JPWO2002094798A1 - Method for producing thiazole compound - Google Patents

Abstract

An object of the present invention is to provide a method for producing a thiazole compound having a good yield and excellent operability and safety in view of establishing an industrial production method. In the method for producing a thiazole compound represented by the formula (I), a compound represented by the formula (II) (wherein X represents a functional group capable of leaving against nucleophilic attack) and the formula (III) ) In a water solvent or in the presence of a base, at least one organic compound selected from the group consisting of halogen solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents The reaction is carried out in a solvent, or the reaction is carried out in the presence of a base in an organic solvent, and (1) the reaction is carried out by adding an acid, or (2) the reaction solution is concentrated.

Description

（式中、Ｒ_１は、水素原子、置換基を有してもよいＣ１〜Ｃ２０の炭化水素基、置換基を有してもよいヘテロ環基、置換基を有してもよいＣ１〜Ｃ２０のアルコキシカルボニル基、または、無置換もしくは置換アミノ基を表し、Ｒ_２は水素原子、ハロゲン原子、置換基を有してもよいＣ１〜Ｃ２０の炭化水素基、置換基を有してもよいヘテロ環基、置換基を有してもよいＣ１〜Ｃ２０アルコキシカルボニル基、置換基を有してもよいＣ１〜Ｃ２０のアシル基、ニトロ基、またはシアノ基を表し、Ｒ_３は、置換基を有してもよいＣ１〜Ｃ２０の炭化水素基、置換基を有してもよいヘテロ環基、置換基を有してもよいＣ１〜Ｃ２０のアルコキシカルボニル基、または、無置換もしくは置換アミノ基を表す。）で表されるチアゾール化合物の製造方法において、式（ＩＩ）

（式中、Ｒ_１、Ｒ_２は前記と同じ意味を表し、Ｘは、求核攻撃に対して脱離する官能基を表す。）で表される化合物と式（ＩＩＩ）

（式中、Ｒ_３は前記と同じ意味を表す。）で表される化合物を、水溶媒中で反応させることを特徴とする式（Ｉ）で表されるチアゾール化合物の製造方法であり、
［１−１］塩基存在下に反応を行うことを特徴とする［１］に記載の製造方法であり、さらに、［１−２］水と混合しない溶媒を添加し、触媒の存在下または非存在下に反応させることを特徴とする［１］に記載の製造方法である。
また、本発明は第２に、
［２］前記式（ＩＩ）で表される化合物と式（ＩＩＩ）で表される化合物を、塩基存在下、ハロゲン系溶媒、エステル系溶媒、炭化水素系溶媒、ケトン系溶媒、エーテル系溶媒からなる群から選ばれる少なくとも１種以上の有機溶媒中で反応させることを特徴とする前記式（Ｉ）で表されるチアゾール化合物の製造方法である。
さらに、本発明は第３に、
［３］前記式（ＩＩ）で表される化合物と式（ＩＩＩ）で表される化合物を有機溶媒中、塩基存在下反応させ、さらに、［３−１］酸を加えて反応させる、または［３−２］反応液を濃縮することを特徴とする式（Ｉ）で表されるチアゾール化合物の製造方法である。
発明の実施の形態：
本発明の製造方法の目的化合物である式（Ｉ）で表される化合物中、式中、Ｒ_１は、水素原子、または、置換基を有してもよい、Ｃ１〜Ｃ２０の炭化水素基、ヘテロ環基、Ｃ１〜Ｃ２０のアルコキシカルボニル基、もしくは置換アミノ基を表す。Ｒ_１として具体的には、水素原子；メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｔ−ブチル基、ｓ−ブチル基、イソブチル基、ｎ−ペンチル基、ｓ−ペンチル基、イソペンチル基、ネオペンチル基、ｎ−ヘキシル基、ｓ−ヘキシル基、１，１−ジメチル−ｎ−ヘキシル基、ｎ−ヘプチル基、ｎ−デシル基、ｎ−ドデシル基等Ｃ１〜Ｃ２０のアルキル基；ビニル基、アリル基、２−ブテニル基、１−メチル−２−プロペニル基、４−オクテニル基等のＣ２〜Ｃ２０のアルケニル基；エチニル基、プロパルギル基、１−メチル−プロピニル基等のＣ２〜Ｃ２０のアルキニル基；シクロプロピル基、シクロブチル基、シクロペンチル基、１−メチルシクロペンチル基、１−メチルシクロヘキシル基、１−アダマンチル基、１−メチルアダマンチル基、２−アダマンチル基、２−メチル−２−アダマンチル基、ノルボルニル基等のＣ３〜Ｃ２０の脂環式炭化水素基；フェニル基、１−ナフチル基、９−アントラセニル基等のＣ６〜Ｃ２０の芳香族炭化水素基；２−ピリジル基、３−ピリジル基、４−ピリジル基、２−フラニル基、２−チエニル基、３−チエニル基、１−ピロロ基、２−オキサゾリル基、３−イオオキサゾリル基、２−チアゾリル基、３−イオチアゾリル基、１−ピラゾリル基、４−ピラゾリル基、２−イミダゾリル基、１，３，４−オキサジアゾール−２−イル、１，２，４−オキサジアゾール−５−イル、１，３，４−チアジアゾール−２−イル、１，２，４−チアジアゾール−５−イル、１，３，４−トリアゾール−２−イル、１，２，３−チアジアゾール−５−イル、１，２，３−トリアゾール−４−イル、１，２，３，４−テトラゾール−５−イル、ピリミジン−２−イル、ピリミジン−４−イル、ピラジン−２−イル、ピリダジン−３−イル、１，２，４−トリアジン−６−イル、１，３，５−トリアジン−２−イル、１−ピロリジニル基、１−ピペリジル基、４−モルホリニル基、２−テトラヒドロフラニル基、４−テトラヒドロピラニル基等のヘテロ環基；メトキシカルボニル基、エトキシカルボニル基、ｎ−プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ−ブトキシカルボニル基、ｔ−ブトキシカルボニル基等のＣ１〜Ｃ２０のアルコキシカルボニル基；アミノ基、メチルアミノ基、ジメチルアミノ基、ｔ−ブトキシカルボニルアミノ基、ｐ−トルエンスルホニルアミノ基等を例示することができる。
また、Ｒ_２は、水素原子、ハロゲン原子、ニトロ基、シアノ基、または、置換基を有してもよい、Ｃ１〜Ｃ２０の炭化水素基、ヘテロ環基、Ｃ１〜Ｃ２０アルコキシカルボニル基、もしくはＣ１〜Ｃ２０のアシル基を表す。Ｒ_２として、具体的には、水素原子；フッ素原子、クロル原子、ブロム原子、ヨウ素原子のハロゲン原子；シアノ基；ニトロ基；メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｔ−ブチル基、ｓ−ブチル基、イソブチル基、ｎ−ペンチル基、ｓ−ペンチル基、イソペンチル基、ネオペンチル基、ｎ−ヘキシル基、ｓ−ヘキシル基、１，１−ジメチル−ｎ−ヘキシル基、ｎ−ヘプチル基、ｎ−デシル基、ｎ−ドデシル基等Ｃ１〜Ｃ２０のアルキル基；ビニル基、アリル基、２−ブテニル基、１−メチル−２−プロペニル基、４−オクテニル基等のＣ２〜Ｃ２０のアルケニル基；エチニル基、プロパルギル基、１−メチル−プロピニル基等のＣ２〜Ｃ２０のアルキニル基；シクロプロピル基、シクロブチル基、シクロペンチル基、１−メチルシクロペンチル基、１−メチルシクロヘキシル基、１−アダマンチル基、１−メチルアダマンチル基、２−アダマンチル基、２−メチル−２−アダマンチル基、ノルボルニル基等のＣ３〜Ｃ２０の脂環式炭化水素基；フェニル基、１−ナフチル基、９−アントラセニル基等のＣ６〜Ｃ２０の芳香族炭化水素基；２−ピリジル基、３−ピリジル基、４−ピリジル基、２−フラニル基、２−チエニル基、３−チエニル基、１−ピロロ基、２−オキサゾリル基、３−イオオキサゾリル基、２−チアゾリル基、３−イオチアゾリル基、１−ピラゾリル基、４−ピラゾリル基、２−イミダゾリル基、１，３，４−オキサジアゾール−２−イル、１，２，４−オキサジアゾール−５−イル、１，３，４−チアジアゾール−２−イル、１，２，４−チアジアゾール−５−イル、１，３，４−トリアゾール−２−イル、１，２，３−チアジアゾール−５−イル、１，２，３−トリアゾール−４−イル、１，２，３，４−テトラゾール−５−イル、ピリミジン−２−イル、ピリミジン−４−イル、ピラジン−２−イル、ピリダジン−３−イル、１，２，４−トリアジン−６−イル、１，３，５−トリアジン−２−イル、１−ピロリジニル基、１−ピペリジル基、４−モルホリニル基、２−テトラヒドロフラニル基、４−テトラヒドロピラニル基等のヘテロ環基；メトキシカルボニル基、エトキシカルボニル基、ｎ−プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ−ブトキシカルボニル基、ｔ−ブトキシカルボニル基等のＣ１〜Ｃ２０のアルコキシカルボニル基；アセチル基、プロパノイル基、ベンゾイル基、２−ピリジルカルボニル基等のＣ２〜Ｃ２０のアシル基；等を例示することができる。
また、Ｒ_３は、置換基を有してもよい、Ｃ１〜Ｃ２０の炭化水素基、ヘテロ環基、Ｃ１〜Ｃ２０のアルコキシカルボニル基、またはアミノ基を表し、Ｒ_１で例示した水素原子以外の具体例と同様の具体例を例示することができる。
上記のＲ_１乃至Ｒ_３の例示した置換基各々は、適当な炭素上の位置にさらに置換基を有していてもよい。その置換基としては、フッ素原子、クロル原子、ブロム原子、ヨウ素原子であるハロゲン原子；メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｔ−ブチル基、ｎ−ヘキシル基等のアルキル基；シクロプロプル基、シクロヘキシル基等のシクロアルキル基；ビニル基、アリル基等のアルケニル基；プロパルギル基等のアルキニル基；フェニル基、４−クロロフェニル基、４−メトキシフェニル基、３，４−ジメチルフェニル基等の置換されてもよいフェニル基；メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、ｓ−ブトキシ基、イソブトキシ基、ｔ−ブトキシ基、フェノキシ基、４−クロロフェノキシ基、ベンジルオキシ基、フェネチルオキシ基等のアルコキシ基；アミノ基、メチルアミノ基、ジメチルアミノ基、ｔ−ブトキシカルボニルアミノ基等のアミノ基；メチルチオ基、フェニルチオ基、２−ピリジルチオ基、メチルスルフィニル基、メチルスルホニル基等のアルキル、アリール、もしくはヘテロ環チオ基またはその酸化体；メトキシカルボニル基、エトキシカルボニル基、ｎ−プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ−ブトキシカルボニル基、ｔ−ブトキシカルボニル基等のＣ１〜Ｃ２０のアルコキシカルボニル基；アセチル基、プロパノイル基、ベンゾイル基、２−ピリジルカルボニル基等のＣ２〜Ｃ２０のアシル基；シアノ基、ニトロ基等を例示することができる。
これら置換基を有するＲ_１、Ｒ_２およびＲ_３の具体例としては、クロロメチル基、フルオロメチル基、ブロモメチル基、ジクロロメチル基、ジフロロメチル基、ジブロモメチル基、トリクロロメチル基、トリフルオロメチル基、トリブロモメチル基、トリクロロメチル基、トリフルオロエチル等のハロアルキル基；ペンタフルオロエチル基；テトラフルオロエテニル基、２，２−ジフロロエテニル基等のハロアルケニル基；メトキシメチル基、メトキシエチル基、フェノキシメチル基等のアルコキシアルキル基またはアリールオキシアルキル基；メチルチオメチル基、フェニルチオメチル基等のアルキルチオアルキル基またはアリールチオアルキル基；ベンジル基、ジフェニルメチル基、トリチル基、フェネチル基等のアラルキル基；ベンゾイルメチル基、アセチルメチル基等のアシルアルキル基；シアノメチル基等を挙げることができる。
式（Ｉ）で表される化合物として具体的には、下記表に示す化合物を例示することができる。
但し、表中、Ａ１〜Ａ４４は下記式の官能基を表し、その他の略語については次に示す意味を表す。
Ｍｅ：メチル、Ｅｔ：エチル、Ｐｒ：プロピル、Ｂｕ：ブチル、Ｐｅｎ：ペンチル、Ｈｅｘ：ヘキシル、Ｐｈ：フェニル、ｎ：ノルマル、ｉ：イソ、ｔ：ターシャリ、ｎｅｏ：ネオ、ｃ：シクロ

本発明に用いられる式（ＩＩ）で表される化合物において、Ｒ_１およびＲ_２は前記と同じ意味を表し、式（Ｉ）で例示されたのと同様の具体例を例示することができる。また、Ｘは、求核攻撃に対して脱離する官能基を表し、具体的には、クロル原子、ブロム原子、ヨウ素原子であるハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ジフェニルホスホニルオキシ基等を例示することができる。式（ＩＩ）で表される化合物の具体例としては、表１〜表９に示された化合物に対応する置換基の組み合わせが考えられ、それらの組み合わせに対して任意にＸを選択することができる。特に、ハロゲン原子を用いた場合、Ｒ_１、Ｒ_２置換基を有するケトン化合物を調整した後、ハロゲン化することにより容易に式（ＩＩ）で表される化合物を得ることができる。
本発明に用いられる式（ＩＩＩ）で表される化合物において、Ｒ_３は、前記と同様の意味を表し、式（Ｉ）で例示されたのと同様の具体例を例示することができる。
本発明の第１の製造方法［１］は、式（ＩＩ）で表される化合物と式（ＩＩＩ）で表される化合物を水溶媒中で反応させることを特徴とする。用いる水は、反応を阻害する不純物が含まれていない限り純水、蒸留水、工業用水、水道水等いずれの水も使用することができる。用いる水の量は、式（ＩＩ）及び（ＩＩ）で表される化合物が水溶媒中で十分に分散できる量であれば特に制限されない。
反応温度は、式（ＩＩ）で表される化合物の分解と反応速度を考慮すると室温〜１００℃の範囲で行うのが好ましく、さらに６０℃以下で行うのが好ましい。
反応方法は特に制限されず、（１）式（ＩＩ）及び（ＩＩＩ）で表される化合物を室温で水と混合し加熱する方法、（２）式（ＩＩ）または（ＩＩ）で表される化合物を水と混合し、加熱しながら他方の原料を添加する方法、（３）水溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩ）で表される化合物を交互にまたは同時に添加する方法等いずれの方法をも採用することができる。
反応に用いられる式（ＩＩ）で表される化合物の量としては、式（ＩＩＩ）で表される化合物に対して、０．５〜２．０好ましくは０．８〜１．２当量の範囲で用いるのが好ましい。
また、水溶媒中塩基存在下に反応を行うこともできる［１−１］。
用いる塩基は特に制限されないが、具体的には水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム等の無機水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸マグネシウム、炭酸カルシウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機炭酸塩または重炭酸塩；１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン、１，５−ジアザビシクロ［４．３．０］ノン−５−エン、６−ジブチルアミノ−１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン、トリエチレンジアミン、Ｎ，Ｎ−ジメチルアミノピリジン、トリメチルアミン、トリエチルアミン、トリ−ｎ−ブチルアミン、Ｎ，Ｎ−ジメチルシクロヘキシルアミン、Ｎ，Ｎ−ジエチルアニリン、ピリジン、キノリン、Ｎ，Ｎ−ジメチルアミノピリジン等の有機塩基等を例示することができる。
これらの塩基は、固体、液体をそのまま、また、水もしくは有機溶媒に希釈して用いることができる。用いる塩基の量は、式（ＩＩ）で表される化合物に対して特に制限はされないが、０．５〜１．５当量の範囲で用いるのが好ましい。
塩基を用いた場合、その反応方法として例えば、（１）式（ＩＩ）及び（ＩＩＩ）で表される化合物及び塩基を室温で水と混合し加熱する方法、（２）式（ＩＩ）及び（ＩＩＩ）で表される化合物を室温で水と混合し加熱し、塩基を添加する方法、（３）式（ＩＩ）または（ＩＩ）で表される化合物を水と混合し、加熱しながら他方の原料を添加し、さらに塩基を添加する方法、（４）水溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩＩ）で表される化合物を交互にまたは同時に添加したのち、塩基添加する方法、（５）水溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩＩ）で表される化合物、及び塩基を交互にまたは同時に添加する方法、（６）式（ＩＩＩ）で表される化合物と塩基を室温、または加熱下に水溶媒に混合し、式（ＩＩ）で表される化合物を添加する方法等いずれの方法をも採用することができるが、式（ＩＩ）、（ＩＩＩ）で表される化合物が塩基に不安定な場合は（２）の方法が好ましい。
また、反応溶媒は、水単独で用いて行うのが好ましいが、分液性、溶媒回収の妨げならない範囲で必要に応じて、メタノール、エタノール等のアルコール系溶媒、Ｎ、Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、Ｎ−メチルピロリドン等の非プロトン性極性溶媒、アセトン、テトラヒドロフラン、ジオキサン等の水溶性溶媒を添加して行うことも、また、水と混合しない溶媒を添加して二相系で反応を行う［１−２］こともできる。
二相系での反応方法［１−２］において使用される水と混合しない溶媒としては、ベンゼン、トルエン、キシレン、ヘキサン、シクロヘキサン等の炭化水素系溶媒、酢酸メチル、酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒、アセトン、メチルエチルケトン、ジエチルケトン、メチルイソブチルケトン等のケトン系溶媒、ジエチルエーテル、テロラヒドロフラン等のエーテル系溶媒、アセトニトリル、ベンゾニトリル等のニトリル系溶媒、塩化メチレン、クロロホルム、ジクロロエタン、クロロベンゼン等のハロゲン系溶媒等を例示することができる。
塩基としては、先に例示した水溶媒での反応で用いることのできる塩基を全て用いることができ、使用量としては、式（ＩＩ）で表される化合物１モルに対して０．５−３．０モル、好ましくは１．０−２．０モルである。
この反応は、相間移動触媒を添加して行ってもよい。本反応で用いられる相間移動触媒としては、４級アンモニウム塩類、４級ホスホニウム塩類等のオニウム塩類、クラウン化合物、有機塩基等が用いられる。具体的には４級アンモニウム塩としては、水酸化テトラメチルアンモニウム、水酸化テトラエチルアンモニウム、水酸化テトラブチルアンモニウム、水酸化トリメチルベンジルアンモニウム、臭化テトラメチルアンモニウム、臭化テトラエチルアンモニウム、臭化テトラブチルアンモニウム、臭化トリエチルベンジルアンモニウム、臭化トリメチルフェニルアンモニウム、塩化テトラメチルアンモニウム、塩化テトラエチルアンモニウム、塩化テトラブチルアンモニウム、塩化トリエチルベンジルアンモニウム、塩化トリメチルフェニルアンモニウム、塩化トリオクチルメチルアンモニウム、塩化トリブチルベンジルアンモニウム、塩化トリメチルベンジルアンモニウム、塩化Ｎ−ラウリルピリジニウム、塩化Ｎ−ベンジルピコリニウム、塩化トリカプリルメチルアンモニウム、沃化テトラメチルアンモニウム、沃化テトラブチルアンモニウム、テトラブチルアンモニウムサルフェート、等が挙げられ、４級ホスホニウム塩としては、塩化テトラエチルホスホニウム、臭化テトラエチルホスホニウム、沃化テトラエチルホスホニウム、臭化テトラブチルホスホニウム、臭化テトラフェニルホスホリウム、臭化取りフェニルベンジルホスホニウム等が挙げられ、クラウン化合物としてはエーテルとしては、１５−クラウン−５，１８−クラウン−６等のクラウンエーテル類、クリプタンド類等が挙げられ、有機塩基としては、１，８−ジアザビシクロ〔５．４．０〕ウンデク−７−エン、１，５−ジアザビシクロ〔４．３．０〕ノン−５−エン、６−ジブチルアミノ−１，８−ジアザビシクロ〔５．４．０〕ウンデク−７−エン、トリエチレンジアミン、Ｎ，Ｎ−ジメチルアミノピリジン等が挙げられる。
用いる触媒の量は、式（ＩＩ）で表される化合物１モルに対して０．０００１〜２．０モル、好ましくは０．００５−０．５モルの範囲である。
反応温度は、−３０℃〜溶媒の沸点の範囲で行うのが好ましく、特に好ましくは−１０〜６０℃の範囲である。
本発明の第２の製造方法［２］は、式（ＩＩ）及び式（ＩＩＩ）で表される化合物を塩基存在下、ハロゲン系溶媒、エステル系溶媒、炭化水素系溶媒、ケトン系溶媒、エーテル系溶媒からなる群から選ばれる少なくとも１種以上の有機溶媒中で反応させることを特徴とする。
用いられる塩基として、反応によって脱離するＨＸを有効に捕捉できるものであれば特に制限されないが、具体的には、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム等の無機水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸マグネシウム、炭酸カルシウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機炭酸塩または重炭酸塩；１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン、１，５−ジアザビシクロ［４．３．０］ノン−５−エン、６−ジブチルアミノ−１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン、トリエチレンジアミン、Ｎ，Ｎ−ジメチルアミノピリジン、トリメチルアミン、トリエチルアミン、トリ−ｎ−ブチルアミン、Ｎ，Ｎ−ジメチルシクロヘキシルアミン、Ｎ，Ｎ−ジエチルアニリン、ピリジン、キノリン、Ｎ，Ｎ−ジメチルアミノピリジン等の有機塩基を例示することができ、有機塩基を用いるのが好ましい。
用いる塩基は、式（ＩＩ）で表される化合物に対して１当量以上であれば、特に制限されないが、１．０〜１．２当量の範囲で用いるのが好ましい。
本発明に用いられる有機溶媒として具体的には、塩化メチレン、クロロホルム、ジクロロエタン、クロロベンゼン等のハロゲン系溶媒；ベンゼン、トルエン、キシレン、ヘキサン、シクロヘキサン等の炭化水素系溶媒；酢酸メチル、酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒；アセトン、メチルエチルケトン、ジエチルケトン、メチルイソブチルケトン等のケトン系溶媒；ジエチルエーテル、テロラヒドロフラン等のエーテル系溶媒；アセトニトリル、ベンゾニトリル等のニトリル系溶媒；ニトロベンゼン、ニトロメタン等のニトロ系溶媒を例示することができ、これらは、１種単独、または２種以上を混合して用いることができる。
用いる溶媒の量は、式（ＩＩ）及び（ＩＩＩ）で表される化合物が溶解または分散するのに十分な量であれば特に制限されない。
反応は、式（ＩＩ）で表される化合物の分解と反応速度を考慮すると室温〜１００℃の範囲で行うのが好ましく、さらに６０℃以下で行うのが好ましい。
反応方法として例えば、（１）式（ＩＩ）及び（ＩＩＩ）で表される化合物及び塩基を室温で有機溶媒と混合し加熱する方法、（２）式（ＩＩ）及び（ＩＩＩ）で表される化合物を室温で有機溶媒と混合し加熱し、塩基を添加する方法、（３）式（ＩＩ）または（ＩＩ）で表される化合物を有機溶媒と混合し、加熱しながら他方の原料を添加し、さらに塩基を添加する方法、（４）有機溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩＩ）で表される化合物を交互にまたは同時に添加したのち、塩基を添加する方法、（５）有機溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩＩ）で表される化合物、及び塩基を交互にまたは同時に添加する方法、（６）式（ＩＩＩ）で表される化合物と塩基を室温、または加熱下に有機溶媒に混合し、式（ＩＩ）で表される化合物を添加する方法等いずれの方法をも採用することができるが、式（ＩＩ）、（ＩＩＩ）で表される化合物が塩基に不安定な場合は（２）の方法が好ましい。
本発明の第３の方法［３］は、式（ＩＩ）、式（ＩＩＩ）で表される化合物を、有機溶媒中、塩基存在下反応させ、さらに（１）酸を加えて反応させる、または（２）反応液を濃縮することを特徴とする。
用いられる塩基としては、反応によって脱離するＨＸを有効に捕捉できるものであれば特に制限されないが、具体的には、水酸化ナトリウム、水酸化カリウム、水酸化マグネシウム、水酸化カルシウム等の無機水酸化物、炭酸ナトリウム、炭酸カリウム、炭酸マグネシウム、炭酸カルシウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機炭酸塩または重炭酸塩、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン、１，５−ジアザビシクロ［４．３．０］ノン−５−エン、６−ジブチルアミノ−１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン、トリエチレンジアミン、Ｎ，Ｎ−ジメチルアミノピリジン、トリメチルアミン、トリエチルアミン、トリ−ｎ−ブチルアミン、Ｎ，Ｎ−ジメチルシクロヘキシルアミン、Ｎ，Ｎ−ジエチルアニリン、ピリジン、キノリン、Ｎ，Ｎ−ジメチルアミノピリジン等の有機塩基を例示することができ、有機塩基を用いるのが好ましい。用いる塩基は、式（ＩＩ）で表される化合物に対して１当量以上であれば、特に制限されないが、１．０〜１．２当量の範囲で用いるのが好ましい。
反応に用いられる酸として具体的には、塩酸、硫酸、燐酸、硝酸等の鉱酸類、塩化水素、臭化水素、臭化臭素酸等のハロゲン化水素またはハロゲン化水素酸類、ｐ−トルエンスルホン酸、メタンスルホン酸、酢酸、トリフルオロ酢酸等の有機酸を例示することができる。用いる量は、反応系内が酸性条件になれば特に制限させず、触媒量以上であればよい。但し、先に用いた塩基が過剰の場合、過剰の塩基に対応する酸に加えて、触媒量以上の酸を添加する必要がある。
用いられる有機溶媒として具体的には、メタノール、エタノール、ｎ−ブタノール等のアルコール系溶媒；塩化メチレン、クロロホルム、ジクロロエタン、クロロベンゼン等のハロゲン系溶媒；ベンゼン、トルエン、キシレン、ヘキサン、シクロヘキサン等の炭化水素系溶媒；酢酸メチル、酢酸エチル、酢酸イソプロピル、酢酸ブチル等のエステル系溶媒；アセトン、メチルエチルケトン、ジエチルケトン、メチルイソブチルケトン等のケトン系溶媒；ジエチルエーテル、テロラヒドロフラン等のエーテル系溶媒；アセトニトリル、ベンゾニトリル等のニトリル系溶媒；ニトロベンゼン、ニトロメタン等のニトロ系溶媒を例示することができ、これらは、１種単独、または２種以上を混合して用いることができる。
用いる溶媒の量は、式（ＩＩ）及び（ＩＩＩ）で表される化合物が溶解または分散するのに十分な量であれば特に制限されない。
反応は、式（ＩＩ）で表される化合物の分解と反応速度を考慮すると室温〜１００℃の範囲で行うのが好ましく、さらに６０℃以下で行うのが好ましい。
反応方法として例えば、（１）式（ＩＩ）及び（ＩＩＩ）で表される化合物及び塩基を室温で有機溶媒と混合、加熱し、さらに酸を加えて加熱する方法、（２）式（ＩＩ）及び（ＩＩＩ）で表される化合物を室温で有機溶媒と混合し加熱し、塩基を添加し、さらに酸を加えて加熱する方法、（３）式（ＩＩ）または（ＩＩ）で表される化合物を有機溶媒と混合し、加熱しながら他方の原料を添加し、さらに塩基を添加し、さらに酸を加えて加熱する方法、（４）有機溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩＩ）で表される化合物を交互にまたは同時に添加したのち、塩基添加し、さらに酸を加えて加熱する方法、（５）有機溶媒のみを加熱しておき、式（ＩＩ）、（ＩＩＩ）で表される化合物、及び塩基を交互にまたは同時に添加し、さらに酸を加えて加熱する方法、（６）式（ＩＩＩ）で表される化合物と塩基を室温、または加熱下に有機溶媒に混合し、式（ＩＩ）で表される化合物を添加し、さらに酸を加えて加熱する方法等いずれの方法をも採用することができるが、式（ＩＩ）、（ＩＩＩ）で表される化合物が塩基に不安定な場合は（２）の方法が好ましい。
酸を用いて反応させる工程または反応液を濃縮する工程は、室温〜１００℃の範囲で行うのが好ましく、さらに６０℃以下で行うのが好ましい。反応液を濃縮する工程は、用いる反応溶媒によるが、常圧下、または減圧下に溶媒を留去することにより行うことができる。また、反応液を処理することなく濃縮することも、また、酸または水等で処理した後、濃縮することもできる。
水を反応溶媒に用いた場合、反応終了後、室温以下に冷却し、析出した結晶を濾過することにより、また、溶媒抽出等通常の単離操作を行うことで目的物である式（Ｉ）で表される化合物を十分な純度、収率で得ることができる。
有機溶媒を反応溶媒に用いた場合、目的物が溶解していればそのまま、溶解していない場合は、溶解する溶媒を添加もしくはそのような溶媒に置換した後、水洗し不純物を除去した後、通常の単離操作を行うことで目的物である式（Ｉ）で表される化合物を十分な純度、収率で得ることができる。また、目的物が析出している場合、或いは反応液に水を、または反応液を水に添加することで結晶が析出する場合、その結晶を濾過し、必要に応じて水洗することにより、同様の目的物を得ることができる場合もある。
以下、実施例を用いて、本発明をさらに詳細に説明するが、本発明は実施例に限定されるものではない。
発明の実施のための最良の形態：
実施例１
水５０ｍｌ中に２，６−ジフルオロフェナシルブロマイド８３ｇ（純度８７％，０．３１ｍｏｌ）と２−シアノチオアセトアミド２５ｇ（純度９７％０．２４ｍｏｌ）を加え、攪拌下４０℃で９時間反応させた。反応後２０℃まで冷却し、析出晶を濾別し、結晶を水洗・乾燥して、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール５３．３ｇを得た。（収率９３．１％）
実施例２
水１００ｍｌ中に２，６−ジフルオロフェナシルブロマイド２６．６ｇ（純度８８％０．１ｍｏｌ）と２−シアノチオアセトアミド１０．８ｇ（純度９７％０．１０５ｍｏｌ）を加え、攪拌下５０℃で８時間反応させた。反応後２０℃まで冷却し、析出晶をクロロホルムで抽出し、水洗して、高速液体クロマトグラフィー（ＨＰＬＣ）で分析したところ、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール２２．４ｇを含有していた。（収率９５％）
実施例３
水５０ｍｌ中に２，６−ジフルオロフェナシルブロマイド２６．７ｇ（純度８８％０．１ｍｏｌ）と２−シアノチオアセトアミド１０．６ｇ（純度９４％０．１ｍｏｌ）を加え、攪拌下５０℃に加温した。５０℃を保ったままこの中へ２８％カセイソーダ水溶液１５．７ｇ（０．１１ｍｏｌ）を４０分で滴下した。滴下終了後、更に５０℃で２０分間攪拌した。この中へクロロホルム５０ｍｌを加え析出晶を溶解せしめた。クロロホルム層を分離し、溶媒を留去した。析出晶をヘキサン１０ｍｌで洗浄後乾燥して、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール２２．２ｇを得た。（収率９４％）
実施例４
水５０ｍｌと２−シアノチオアセトアミド５．３ｇの混合液中に２，６−ジフルオロフェナシルブロマイド１１．７ｇを含むクロロホルム溶液１７ｇを加え、攪拌下５０℃で８時間反応させた。反応後室温まで冷却し、クロロホルム５０ｍｌを加えて抽出した。水層を更にクロロホルムで抽出し、クロロホルム層をＨＰＬＣにて分析したところ、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール１０．９ｇを含んでいた。（収率９２％）
実施例５
水５０ｍｌと２−シアノチオアセトアミド５．３ｇの混合液中に２，６−ジフルオロフェナシルブロマイド１１．７ｇを含むクロロホルム溶液２３．５ｇを加え、攪拌下５０℃にて２８．２％水酸化ナトリウム水溶液７．７ｇを滴下した。滴下終了後、同温度で１．５時間反応させたのち、反応後室温まで冷却し、クロロホルム５０ｍｌを加えて抽出した。クロロホルム層をＨＰＬＣにて分析したところ、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール１０ｇを含んでいた。（収率８５％）
実施例６
水酸化ナトリウム水溶液（水酸化ナトリウム１．１ｇを含む）１１ｇと２−シアノチオアセトアミド２．７ｇおよびベンジルトリエチルアンモニウムクロリド０．３５ｇの混合液中に２，６−ジフルオロフェナシルブロマイド５．９ｇを含むクロロホルム溶液３０ｍｌを、攪拌下０℃にて滴下した。滴下終了後同温度で１時間攪拌後、更に５０℃にて５時間反応させた。反応終了後、室温まで冷却し、クロロホルム層を分液した。水層をクロロホルム１０ｍｌにて再度抽出した。クロロホルム層を合せてＨＰＬＣにて分析したところ、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール５．１ｇを含んでいた。（収率８６％）
実施例７
クロロホルム２５ｍｌ中に２，６−ジフルオロフェナシルブロマイド１３．３５ｇ（純度８８％０．０５ｍｏｌ）と２−シアノチオアセトアミド５．１５ｇ（純度９４％０．０５ｍｏｌ）を加え、攪拌下５０℃に加温した。５０℃を保ったままこの中へトリエチルアミン５．５ｇ（０．０５５ｍｏｌ）を２０分で滴下した。滴下終了後、更に５０℃で２０分間攪拌した。この中へ水２５ｍｌを加えクロロホルム層を分離した。溶媒を留去して得られる結晶をヘキサン１０ｍｌで洗浄後乾燥して、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール１０．４ｇを得た。（収率８８％）
実施例８
酢酸エチル２５ｍｌ中に２，６−ジフルオロフェナシルブロマイド１３．３５ｇ（純度８８％０．０５ｍｏｌ）と２−シアノチオアセトアミド５．１５ｇ（純度９４％０．０５ｍｏｌ）を加え、攪拌下５０℃に加温した。５０℃を保ったままこの中へトリエチルアミン５．５ｇ（０．０５５ｍｏｌ）を２０分で滴下した。滴下終了後、更に５０℃で２０分間攪拌した。この中へ水２５ｍｌを加え酢酸エチル層を分離した。溶媒を留去して得られる結晶をヘキサン１０ｍｌで洗浄し、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール６．８ｇを得た。（収率５７％）
実施例９
酢酸ブチル５０ｍｌ中に２，６−ジフルオロフェナシルブロマイド１３．３５ｇ（純度８８％０．０５ｍｏｌ）と２−シアノチオアセトアミド５．１５ｇ（純度９４％０．０５ｍｏｌ）を加え、攪拌下５０℃に加温した。５０℃を保ったままこの中へトリエチルアミン５．５ｇ（０．０５５ｍｏｌ）を２０分で滴下した。滴下終了後、更に５０℃で２０分間攪拌した。この中へ水２５ｍｌを加え酢酸エチル層を分離した。溶媒を留去して得られる結晶をヘキサン１０ｍｌで洗浄し、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール８．２ｇを得た。（収率６９．６％）
実施例１０
２−シアノ−３−オキソ−３−（２−トリフルオロメチルフェニル）チオプロピオンアミド１．２ｇを水１５ｍｌに懸濁させ、この溶液に２，６−ジフルオロフェナシルブロミド１．３４ｇを室温にて加えた。混合物を室温にて４．５時間攪拌した。反応終了後酢酸エチルで抽出し、有機層を乾燥、濃縮して２−［４−（２、６−ジフルオロフェニル）−チアゾール−２−イル］−３−ヒドロキシ−３−（２−トリフルオロメチルフェニル）−アクリロニトリル１．３４ｇ（収率７４％）を得た。
実施例１１
２−シアノチオアセトアミド５．３ｇと２，６−ジフルオロフェナシルブロマイド１１．７ｇを含むクロロホルム溶液６０ｍｌにトリエチルアミン５．６ｇを攪拌下３０℃にて滴下した。更に同温度で６時間反応させた後、室温まで冷却し、水２５ｍｌを加えて洗浄した。水層をクロロホルム２０ｍｌにて抽出し、クロロホルム層を合せてＨＰＬＣにて分析したところ、２−シアノメチル−４−（２，６−ジフルオロフェニル）チアゾール９．６ｇを含んでいた。（収率８２％）
実施例１２
２−シアノ−３−オキソ−３−（２−トリフルオロメチルフェニル）チオプロピオンアミド１．３６ｇをＮａＯＨ０．２ｇが溶解している水１５ｍｌに加え、溶解した。この溶液に２，６−ジフルオロフェナシルブロミド１．２９ｇを室温にて加えた。混合物を室温にて４．５時間攪拌したのち、７０℃に昇温して３時間攪拌した。反応終了後酢酸エチルで抽出し、有機層を乾燥、濃縮して２−［４−（２，６−ジフルオロフェニル）−チアゾール−２−イル］−３−ヒドロキシ−３−（２−トリフルオロメチルフェニル）−アクリロニトリル１．９３ｇ（収率９５％）を得た。
実施例１３
２−シアノ−３−オキソ−３−（２−トリフルオロメチルフェニル）チオプロピオンアミド１．３６ｇとトリエチルアミン０．５６ｇをトルエン３０ｍｌに加えた。この溶液に２，６−ジフルオロフェナシルブロミド１．１８ｇを室温にて加えた。混合物を室温にて４時間攪拌したのち、１Ｎ塩酸１０ｍｌを加えた。酢酸エチルで抽出し、有機層を乾燥、濃縮して２−［４−（２，６−ジフルオロフェニル）−チアゾール−２−イル］−３−ヒドロキシ−３−（２−トリフルオロメチルフェニル）−アクリロニトリル１．４２ｇ（収率７０％）を得た。
実施例１４
２−シアノ−３−オキソ−３−（２−トリフルオロメチルフェニル）チオプロピオンアミド１．３６ｇとトリエチルアミン０．５６ｇをトルエン１５ｍｌに加えた。この溶液に２，６−ジフルオロフェナシルブロミド１．１８ｇを室温にて加えた。混合物を５０℃にて２時間攪拌したのち、１Ｎ塩酸５．５ｍｌを加え、５０℃にて３時間攪拌した。酢酸エチルで抽出し、有機層を乾燥、濃縮して２−［４−（２，６−ジフルオロフェニル）−チアゾール−２−イル］−３−ヒドロキシ−３−（２−トリフルオロメチルフェニル）−アクリロニトリル１．９４ｇ（収率９５％）を得た。
実施例１５
２−シアノ−３−オキソ−３−（２−トリフルオロメチルフェニル）チオプロピオンアミド１．３９ｇとトリエチルアミン０．５６ｇを酢酸エチル１５ｍｌに加えた。この溶液に２，６−ジフルオロフェナシルブロミド１．１８ｇを室温にて加えた。混合物を１８℃にて４時間攪拌したのち、１Ｎ塩酸１０ｍｌで洗浄した。有機層を水洗した後、有機層を５０℃の温水バス上で減圧濃縮して、２−［４−（２，６−ジフルオロフェニル）−チアゾール−２−イル］−３−ヒドロキシ−３−（２−トリフルオロメチルフェニル）−アクリロニトリル２．０ｇ（収率９６％）を得た。
産業上の利用可能性：
以上、述べたように、本発明の方法を用いれば、（１）従来の方法と比較して工業的に満足のいく収率、純度で目的物を得ることができ、（２）有機溶媒を用いることなく反応を行えるので、操業上環境面で好ましく有機溶媒の回収、廃棄の問題を考慮しなくてよく、（３）有機溶媒を用いた系においても、従来用いられていたアルコール系溶媒、極性溶媒と比較して、分液性が向上することから目的物の単離操作が容易になり、水洗、蒸留等の操作により不純物である酸分、塩を容易に除去できることから、溶媒の回収操作が軽減される等、工業的に大きなスケールの反応においてその産業上の有用性は高いものといえる。Technical field:
The present invention relates to a method for producing a thiazole compound useful as an agricultural pharmaceutical intermediate.
Background technology:
Among the thiazole compounds according to the present invention, a thiazole compound having a cyanomethyl group at the 2-position is a useful compound as an intermediate of an insecticide, and several production methods thereof have been reported in the past.
For example, Japanese Patent Publication No. 6-76394 (= EP189960) discloses 2-cyanothioacetamide and 1-bromo-3,3-dimethyl-2-pentanone or bromopinacolone at room temperature using potassium hydroxide in ethanol. And the desired 2-cyanomethyl-4-substituted thiazole in a yield of 66% and 52%, respectively.
JP-A-4-89869 describes that 2-cyanothioacetamide and phenacylpromide were reacted in ethanol at a reflux temperature to obtain 2-cyanomethyl-5-phenyl-thiazole in a yield of 60%. ing.
Org. Synth. , Coll. Vol. 3, 332 describes that as a method for producing 2,4-dimethylthiazole, thioacetamide and chloroacetone are reacted in refluxing temperature in benzene, and the desired product is obtained in a yield of 41-45%.
However, none of these known methods are satisfactory in terms of yield. In addition, when the reaction is performed using a polar solvent such as alcohol, there is a problem that the separation and recovery operations are time-consuming as compared with the case where another organic solvent is used.
Disclosure of the invention:
An object of the present invention is to provide an industrial method for producing a thiazole compound with a good yield and excellent operability and safety.
As a result of intensive studies to solve the above-mentioned problems, the inventors have improved the yield and operability by using water as a reaction solvent or combining an organic solvent other than a polar solvent such as alcohol and a base. As a result, the present invention has been completed.
That is, the present invention firstly,
[1] Formula (I)

(Wherein R ₁ Is a hydrogen atom, a C1-C20 hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C1-C20 alkoxycarbonyl group which may have a substituent, or Represents an unsubstituted or substituted amino group, R ₂ Is a hydrogen atom, a halogen atom, a C1-C20 hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C1-C20 alkoxycarbonyl group which may have a substituent, Represents a C1-C20 acyl group, nitro group, or cyano group which may have a substituent, and R ₃ Is a C1-C20 hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, a C1-C20 alkoxycarbonyl group which may have a substituent, or unsubstituted Or a substituted amino group is represented. In the method for producing a thiazole compound represented by formula (II):

(Wherein R ₁ , R ₂ Represents the same meaning as described above, and X represents a functional group capable of leaving against a nucleophilic attack. And a compound represented by formula (III)

(Wherein R ₃ Represents the same meaning as described above. And a method for producing a thiazole compound represented by the formula (I), wherein the compound represented by formula (I) is reacted in an aqueous solvent,
[1-1] The production method according to [1], wherein the reaction is performed in the presence of a base, and [1-2] a solvent that is not mixed with water is added, and in the presence or absence of a catalyst. It is a manufacturing method as described in [1] characterized by making it react in presence.
In addition, the present invention secondly,
[2] The compound represented by the formula (II) and the compound represented by the formula (III) in the presence of a base from a halogen solvent, an ester solvent, a hydrocarbon solvent, a ketone solvent, and an ether solvent. A method for producing a thiazole compound represented by the formula (I), wherein the reaction is performed in at least one organic solvent selected from the group consisting of:
Furthermore, the present invention thirdly,
[3] The compound represented by the formula (II) and the compound represented by the formula (III) are reacted in an organic solvent in the presence of a base, and further [3-1] an acid is added, or [ 3-2] A method for producing a thiazole compound represented by formula (I), wherein the reaction solution is concentrated.
DETAILED DESCRIPTION OF THE INVENTION
In the compound represented by formula (I) which is the target compound of the production method of the present invention, ₁ Represents a hydrogen atom or a C1-C20 hydrocarbon group, heterocyclic group, C1-C20 alkoxycarbonyl group or substituted amino group which may have a substituent. R ₁ Specifically, a hydrogen atom; methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, s-butyl group, isobutyl group, n-pentyl group, s-pentyl group , Isopentyl group, neopentyl group, n-hexyl group, s-hexyl group, 1,1-dimethyl-n-hexyl group, n-heptyl group, n-decyl group, n-dodecyl group and the like, C1-C20 alkyl group; C2-C20 alkenyl groups such as vinyl group, allyl group, 2-butenyl group, 1-methyl-2-propenyl group, 4-octenyl group; C2-C20 such as ethynyl group, propargyl group, 1-methyl-propynyl group An alkynyl group of: cyclopropyl group, cyclobutyl group, cyclopentyl group, 1-methylcyclopentyl group, 1-methylcyclohexyl group, 1-adamantyl group, 1 C3-C20 alicyclic hydrocarbon group such as methyladamantyl group, 2-adamantyl group, 2-methyl-2-adamantyl group, norbornyl group; C6-C20 such as phenyl group, 1-naphthyl group, 9-anthracenyl group 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furanyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolo group, 2-oxazolyl group, 3-iooxazolyl Group, 2-thiazolyl group, 3-iothiazolyl group, 1-pyrazolyl group, 4-pyrazolyl group, 2-imidazolyl group, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazole -5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-triazol-2-yl, 1,2,3-thi Diazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3,4-tetrazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, Pyridazin-3-yl, 1,2,4-triazin-6-yl, 1,3,5-triazin-2-yl, 1-pyrrolidinyl group, 1-piperidyl group, 4-morpholinyl group, 2-tetrahydrofuranyl group Heterocyclic groups such as 4-tetrahydropyranyl group; C1-C20 alkoxy such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group, etc. Carbonyl group; amino group, methylamino group, dimethylamino group, t-butoxycarbonylamino group, p-toluenesulfo Examples thereof include a nylamino group.
R ₂ Is a hydrogen atom, a halogen atom, a nitro group, a cyano group, or a C1-C20 hydrocarbon group, heterocyclic group, C1-C20 alkoxycarbonyl group, or C1-C20 acyl which may have a substituent. Represents a group. R ₂ Specifically, hydrogen atom; fluorine atom, chloro atom, bromine atom, halogen atom of iodine atom; cyano group; nitro group; methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, s-butyl group, isobutyl group, n-pentyl group, s-pentyl group, isopentyl group, neopentyl group, n-hexyl group, s-hexyl group, 1,1-dimethyl-n-hexyl group, C1-C20 alkyl group such as n-heptyl group, n-decyl group, n-dodecyl group, etc .; C2-C2 such as vinyl group, allyl group, 2-butenyl group, 1-methyl-2-propenyl group, 4-octenyl group, etc. C20 alkenyl group; C2-C20 alkynyl group such as ethynyl group, propargyl group, 1-methyl-propynyl group; cyclopropyl group, cyclobutyl group, cyclopentyl C3-C20 alicyclic group such as 1-methylcyclopentyl group, 1-methylcyclohexyl group, 1-adamantyl group, 1-methyladamantyl group, 2-adamantyl group, 2-methyl-2-adamantyl group, norbornyl group Hydrocarbon group; C6-C20 aromatic hydrocarbon group such as phenyl group, 1-naphthyl group, 9-anthracenyl group; 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furanyl group, 2- Thienyl group, 3-thienyl group, 1-pyrrolo group, 2-oxazolyl group, 3-iooxazolyl group, 2-thiazolyl group, 3-iothiazolyl group, 1-pyrazolyl group, 4-pyrazolyl group, 2-imidazolyl group, 1, 3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1, , 4-thiadiazol-5-yl, 1,3,4-triazol-2-yl, 1,2,3-thiadiazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3 , 4-tetrazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-3-yl, 1,2,4-triazin-6-yl, 1,3,5 -Heterocyclic groups such as triazin-2-yl, 1-pyrrolidinyl group, 1-piperidyl group, 4-morpholinyl group, 2-tetrahydrofuranyl group, 4-tetrahydropyranyl group; methoxycarbonyl group, ethoxycarbonyl group, n- C1-C20 alkoxycarbonyl groups such as propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group; acetyl group , Propanoyl group, benzoyl group, C2-C20 acyl group such as 2-pyridylcarbonyl group; and the like.
R ₃ Represents a C1-C20 hydrocarbon group, heterocyclic group, C1-C20 alkoxycarbonyl group, or amino group, which may have a substituent, and R ₁ Specific examples similar to the specific examples other than the hydrogen atom exemplified in (1) can be exemplified.
R above ₁ To R ₃ Each of the exemplified substituents may further have a substituent at an appropriate carbon position. Examples of the substituent include a fluorine atom, a chloro atom, a bromine atom, a halogen atom which is an iodine atom; a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, and an n-hexyl group. Alkyl groups such as cyclopropyl groups, cyclohexyl groups, etc .; alkenyl groups such as vinyl groups and allyl groups; alkynyl groups such as propargyl groups; phenyl groups, 4-chlorophenyl groups, 4-methoxyphenyl groups, 3,4 -Phenyl group which may be substituted such as dimethylphenyl group; methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, isobutoxy group, t-butoxy group, phenoxy group, Alkoxy groups such as 4-chlorophenoxy group, benzyloxy group, phenethyloxy group; amino group, methyl Amino group such as amino group, dimethylamino group, t-butoxycarbonylamino group; alkylthio group such as methylthio group, phenylthio group, 2-pyridylthio group, methylsulfinyl group, methylsulfonyl group, aryl, or heterocyclic thio group or its oxidation Body: C1-C20 alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group; acetyl group, propanoyl group, benzoyl group And C2-C20 acyl group such as 2-pyridylcarbonyl group; cyano group, nitro group and the like.
R having these substituents ₁ , R ₂ And R ₃ Specific examples of chloromethyl, fluoromethyl, bromomethyl, dichloromethyl, difluoromethyl, dibromomethyl, trichloromethyl, trifluoromethyl, tribromomethyl, trichloromethyl, trifluoroethyl, etc. Pentafluoroethyl group; haloalkenyl group such as tetrafluoroethenyl group and 2,2-difluoroethenyl group; alkoxyalkyl group such as methoxymethyl group, methoxyethyl group and phenoxymethyl group; or aryloxyalkyl group; Alkylthioalkyl groups or arylthioalkyl groups such as methyl group and phenylthiomethyl group; aralkyl groups such as benzyl group, diphenylmethyl group, trityl group and phenethyl group; acyl such as benzoylmethyl group and acetylmethyl group And the like cyanomethyl group; alkyl groups.
Specific examples of the compound represented by the formula (I) include the compounds shown in the following table.
However, in the table, A1 to A44 represent functional groups of the following formula, and the other abbreviations have the following meanings.
Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Pen: pentyl, Hex: hexyl, Ph: phenyl, n: normal, i: iso, t: tertiary, neo: neo, c: cyclo

In the compound represented by the formula (II) used in the present invention, R ₁ And R ₂ Represents the same meaning as described above, and specific examples similar to those exemplified in Formula (I) can be exemplified. X represents a functional group capable of leaving against nucleophilic attack, specifically, a chloro atom, a bromine atom, a halogen atom which is an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoro group. Examples include a lomethanesulfonyloxy group and a diphenylphosphonyloxy group. Specific examples of the compound represented by the formula (II) include combinations of substituents corresponding to the compounds shown in Tables 1 to 9, and X may be arbitrarily selected for these combinations. it can. In particular, when a halogen atom is used, R ₁ , R ₂ A compound represented by the formula (II) can be easily obtained by adjusting a ketone compound having a substituent and then halogenating it.
In the compound represented by the formula (III) used in the present invention, R ₃ Represents the same meaning as described above, and specific examples similar to those exemplified in Formula (I) can be exemplified.
The first production method [1] of the present invention is characterized in that the compound represented by the formula (II) and the compound represented by the formula (III) are reacted in an aqueous solvent. As the water to be used, any water such as pure water, distilled water, industrial water and tap water can be used as long as impurities which inhibit the reaction are not contained. The amount of water to be used is not particularly limited as long as the compounds represented by formulas (II) and (II) can be sufficiently dispersed in an aqueous solvent.
Considering the decomposition of the compound represented by formula (II) and the reaction rate, the reaction temperature is preferably in the range of room temperature to 100 ° C, more preferably 60 ° C or less.
The reaction method is not particularly limited, and (1) a method in which compounds represented by formulas (II) and (III) are mixed with water at room temperature and heated, (2) represented by formula (II) or (II) A method of mixing the compound with water and adding the other raw material while heating, (3) heating only the aqueous solvent, and adding the compounds represented by formulas (II) and (II) alternately or simultaneously Any method such as a method can be employed.
The amount of the compound represented by formula (II) used in the reaction is in the range of 0.5 to 2.0, preferably 0.8 to 1.2 equivalents relative to the compound represented by formula (III). Is preferably used.
The reaction can also be carried out in the presence of a base in an aqueous solvent [1-1].
Although the base to be used is not particularly limited, specifically, an inorganic hydroxide such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, Inorganic carbonates or bicarbonates such as potassium hydrogen carbonate; 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 6 -Dibutylamino-1,8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, N, N-dimethylaminopyridine, trimethylamine, triethylamine, tri-n-butylamine, N, N-dimethylcyclohexylamine N, N-diethylaniline, pyridine, quinoline, N, N-dimethylaminopi The organic base and the like can be exemplified such as gin.
These bases can be used as solids or liquids as they are, or diluted with water or organic solvents. The amount of the base used is not particularly limited with respect to the compound represented by the formula (II), but it is preferably used in the range of 0.5 to 1.5 equivalents.
When a base is used, examples of the reaction method include (1) a method in which a compound represented by formulas (II) and (III) and a base are mixed with water at room temperature and heated, and (2) formulas (II) and ( III) A method in which a compound represented by formula (II) or (II) is mixed with water at the room temperature and mixed with water and heated, and a base is added. A method of adding a raw material and further adding a base, (4) A method of adding a base after heating only an aqueous solvent and adding the compounds represented by formulas (II) and (III) alternately or simultaneously (5) A method in which only a water solvent is heated and a compound represented by formulas (II) and (III) and a base are added alternately or simultaneously, (6) a compound represented by formula (III) And the base are mixed with an aqueous solvent at room temperature or under heating, It can be adopted any method such as a method of adding a the compound, Formula (II), a method where the compound represented by formula (III) is unstable to bases (2) preferred.
In addition, the reaction solvent is preferably used alone with water, but if necessary, it is liquid separation, alcohol-based solvents such as methanol and ethanol, N, N-dimethylformamide, dimethyl as long as solvent recovery is not hindered. The reaction can be carried out by adding an aprotic polar solvent such as sulfoxide or N-methylpyrrolidone, or a water-soluble solvent such as acetone, tetrahydrofuran or dioxane, or by adding a solvent which is not mixed with water. [1-2] can also be used.
Solvents that are not mixed with water used in the two-phase reaction method [1-2] include hydrocarbon solvents such as benzene, toluene, xylene, hexane, and cyclohexane, methyl acetate, ethyl acetate, isopropyl acetate, and acetic acid. Ester solvents such as butyl, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone, ether solvents such as diethyl ether and terahydrofuran, nitrile solvents such as acetonitrile and benzonitrile, methylene chloride, chloroform, Examples thereof include halogen solvents such as dichloroethane and chlorobenzene.
As the base, any base that can be used in the reaction with the aqueous solvent exemplified above can be used, and the amount used is 0.5-3 with respect to 1 mol of the compound represented by the formula (II). 0.0 mol, preferably 1.0-2.0 mol.
This reaction may be performed by adding a phase transfer catalyst. As the phase transfer catalyst used in this reaction, onium salts such as quaternary ammonium salts and quaternary phosphonium salts, crown compounds, organic bases and the like are used. Specific examples of the quaternary ammonium salt include tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide, tetramethylammonium bromide, tetraethylammonium bromide, and tetrabutylammonium bromide. , Triethylbenzylammonium bromide, trimethylphenylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium chloride, trimethylphenylammonium chloride, trioctylmethylammonium chloride, tributylbenzylammonium chloride, trimethyl chloride Benzylammonium, N-laurylpyridinium chloride, N-benzylpicolinium chloride, salt Tricaprylmethylammonium, tetramethylammonium iodide, tetrabutylammonium iodide, tetrabutylammonium sulfate, and the like. Examples of the quaternary phosphonium salts include tetraethylphosphonium chloride, tetraethylphosphonium bromide, tetraethylphosphonium iodide, bromide bromide. Examples thereof include tetrabutylphosphonium, tetraphenylphospholium bromide, and phenylbenzylphosphonium bromide. Examples of the crown compound include ethers such as 15-crown-5, 18-crown-6 and the like, cryptands, etc. Examples of the organic base include 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 6-dibutylamino- 1,8-diaza Cyclo [5.4.0] undec-7-ene, triethylenediamine, N, N- dimethylaminopyridine, and the like.
The amount of the catalyst used is in the range of 0.0001 to 2.0 mol, preferably 0.005 to 0.5 mol, relative to 1 mol of the compound represented by the formula (II).
The reaction temperature is preferably -30 ° C to the boiling point of the solvent, particularly preferably -10 to 60 ° C.
In the second production method [2] of the present invention, the compounds represented by formula (II) and formula (III) are subjected to halogenated solvent, ester solvent, hydrocarbon solvent, ketone solvent, ether in the presence of a base. The reaction is performed in at least one organic solvent selected from the group consisting of system solvents.
The base to be used is not particularly limited as long as it can effectively capture HX eliminated by the reaction. Specifically, inorganic hydroxide such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, etc. Products; inorganic carbonates or bicarbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate; 1,8-diazabicyclo [5.4.0] undec-7-ene, , 5-diazabicyclo [4.3.0] non-5-ene, 6-dibutylamino-1,8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, N, N-dimethylaminopyridine , Trimethylamine, triethylamine, tri-n-butylamine, N, N-dimethylcyclohexylamine, N, - diethylaniline, pyridine, quinoline, N, can be exemplified organic bases such as N- dimethylaminopyridine, to use an organic base preferably.
Although the base to be used will not be restrict | limited especially if it is 1 equivalent or more with respect to the compound represented by Formula (II), It is preferable to use in the range of 1.0-1.2 equivalent.
Specific examples of the organic solvent used in the present invention include halogen solvents such as methylene chloride, chloroform, dichloroethane and chlorobenzene; hydrocarbon solvents such as benzene, toluene, xylene, hexane and cyclohexane; methyl acetate, ethyl acetate and acetic acid. Ester solvents such as isopropyl and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone; ether solvents such as diethyl ether and terahydrofuran; nitrile solvents such as acetonitrile and benzonitrile; nitrobenzene, Nitro solvents such as nitromethane can be exemplified, and these can be used alone or in combination of two or more.
The amount of the solvent used is not particularly limited as long as it is an amount sufficient to dissolve or disperse the compounds represented by formulas (II) and (III).
The reaction is preferably performed in the range of room temperature to 100 ° C. in consideration of the decomposition of the compound represented by formula (II) and the reaction rate, and more preferably 60 ° C. or less.
Examples of the reaction method include: (1) a method in which a compound represented by formulas (II) and (III) and a base are mixed with an organic solvent at room temperature and heated; A method in which a compound is mixed with an organic solvent at room temperature and heated, and a base is added. (3) A compound represented by formula (II) or (II) is mixed with an organic solvent, and the other raw material is added while heating. (4) A method of adding a base, (4) A method of adding only a compound represented by the formulas (II) and (III) after heating only an organic solvent, and then adding a base (5) ) A method in which only the organic solvent is heated, and the compound represented by formulas (II) and (III) and the base are added alternately or simultaneously, and (6) the compound represented by formula (III) and the base are added. Mix with organic solvent at room temperature or under heating to give the formula (II Any method such as a method of adding a compound represented by the formula (II) can be employed, but the method (2) is preferred when the compound represented by the formula (II) or (III) is unstable to a base. .
In the third method [3] of the present invention, the compound represented by the formula (II) or the formula (III) is reacted in the presence of a base in an organic solvent, and (1) the reaction is performed by adding an acid, or (2) The reaction solution is concentrated.
The base to be used is not particularly limited as long as it can effectively capture HX eliminated by the reaction. Specifically, inorganic water such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like can be used. Oxides, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and other inorganic carbonates or bicarbonates, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 6-dibutylamino-1,8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, N, N-dimethylamino Pyridine, trimethylamine, triethylamine, tri-n-butylamine, N, N-dimethylcyclohexylamine, N N- diethylaniline, pyridine, quinoline, N, can be exemplified organic bases such as N- dimethylaminopyridine is preferable to use an organic base. Although the base to be used will not be restrict | limited especially if it is 1 equivalent or more with respect to the compound represented by Formula (II), It is preferable to use in the range of 1.0-1.2 equivalent.
Specific examples of acids used in the reaction include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, hydrogen halides such as hydrogen chloride, hydrogen bromide, bromide, and hydrohalic acids, and p-toluenesulfonic acid. And organic acids such as methanesulfonic acid, acetic acid and trifluoroacetic acid. The amount to be used is not particularly limited as long as the reaction system is in an acidic condition, and it may be more than the amount of catalyst. However, when the previously used base is in excess, it is necessary to add a catalytic amount or more of acid in addition to the acid corresponding to the excess base.
Specific examples of the organic solvent used include alcohol solvents such as methanol, ethanol and n-butanol; halogen solvents such as methylene chloride, chloroform, dichloroethane and chlorobenzene; hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane. System solvents; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone; ether solvents such as diethyl ether and terahydrofuran; acetonitrile, Nitrile solvents such as benzonitrile; nitro solvents such as nitrobenzene and nitromethane can be exemplified, and these can be used alone or in combination of two or more.
The amount of the solvent used is not particularly limited as long as it is an amount sufficient to dissolve or disperse the compounds represented by formulas (II) and (III).
The reaction is preferably performed in the range of room temperature to 100 ° C. in consideration of the decomposition of the compound represented by formula (II) and the reaction rate, and more preferably 60 ° C. or less.
Examples of the reaction method include (1) a method in which a compound represented by formulas (II) and (III) and a base are mixed with an organic solvent at room temperature, heated, and further heated by adding an acid; (2) formula (II) And a method in which a compound represented by (III) is mixed with an organic solvent at room temperature and heated, a base is added, and an acid is further added to heat, (3) a compound represented by formula (II) or (II) Is mixed with an organic solvent, the other raw material is added while heating, a base is added, and an acid is further added and heated. (4) Only the organic solvent is heated, and the formula (II), ( (III) A method in which the compounds represented by (III) are added alternately or simultaneously, followed by addition of a base, followed by addition of an acid and heating, (5) Only the organic solvent is heated, and in formulas (II) and (III) Alternately or simultaneously adding the compound represented and the base, (6) A compound represented by the formula (III) and a base are mixed with an organic solvent at room temperature or under heating, and a compound represented by the formula (II) is added. Further, any method such as a method of adding an acid and heating can be employed, but the method of (2) is preferred when the compounds represented by the formulas (II) and (III) are unstable to a base.
The step of reacting with an acid or the step of concentrating the reaction solution is preferably performed in the range of room temperature to 100 ° C, more preferably 60 ° C or less. The step of concentrating the reaction solution depends on the reaction solvent used, but can be carried out by distilling off the solvent under normal pressure or reduced pressure. Further, the reaction solution can be concentrated without treatment, or can be concentrated after treatment with acid or water.
When water is used as a reaction solvent, after completion of the reaction, the reaction product is cooled to room temperature or lower, and the precipitated crystals are filtered, and the target compound of formula (I) is obtained by performing a normal isolation operation such as solvent extraction. Can be obtained in sufficient purity and yield.
When an organic solvent is used as a reaction solvent, if the target product is dissolved, if not dissolved, after adding a solvent to be dissolved or replacing with such a solvent, washing with water to remove impurities, By performing a normal isolation operation, the compound represented by the formula (I), which is the target product, can be obtained with sufficient purity and yield. In addition, when the target product is precipitated, or when crystals are precipitated by adding water to the reaction solution or adding the reaction solution to water, the crystals are filtered and washed with water as necessary. In some cases, the desired product can be obtained.
EXAMPLES Hereinafter, although this invention is demonstrated further in detail using an Example, this invention is not limited to an Example.
Best Mode for Carrying Out the Invention:
Example 1
In 50 ml of water, 83 g of 2,6-difluorophenacyl bromide (purity 87%, 0.31 mol) and 25 g of 2-cyanothioacetamide (purity 97% 0.24 mol) were added and reacted at 40 ° C. for 9 hours with stirring. . After the reaction, the reaction mixture was cooled to 20 ° C., the precipitated crystals were separated by filtration, and the crystals were washed with water and dried to obtain 53.3 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 93.1%)
Example 2
In 1 ml of water, 26.6 g of 2,6-difluorophenacyl bromide (purity 88% 0.1 mol) and 10.8 g of 2-cyanothioacetamide (purity 97% 0.105 mol) were added and stirred at 50 ° C. for 8 hours. Reacted. After the reaction, the mixture was cooled to 20 ° C., and the precipitated crystals were extracted with chloroform, washed with water, and analyzed by high performance liquid chromatography (HPLC). As a result, 22.4 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole was obtained. Contained. (Yield 95%)
Example 3
Add 26.7 g of 2,6-difluorophenacyl bromide (purity 88% 0.1 mol) and 10.6 g of 2-cyanothioacetamide (purity 94% 0.1 mol) in 50 ml of water, and warm to 50 ° C. with stirring. did. While maintaining the temperature at 50 ° C., 15.7 g (0.11 mol) of a 28% sodium hydroxide aqueous solution was dropped into this over 40 minutes. After completion of dropping, the mixture was further stirred at 50 ° C. for 20 minutes. To this, 50 ml of chloroform was added to dissolve the precipitated crystals. The chloroform layer was separated and the solvent was distilled off. The precipitated crystals were washed with 10 ml of hexane and dried to obtain 22.2 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 94%)
Example 4
17 g of a chloroform solution containing 11.7 g of 2,6-difluorophenacyl bromide was added to a mixed solution of 50 ml of water and 5.3 g of 2-cyanothioacetamide, and reacted at 50 ° C. for 8 hours with stirring. After the reaction, the reaction mixture was cooled to room temperature and extracted with 50 ml of chloroform. The aqueous layer was further extracted with chloroform, and the chloroform layer was analyzed by HPLC. As a result, 10.9 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole was contained. (Yield 92%)
Example 5
23.5 g of a chloroform solution containing 11.7 g of 2,6-difluorophenacyl bromide was added to a mixture of 50 ml of water and 5.3 g of 2-cyanothioacetamide, and 28.2% sodium hydroxide at 50 ° C. with stirring. 7.7 g of an aqueous solution was added dropwise. After completion of the dropwise addition, the mixture was reacted at the same temperature for 1.5 hours, then cooled to room temperature after the reaction, and extracted with 50 ml of chloroform. When the chloroform layer was analyzed by HPLC, it contained 10 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 85%)
Example 6
5.9 g of 2,6-difluorophenacyl bromide is contained in a mixture of 11 g of an aqueous sodium hydroxide solution (including 1.1 g of sodium hydroxide), 2.7 g of 2-cyanothioacetamide and 0.35 g of benzyltriethylammonium chloride 30 ml of chloroform solution was added dropwise at 0 ° C. with stirring. After completion of dropping, the mixture was stirred at the same temperature for 1 hour, and further reacted at 50 ° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the chloroform layer was separated. The aqueous layer was extracted again with 10 ml of chloroform. When the chloroform layers were combined and analyzed by HPLC, it contained 5.1 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 86%)
Example 7
In 25 ml of chloroform, 13.35 g (purity 88% 0.05 mol) of 2,6-difluorophenacyl bromide and 5.15 g (purity 94% 0.05 mol) of 2-cyanothioacetamide were added and heated to 50 ° C. with stirring. did. While maintaining 50 ° C., 5.5 g (0.055 mol) of triethylamine was dropped into this over 20 minutes. After completion of dropping, the mixture was further stirred at 50 ° C. for 20 minutes. To this was added 25 ml of water, and the chloroform layer was separated. The crystals obtained by distilling off the solvent were washed with 10 ml of hexane and dried to obtain 10.4 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 88%)
Example 8
In 25 ml of ethyl acetate, 13.35 g (purity 88% 0.05 mol) of 2,6-difluorophenacyl bromide and 5.15 g (purity 94% 0.05 mol) of 2-cyanothioacetamide were added and heated to 50 ° C. with stirring. Warm up. While maintaining 50 ° C., 5.5 g (0.055 mol) of triethylamine was dropped into this over 20 minutes. After completion of dropping, the mixture was further stirred at 50 ° C. for 20 minutes. 25 ml of water was added to this, and the ethyl acetate layer was separated. Crystals obtained by distilling off the solvent were washed with 10 ml of hexane to obtain 6.8 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 57%)
Example 9
Add 13.35 g (purity 88% 0.05 mol) of 2,6-difluorophenacyl bromide and 5.15 g (purity 94% 0.05 mol) of 2-cyanothioacetamide to 50 ml of butyl acetate, and heat to 50 ° C. with stirring. Warm up. While maintaining 50 ° C., 5.5 g (0.055 mol) of triethylamine was dropped into this over 20 minutes. After completion of dropping, the mixture was further stirred at 50 ° C. for 20 minutes. 25 ml of water was added to this, and the ethyl acetate layer was separated. Crystals obtained by distilling off the solvent were washed with 10 ml of hexane to obtain 8.2 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole. (Yield 69.6%)
Example 10
1.2 g of 2-cyano-3-oxo-3- (2-trifluoromethylphenyl) thiopropionamide is suspended in 15 ml of water, and 1.34 g of 2,6-difluorophenacyl bromide is added to this solution at room temperature. added. The mixture was stirred at room temperature for 4.5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated to give 2- [4- (2,6-difluorophenyl) -thiazol-2-yl] -3-hydroxy-3- (2-trifluoromethyl). 1.34 g (74% yield) of phenyl) -acrylonitrile was obtained.
Example 11
To 60 ml of a chloroform solution containing 5.3 g of 2-cyanothioacetamide and 11.7 g of 2,6-difluorophenacyl bromide, 5.6 g of triethylamine was added dropwise at 30 ° C. with stirring. Furthermore, after making it react at the same temperature for 6 hours, it cooled to room temperature and added 25 ml of water and wash | cleaned. The aqueous layer was extracted with 20 ml of chloroform, and the chloroform layers were combined and analyzed by HPLC. As a result, 9.6 g of 2-cyanomethyl-4- (2,6-difluorophenyl) thiazole was contained. (Yield 82%)
Example 12
1.36 g of 2-cyano-3-oxo-3- (2-trifluoromethylphenyl) thiopropionamide was added and dissolved in 15 ml of water in which 0.2 g of NaOH was dissolved. To this solution, 1.29 g of 2,6-difluorophenacyl bromide was added at room temperature. The mixture was stirred at room temperature for 4.5 hours, then heated to 70 ° C. and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated to give 2- [4- (2,6-difluorophenyl) -thiazol-2-yl] -3-hydroxy-3- (2-trifluoromethyl). 1.93 g (95% yield) of phenyl) -acrylonitrile were obtained.
Example 13
1.36 g of 2-cyano-3-oxo-3- (2-trifluoromethylphenyl) thiopropionamide and 0.56 g of triethylamine were added to 30 ml of toluene. To this solution, 1.18 g of 2,6-difluorophenacyl bromide was added at room temperature. After the mixture was stirred at room temperature for 4 hours, 10 ml of 1N hydrochloric acid was added. Extraction with ethyl acetate, drying and concentration of the organic layer, 2- [4- (2,6-difluorophenyl) -thiazol-2-yl] -3-hydroxy-3- (2-trifluoromethylphenyl)- Acrylonitrile (1.42 g, yield 70%) was obtained.
Example 14
1.36 g of 2-cyano-3-oxo-3- (2-trifluoromethylphenyl) thiopropionamide and 0.56 g of triethylamine were added to 15 ml of toluene. To this solution, 1.18 g of 2,6-difluorophenacyl bromide was added at room temperature. The mixture was stirred at 50 ° C. for 2 hours, 5.5 ml of 1N hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 3 hours. Extraction with ethyl acetate, drying and concentration of the organic layer, 2- [4- (2,6-difluorophenyl) -thiazol-2-yl] -3-hydroxy-3- (2-trifluoromethylphenyl)- Acrylonitrile 1.94 g (95% yield) was obtained.
Example 15
1.39 g of 2-cyano-3-oxo-3- (2-trifluoromethylphenyl) thiopropionamide and 0.56 g of triethylamine were added to 15 ml of ethyl acetate. To this solution, 1.18 g of 2,6-difluorophenacyl bromide was added at room temperature. The mixture was stirred at 18 ° C. for 4 hours and then washed with 10 ml of 1N hydrochloric acid. After the organic layer was washed with water, the organic layer was concentrated under reduced pressure on a hot water bath at 50 ° C. to give 2- [4- (2,6-difluorophenyl) -thiazol-2-yl] -3-hydroxy-3- ( 2.0 g (yield 96%) of 2-trifluoromethylphenyl) -acrylonitrile was obtained.
Industrial applicability:
As described above, by using the method of the present invention, (1) the target product can be obtained in industrially satisfactory yield and purity as compared with the conventional method, and (2) the organic solvent is used. Since the reaction can be carried out without using it, there is no need to consider the problem of recovery and disposal of the organic solvent, which is preferable in terms of operation environment. (3) Even in the system using the organic solvent, Compared to polar solvents, the separation of liquid is improved, making it easy to isolate the target product, and removing impurities and salts that are impurities by operations such as washing with water and distillation. It can be said that the industrial utility is high in a reaction on a large scale industrially, such as reduction of operation.

Claims (5)

Formula (I)

Wherein R ₁ is a hydrogen atom, a C1-C20 hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a C1-C20 which may have a substituent. Represents an alkoxycarbonyl group or an unsubstituted or substituted amino group, and R ₂ represents a hydrogen atom, a halogen atom, a C1-C20 hydrocarbon group which may have a substituent, or a hetero which may have a substituent. Represents a cyclic group, a C1-C20 alkoxycarbonyl group which may have a substituent, a C1-C20 acyl group, a nitro group or a cyano group which may have a substituent, and R ₃ has a substituent. Represents a C1-C20 hydrocarbon group which may be substituted, a heterocyclic group which may have a substituent, a C1-C20 alkoxycarbonyl group which may have a substituent, or an unsubstituted or substituted amino group. .) Production of thiazole compounds represented by In law, the formula (II)

(Wherein R ₁ and R ₂ represent the same meaning as described above, and X represents a functional group capable of leaving against nucleophilic attack) and the formula (III)

(In the formula, R ₃ represents the same meaning as described above.) A method for producing a thiazole compound represented by the formula (I), wherein the compound represented by the formula (I) is reacted in an aqueous solvent. The production method according to claim 1, wherein the reaction is carried out in the presence of a base. The method according to claim 1 or 2, wherein a solvent that is not mixed with water is added and the reaction is carried out in the presence or absence of a catalyst. Formula (I)

(Wherein R ₁ , R ₂ and R ₃ represent the same meaning as in claim 1), the method for producing a thiazole compound represented by formula (II)

(Wherein R ₁ and R ₂ represent the same meaning as described above, and X represents a functional group capable of leaving against nucleophilic attack) and the formula (III)

(Wherein R ₃ represents the same meaning as described above) in the presence of a base, from the group consisting of a halogen-based solvent, an ester-based solvent, a hydrocarbon-based solvent, a ketone-based solvent, and an ether-based solvent. A method for producing a thiazole compound represented by formula (I), wherein the reaction is performed in at least one selected organic solvent. Formula (I)

(Wherein R ₁ , R ₂ and R ₃ represent the same meaning as in claim 1), the method for producing a thiazole compound represented by formula (II)

(Wherein R ₁ and R ₂ represent the same meaning as described above, and X represents a functional group capable of leaving against nucleophilic attack) and the formula (III)

(Wherein R ₃ represents the same meaning as described above) is reacted in the presence of a base in an organic solvent, and (1) an acid is added to react, or (2) a reaction solution A method for producing a thiazole compound represented by the formula (I), wherein the method is concentrated.