチルスルフェニル基、ｔｅｒｔ−ブチルスルフェニル基、ペンチルスルフェニル基、ヘキシルスルフェニル基、シクロプロピルスルフェニル基、シクロペンチルスルフェニル基、シクロヘキシルスルフェニル基等が挙げられ、アルキルスルホニル基としては、例えばメチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、イソプロピルスルホニル基、ブチルスルホニル基、ｓｅｃ−ブチルスルホニル基、ｔｅｒｔ−ブチルスルホニル基、ペンチルスルホニル基、ヘキシルスルホニル基、シクロプロピルスルホニル基、シクロペンチルスルホニル基、シクロヘキシルスルホニル基等が挙げられる。また、ジアルキルアミノ基の２つのアルキル基は、互いに同一であっても相異なっていてもよく、かかるジアルキルアミノ基としては、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジイソプロピルアミノ基、ジブチルアミノ基、ジヘキシルアミノ基、ジシクロプロピルアミノ基、ジシクロペンチルアミノ基、ジシクロヘキシルアミノ基、メチルエチルアミノ基、エチルイソプロピルアミノ基等が挙げられる。また、ジアルキルアミノ基の２つのアルキル基が結合し、その結合窒素原子とともに環構造を形成していてもよく、かかる環状のジアルキルアミノ基としては、例えばアジリジノ基、ピロリジノ基、ピペリジノ基等が挙げられる。 Examples of the alkyl group in the alkylthio group, the alkylsulfenyl group, the alkylsulfonyl group, and the dialkylamino group include the aforementioned unsubstituted alkyl groups. Examples of the alkylthio group include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a sec-butylthio group, a tert-butylthio group, a pentylthio group, a hexylthio group, a cyclopropylthio group, a cyclopentylthio group, and a cyclohexylthio group. Examples of the alkylsulfenyl group include methylsulfenyl group, ethylsulfenyl group, propylsulfenyl group, isopropylsulfenyl group, butylsulfenyl group, sec-butylsulfenyl group, tert-butylsulfuryl group. Phenyl group, pentylsulfenyl group, hexylsulfenyl group, cyclopropylsulfenyl group, cyclopentylsulfenyl group, cyclohexylsulfenyl group, etc. For example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group, cyclopropylsulfonyl group, cyclopentylsulfonyl group, Examples include a cyclohexylsulfonyl group. Further, the two alkyl groups of the dialkylamino group may be the same or different from each other. Examples of the dialkylamino group include a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group. Group, dihexylamino group, dicyclopropylamino group, dicyclopentylamino group, dicyclohexylamino group, methylethylamino group, ethylisopropylamino group and the like. Further, two alkyl groups of a dialkylamino group may be bonded to form a ring structure together with the bonded nitrogen atom. Examples of the cyclic dialkylamino group include an aziridino group, a pyrrolidino group, and a piperidino group. It is done.
３−アミノピリダジン化合物（１）としては、３−アミノピリダジン、３−アミノ−６−クロロピリダジン、３−アミノ−６−メチルピリダジン、３−アミノ−６−ジメチルアミノピリダジン、３−アミノ−６−メトキシピリダジン、３−アミノ−６−エトキシピリダジン、３−アミノ−６−メチルチオピリダジン、３−アミノ−６−メタンスルホニルピリダジン、３−アミノ−６−トリフルオロメチルピリダジン、３−アミノー４−メチルーピリダジン、３−アミノー４ーメチルー６−ジメチルアミノピリダジン、３−アミノー４ーメチルー６−メチルチオピリダジン等が挙げられる。 Examples of the 3-aminopyridazine compound (1) include 3-aminopyridazine, 3-amino-6-chloropyridazine, 3-amino-6-methylpyridazine, 3-amino-6-dimethylaminopyridazine, 3-amino-6- Methoxypyridazine, 3-amino-6-ethoxypyridazine, 3-amino-6-methylthiopyridazine, 3-amino-6-methanesulfonylpyridazine, 3-amino-6-trifluoromethylpyridazine, 3-amino-4-methyl-pyridazine , 3-amino-4-methyl-6-dimethylaminopyridazine, 3-amino-4-methyl-6-methylthiopyridazine and the like.
かかる３−アミノピリダジン化合物（１）は、市販のものを用いてもよいし、例えば、特許第３０１２９９３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 this 3-aminopyridazine compound (1), a commercially available product may be used, for example, a product produced according to the method described in Japanese Patent No. 3012993 may be used.
ブロモ酢酸とアミン化合物とからなる塩（以下、単に「塩」と記載することもある。）としては、通常、溶媒の存在下にブロモ酢酸とアミン化合物とを反応させることにより調製させるものを用いる。アミン化合物としては、例えばトリメチルアミン、トリエチルアミン、トリ（ｎ−プロピル）アミン、ジイソプロピルメチルアミン、ジイソプロピルエチルアミン、トリ（ｎ−ブチル）アミン、ジシクロヘキシルメチルアミン、ジメチルシクロヘキシルアミン等の第三級アミンを用いることが好ましい。ブロモ酢酸およびアミン化合物は、通常、市販のものを用いることができる。アミン化合物の使用量は、ブロモ酢酸１モルに対して、通常０．９〜１．１モルの範囲である。 As a salt composed of bromoacetic acid and an amine compound (hereinafter sometimes simply referred to as “salt”), a salt prepared by reacting bromoacetic acid with an amine compound in the presence of a solvent is usually used. . As the amine compound, for example, a tertiary amine such as trimethylamine, triethylamine, tri (n-propyl) amine, diisopropylmethylamine, diisopropylethylamine, tri (n-butyl) amine, dicyclohexylmethylamine, dimethylcyclohexylamine or the like can be used. preferable. Commercially available bromoacetic acid and amine compounds can be used. The usage-amount of an amine compound is the range of 0.9-1.1 mol normally with respect to 1 mol of bromoacetic acids.
塩調製時に用いる溶媒としては、塩を溶解できるものであれば特に限定されない。かかる溶媒としては、例えば、水；メタノール、エタノール、イソプロイパノール等のアルコール溶媒；ジエチルエーテル、メチルイソブチルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、テトラヒドロフラン等のエーテル溶媒；などの単独または混合溶媒が挙げられ、その使用量は特に制限されない。 The solvent used in preparing the salt is not particularly limited as long as it can dissolve the salt. Examples of such solvents include water; alcohol solvents such as methanol, ethanol, and isopropylamine; ether solvents such as diethyl ether, methyl isobutyl ether, methyl-tert-butyl ether, and tetrahydrofuran; The amount used is not particularly limited.
塩調製時の反応温度は、高すぎると塩の分解が促進されるため、なるべく低温で実施することが好ましい。実用的には−５０〜３０℃、より好ましくは−１０〜２０℃の範囲である。 If the reaction temperature at the time of preparing the salt is too high, the decomposition of the salt is promoted, so it is preferable to carry out the reaction at as low a temperature as possible. Practically, it is -50-30 degreeC, More preferably, it is the range of -10-20 degreeC.
ブロモ酢酸とアミン化合物との混合順序は特に限定されないが、通常、該反応は発熱を伴うため、得られる塩が分解することを抑制するため、一方の反応試剤に、もう一方の反応試剤を加えていくことが好ましい。具体的に好ましい態様としては、溶媒とブロモ酢酸との混合溶液を反応温度以下に調製し、反応温度を越えないよう徐々にアミン化合物を加えていく方法が挙げられる。 The order of mixing the bromoacetic acid and the amine compound is not particularly limited. However, since the reaction is usually exothermic, the other reaction reagent is added to one reaction reagent in order to suppress decomposition of the resulting salt. It is preferable to continue. A specific preferred embodiment is a method in which a mixed solution of a solvent and bromoacetic acid is prepared at a reaction temperature or lower and the amine compound is gradually added so as not to exceed the reaction temperature.
得られたブロモ酢酸とアミン化合物とからなる塩を含む反応混合物は、そのまま３−アミノピリダジン化合物（１）との反応に用いてもよいし、該反応混合物から、濃縮等の手段により、ブロモ酢酸とアミン化合物とからなる塩を取り出した後、３−アミノピリダジン化合物（１）との反応に用いてもよい。また、該反応混合物から溶媒の一部を留去し、ブロモ酢酸とアミン化合物とからなる塩のスラリーを調製した後、３−アミノピリダジン化合物（１）との反応に用いてもよい。操作性の点で、得られたブロモ酢酸とアミン化合物とからなる塩を含む反応混合物をそのまま用いることが好ましい。 The obtained reaction mixture containing a salt composed of bromoacetic acid and an amine compound may be used for the reaction with the 3-aminopyridazine compound (1) as it is, or from the reaction mixture by means such as concentration. After taking out a salt consisting of amide and an amine compound, it may be used for the reaction with the 3-aminopyridazine compound (1). Moreover, after removing a part of solvent from this reaction mixture and preparing the slurry of the salt which consists of bromoacetic acid and an amine compound, you may use for reaction with 3-amino pyridazine compound (1). From the viewpoint of operability, it is preferable to use the obtained reaction mixture containing a salt composed of bromoacetic acid and an amine compound as it is.
ブロモ酢酸とアミン化合物とからなる塩と３−アミノピリダジン化合物（１）との反応は、通常、溶媒の存在下に実施される。溶媒としては、塩調整に用いられる溶媒として例示したものが挙げられ、好ましくは、塩調整に用いた溶媒と同一の溶媒を用いる。その使用量は特に制限されず、塩調製時に溶媒を用いた場合は、新たに溶媒を使用することなく実施することもできる。 The reaction of a salt composed of bromoacetic acid and an amine compound and the 3-aminopyridazine compound (1) is usually carried out in the presence of a solvent. As a solvent, what was illustrated as a solvent used for salt adjustment is mentioned, Preferably the same solvent as the solvent used for salt adjustment is used. The amount to be used is not particularly limited, and when a solvent is used at the time of salt preparation, it can be carried out without newly using a solvent.
ブロモ酢酸とアミン化合物とからなる塩の使用量は、３−アミノピリダジン化合物（１）１モルに対し、ブロモ酢酸基準で１モル以上用いれば、本発明の目的は達成できる。上述したように、塩が分解し易いことを考慮して、通常は過剰量用いる。好ましくは、１．１〜２．０モルの範囲である。 The amount of the salt composed of bromoacetic acid and an amine compound is 1 mol or more based on bromoacetic acid based on 1 mol of 3-aminopyridazine compound (1), thereby achieving the object of the present invention. As described above, an excessive amount is usually used in consideration of the salt being easily decomposed. Preferably, it is the range of 1.1-2.0 mol.
反応温度は、通常２０℃以上、用いる溶媒の沸点以下の範囲であり、好ましくは４０〜６０℃の範囲である。 The reaction temperature is usually in the range of 20 ° C. or higher and below the boiling point of the solvent used, and preferably in the range of 40 to 60 ° C.
ブロモ酢酸とアミン化合物とからなる塩と３−アミノピリダジン化合物（１）との混合順序は、特に限定されないが、好ましくは、反応温度に調製した溶媒と３−アミノピリダジン化合物（１）との混合物に、ブロモ酢酸とアミン化合物とからなる塩を加えていく。ブロモ酢酸とアミン化合物とからなる塩の安定性の面から、ブロモ酢酸とアミン化合物とからなる塩は、−５０〜３０℃で保持することが好ましい。また、ブロモ酢酸とアミン化合物とからなる塩を調製してから、その全量を３−アミノピリダジン化合物（１）と混合するまでの時間は、通常５０時間以内であり、０．１〜２４時間の範囲が好ましい。 The mixing order of the salt comprising bromoacetic acid and an amine compound and 3-aminopyridazine compound (1) is not particularly limited, but preferably a mixture of a solvent prepared at the reaction temperature and 3-aminopyridazine compound (1). A salt composed of bromoacetic acid and an amine compound is added. From the viewpoint of the stability of a salt composed of bromoacetic acid and an amine compound, the salt composed of bromoacetic acid and an amine compound is preferably maintained at −50 to 30 ° C. In addition, the time from the preparation of a salt composed of bromoacetic acid and an amine compound to the mixing of the total amount with the 3-aminopyridazine compound (1) is usually within 50 hours, 0.1 to 24 hours. A range is preferred.
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。 Although reaction time changes with conditions, such as a solvent to be used and reaction temperature, it is the range of about 1 to 24 hours normally. 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、例えば濃縮、抽出、晶析などの常法により反応液から式（２）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（２）と略記する。）を得ることができる。得られた３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（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。 After completion of the reaction, the 3-imino-2,3-dihydropyridazine-2-acetic acid compound represented by the formula (2) (hereinafter referred to as 3-imino-2, hereinafter) is represented from the reaction solution by a conventional method such as concentration, extraction or crystallization. 3-dihydropyridazine-2-acetic acid compound (2)). The obtained 3-imino-2,3-dihydropyridazine-2-acetic acid compound (2) may be further purified, for example, by performing treatment such as recrystallization or column chromatography.
本発明の反応により得られる３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物（２）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−（ジメチルアミノ）−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−メチルチオ−２，３−ジヒドロピリダジン−２−酢酸、３−イミノ−６−メタンスルホニル−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−イミノー４−メチルー２，３ージヒドロピリダジンー２−酢酸、３−イミノー４−メチルー６−ジメチルアミノー２，３ージヒドロピリダジンー２−酢酸、３−イミノー４−メチルー６−メチルチオー２，３ージヒドロピリダジンー２−酢酸等が挙げられる。 Examples of the 3-imino-2,3-dihydropyridazine-2-acetic acid compound (2) obtained by the reaction of the present invention include 3-imino-2,3-dihydropyridazine-2-acetic acid and 3-imino-6. -Chloro-2,3-dihydropyridazine-2-acetic acid, 3-imino-6-methyl-2,3-dihydropyridazine-2-acetic acid, 3-imino-6- (dimethylamino) -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-methylthio -2,3-dihydropyridazine-2-acetic acid, 3-imino-6-methanesulfonyl-2,3-dihydropyridazine-2-acetic acid, 3-imino-6-trifluoromethyl-2,3-dihi Ropyridazine-2-acetic acid, 3-imino 4-methyl-2,3-dihydropyridazine-2-acetic acid, 3-imino 4-methyl-6-dimethylamino-2,3-dihydropyridazine-2-acetic acid, 3-imino 4- And methyl-6-methylthio-2,3-dihydropyridazine-2-acetic acid.
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標準法を用いて実施した。 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 standard method.
実施例１
ブロモ酢酸１６４．６ｇと１０重量％含水メタノール２００ｇとを混合し、得られた溶液を、内温５℃に調整した。内温５〜７℃に保ちながら、該溶液にジイソプロピルエチルアミン１５３．１ｇを約３時間かけて加え、ブロモ酢酸とジイソプロピルエチルアミンとからなる塩を含む溶液を得た。得られた溶液を内温５〜７℃で３０分保温した後、内温５０℃に調整した３−アミノ−６−クロロピリダジン１００．０ｇ（含量：９９．２重量％）と１０重量％含水メタノール２００ｇとの混合物に、３０分かけて滴下した。ブロモ酢酸とジイソプロピルエチルアミンとからなる塩を含む溶液は、滴下が終了するまで、内温５〜７℃で保持した。
滴下終了後、得られた混合物を内温５０℃で１２時間保温した。反応終了後、反応混合物を約３時間かけて内温５℃まで冷却した。析出した固体を濾過により、反応混合物から分離した。分離した固体を１０重量％含水メタノール２４０ｇで２回洗浄した後、減圧乾燥し、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸１３０．０ｇ（含量：９８．３重量％）を得た。収率：８９％。
Example 1
164.6 g of bromoacetic acid and 200 g of 10 wt% aqueous methanol were mixed, and the resulting solution was adjusted to an internal temperature of 5 ° C. While maintaining the internal temperature at 5 to 7 ° C., 153.1 g of diisopropylethylamine was added to the solution over about 3 hours to obtain a solution containing a salt composed of bromoacetic acid and diisopropylethylamine. The obtained solution was kept at an internal temperature of 5-7 ° C. for 30 minutes, and then 100.0 g of 3-amino-6-chloropyridazine adjusted to an internal temperature of 50 ° C. (content: 99.2 wt%) and 10 wt% water content The mixture was added dropwise to a mixture with 200 g of methanol over 30 minutes. A solution containing a salt composed of bromoacetic acid and diisopropylethylamine was kept at an internal temperature of 5 to 7 ° C. until the dropping was completed.
After completion of dropping, the obtained mixture was kept at an internal temperature of 50 ° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to an internal temperature of 5 ° C. over about 3 hours. The precipitated solid was separated from the reaction mixture by filtration. The separated solid was washed twice with 240 g of 10 wt% aqueous methanol and then dried under reduced pressure to give 130.0 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 98.3% by weight). ) Yield: 89%.
実施例２
ブロモ酢酸１６４．６ｇと１０重量％含水メタノール２００ｇとを混合し、得られた溶液を、内温５℃に調整した。内温５〜７℃に保ちながら、該溶液にジイソプロピルエチルアミン１５３．１ｇを約３時間かけて加え、ブロモ酢酸とジイソプロピルエチルアミンとからなる塩を含む溶液を得た。得られた溶液を内温５〜７℃で３０分保温した後、内温５０℃に調整した３−アミノ−６−クロロピリダジン１００．０ｇ（含量：９９．２重量％）と１０重量％含水メタノール２００ｇとの混合物に、３時間かけて滴下した。ブロモ酢酸とジイソプロピルエチルアミンとからなる塩を含む溶液は、滴下が終了するまで、内温５〜７℃で保持した。
滴下終了後、得られた混合物を内温５０℃で１３時間保温した。反応終了後、反応混合物を約３時間かけて内温５℃まで冷却した。析出した固体を濾過により、反応混合物から分離した。分離した固体を１０重量％含水メタノール２４０ｇで２回洗浄した後、減圧乾燥し、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸１２６．９ｇ（含量：９８．３重量％）を得た。収率：８７％。
Example 2
164.6 g of bromoacetic acid and 200 g of 10 wt% aqueous methanol were mixed, and the resulting solution was adjusted to an internal temperature of 5 ° C. While maintaining the internal temperature at 5 to 7 ° C., 153.1 g of diisopropylethylamine was added to the solution over about 3 hours to obtain a solution containing a salt composed of bromoacetic acid and diisopropylethylamine. The obtained solution was kept at an internal temperature of 5-7 ° C. for 30 minutes, and then 100.0 g of 3-amino-6-chloropyridazine adjusted to an internal temperature of 50 ° C. (content: 99.2 wt%) and 10 wt% water content The mixture was added dropwise to a mixture with 200 g of methanol over 3 hours. A solution containing a salt composed of bromoacetic acid and diisopropylethylamine was kept at an internal temperature of 5 to 7 ° C. until the dropping was completed.
After completion of dropping, the obtained mixture was kept at an internal temperature of 50 ° C. for 13 hours. After completion of the reaction, the reaction mixture was cooled to an internal temperature of 5 ° C. over about 3 hours. The precipitated solid was separated from the reaction mixture by filtration. The separated solid was washed twice with 240 g of 10 wt% aqueous methanol and then dried under reduced pressure to give 126.9 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 98.3 wt%). ) Yield: 87%.
実施例３
実施例１において、ジイソブチルエチルアミンに代えて、トリエチルアミン１２０．３ｇを用いた以外は、実施例１と同様に実施し、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸１２９．６ｇ（含量：９７．５重量％）を得た。
収率：８８％
Example 3
The same procedure as in Example 1 was carried out except that 120.3 g of triethylamine was used instead of diisobutylethylamine in Example 1, and 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid 129. 6 g (content: 97.5% by weight) was obtained.
Yield: 88%
実施例４
ブロモ酢酸８５．８ｇとメタノール１５０ｇとを混合し、得られた溶液を、内温５℃に調整した。内温５〜７℃に保ちながら、該溶液にトリエチルアミン６２．５ｇを約３時間かけて加え、ブロモ酢酸とトリエチルアミンとからなる塩を含む溶液を得た。得られた溶液を内温２５℃で１時間保温した後、内温４５℃に調整した３−アミノ−６−クロロピリダジン５０ｇ（含量：９９．２重量％）とメタノール５０ｇとの混合物に、１．５時間かけて滴下した。ブロモ酢酸とトリエチルアミンとからなる塩を含む溶液は、滴下が終了するまで、内温２５℃で保持した。
滴下終了後、得られた混合物を内温４５℃で２２時間保温した。反応終了後、反応混合物に、蒸留水５０ｇを加え、約３時間かけて内温５℃まで冷却した。析出した固体を濾過により、反応混合物から分離した。分離した固体をメタノール１２０ｇで２回洗浄した後、減圧乾燥し、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸６０．６ｇ（含量：９３．７重量％）を得た。収率：７９％。
Example 4
85.8 g of bromoacetic acid and 150 g of methanol were mixed, and the resulting solution was adjusted to an internal temperature of 5 ° C. While maintaining the internal temperature at 5 to 7 ° C., 62.5 g of triethylamine was added to the solution over about 3 hours to obtain a solution containing a salt composed of bromoacetic acid and triethylamine. The obtained solution was kept at an internal temperature of 25 ° C. for 1 hour, and then mixed with 50 g of 3-amino-6-chloropyridazine adjusted to an internal temperature of 45 ° C. (content: 99.2 wt%) and 50 g of methanol. Added dropwise over 5 hours. A solution containing a salt composed of bromoacetic acid and triethylamine was kept at an internal temperature of 25 ° C. until the dropping was completed.
After completion of dropping, the obtained mixture was kept at an internal temperature of 45 ° C. for 22 hours. After completion of the reaction, 50 g of distilled water was added to the reaction mixture and cooled to an internal temperature of 5 ° C. over about 3 hours. The precipitated solid was separated from the reaction mixture by filtration. The separated solid was washed twice with 120 g of methanol and then dried under reduced pressure to obtain 60.6 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 93.7% by weight). . Yield: 79%.
実施例５
ブロモ酢酸８５．８ｇとメタノール１５０ｇとを混合し、得られた溶液を、内温５℃に調整した。内温５〜７℃に保ちながら、該溶液にトリエチルアミン６２．５ｇを約３時間かけて加え、ブロモ酢酸とトリエチルアミンとからなる塩を含む溶液を得た。得られた溶液を内温２５℃で２０時間保温した後、内温４５℃に調整した３−アミノ−６−クロロピリダジン５０ｇ（含量：９９．２重量％）とメタノール５０ｇとの混合物に、１．５時間かけて滴下した。ブロモ酢酸とトリエチルアミンとからなる塩を含む溶液は、滴下が終了するまで、内温２５℃で保持した。
滴下終了後、得られた混合物を内温４５℃で２２時間保温した。反応終了後、反応混合物に、蒸留水５０ｇを加え、約３時間かけて内温５℃まで冷却した。析出した固体を濾過により、反応混合物から分離した。分離した固体をメタノール１２０ｇで２回洗浄した後、減圧乾燥し、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸４８．５ｇ（含量：８９．６重量％）を得た。収率：６１％。
Example 5
85.8 g of bromoacetic acid and 150 g of methanol were mixed, and the resulting solution was adjusted to an internal temperature of 5 ° C. While maintaining the internal temperature at 5 to 7 ° C., 62.5 g of triethylamine was added to the solution over about 3 hours to obtain a solution containing a salt composed of bromoacetic acid and triethylamine. After the resulting solution was kept at an internal temperature of 25 ° C. for 20 hours, a mixture of 50 g of 3-amino-6-chloropyridazine (content: 99.2 wt%) adjusted to an internal temperature of 45 ° C. and 50 g of methanol was added to 1 Added dropwise over 5 hours. A solution containing a salt composed of bromoacetic acid and triethylamine was kept at an internal temperature of 25 ° C. until the dropping was completed.
After completion of dropping, the obtained mixture was kept at an internal temperature of 45 ° C. for 22 hours. After completion of the reaction, 50 g of distilled water was added to the reaction mixture and cooled to an internal temperature of 5 ° C. over about 3 hours. The precipitated solid was separated from the reaction mixture by filtration. The separated solid was washed twice with 120 g of methanol and then dried under reduced pressure to obtain 48.5 g (content: 89.6 wt%) of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid. . Yield: 61%.
実施例６
ブロモ酢酸８５．８ｇと１０重量％含水メタノール１５０ｇとを混合し、得られた溶液を、内温５℃に調整した。内温５〜７℃に保ちながら、該溶液にトリエチルアミン６２．５ｇを約３時間かけて加え、ブロモ酢酸とトリエチルアミンとからなる塩を含む溶液を得た。得られた溶液を内温７℃で１８時間保温した後、内温４５℃に調整した３−アミノ−６−クロロピリダジン５０ｇ（含量：９９．２重量％）と１０重量％含水メタノール５０ｇとの混合物に、１．５時間かけて滴下した。ブロモ酢酸とトリエチルアミンとからなる塩を含む溶液は、滴下が終了するまで、内温７℃で保持した。
滴下終了後、得られた混合物を内温４５℃で１８時間保温した。反応終了後、反応混合物に、蒸留水５０ｇを加え、約３時間かけて内温５℃まで冷却した。析出した固体を濾過により、反応混合物から分離した。分離した固体を１０重量％含水メタノール１２０ｇで２回洗浄した後、減圧乾燥し、３−イミノ−６−クロロ−２，３−ジヒドロピリダジン−２−酢酸７１．９ｇ（含量：７８．３重量％）を得た。収率：７８％。
Example 6
85.8 g of bromoacetic acid and 150 g of 10 wt% aqueous methanol were mixed, and the resulting solution was adjusted to an internal temperature of 5 ° C. While maintaining the internal temperature at 5 to 7 ° C., 62.5 g of triethylamine was added to the solution over about 3 hours to obtain a solution containing a salt composed of bromoacetic acid and triethylamine. The obtained solution was kept at an internal temperature of 7 ° C. for 18 hours, and then adjusted with 50 g of 3-amino-6-chloropyridazine adjusted to an internal temperature of 45 ° C. (content: 99.2 wt%) and 50 g of 10 wt% aqueous methanol. It was dripped at the mixture over 1.5 hours. A solution containing a salt composed of bromoacetic acid and triethylamine was kept at an internal temperature of 7 ° C. until the dropping was completed.
After completion of the dropwise addition, the obtained mixture was kept at an internal temperature of 45 ° C. for 18 hours. After completion of the reaction, 50 g of distilled water was added to the reaction mixture and cooled to an internal temperature of 5 ° C. over about 3 hours. The precipitated solid was separated from the reaction mixture by filtration. The separated solid was washed twice with 120 g of 10 wt% aqueous methanol and dried under reduced pressure to give 71.9 g of 3-imino-6-chloro-2,3-dihydropyridazine-2-acetic acid (content: 78.3 wt%). ) Yield: 78%.
Claims (8)
で示される３−イミノ−２，３−ジヒドロピリダジン−２−酢酸化合物の製造方法。 A salt comprising bromoacetic acid and an amine compound and formula (1)
The manufacturing method of 3-imino-2,3-dihydropyridazine-2-acetic acid compound shown by these.
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