JP3968136B2 - Method for producing 3- (substituted aminomethyl) -6-chloropyridine - Google Patents

Description

（式中、Ｒ²'は水素原子又は低級アルキル基を示す）で表される３−（アミノメチル）−６−クロロピリジン類は農薬殺虫剤製造の重要原料であるため種々の製造方法が提案されている。
６−クロロ−３−（クロロメチル）ピリジンを原料として３−（アミノメチル）−６−クロロピリジン類を得る方法は多数報告されている（ＥＰ４２５０３０，ＥＰ３９１２０５，ＥＰ３０２３８９，ＥＰ３６６０８５，ＥＰ３７６２７９，ＪＰ５２８６９３６）。しかしながら、この方法ではメチル基上の塩素をアミノ基へ置換する反応でダイマー等の副生成物を生ずる等の問題があった。また、原料の６−クロロ−３−（クロロメチル）ピリジンの製造方法にも問題があった。原料ピリジンの製造方法は、（１）ＥＰ５５６６８３等に記載されている方法により製造される６−クロロ−３−メチルピリジンのメチル基を塩素化する方法（ＤＥ３６３００４６，ＤＥ４０１６１７５）、（２）６−クロロ−３−（トリクロロメチル）ピリジンを還元する方法（ＥＰ５１２４６３，ＪＰ５３２０１３２）、（３）ニコチン酸やβ−ピコリンから誘導した３−（ポリクロロメチル）ピリジンから転位・加水分解・塩素化工程等を経て得る方法（ＥＰ３７３４６４，ＪＰ２２１２４７５，ＥＰ２２９２２６２）、あるいは（４）出発原料に６−ヒドロキシニコチン酸や６−クロロニコチン酸およびそのエステル体を用いる方法（ＥＰ５６９９４７，４２５０３０，２５６９９０）、と多数報告されているものの、（１）の方法では、ピリジン環３位メチル基への塩素化の選択性・収率が不充分であり、（２）はトリクロロメチル基のモノクロロメチル基への還元収率が不満足であり、（３）（４）は工程数が多く総合収率が低いため、いずれの製造方法も実用性は低かった。
６−クロロ−３−シアノピリジンを前駆体としてこのもののシアノ基をアミノメチル基に還元する方法（ＤＥ４２２２１５２，ＷＯ９２１３８４０）も知られている。しかしながら、この方法ではシアノ基還元工程で塩素の脱離やダイマー等が副生成する問題があり、原料の製造においても３−シアノピリジンの６位塩素化の際位置異性体が生成するため６−クロロ−３−シアノピリジンを効率よく得られない等の問題があった。
このように一般式［II］で表される３−（アミノメチル）−６−クロロピリジン類の製造方法は種々提案されているものの、いまだ工業的な製造方法は確立していなかった。
【課題を解決するための手段】
本発明者らは一般式［II］
【化７】

（式中、Ｒ²'は前記と同じ意味を示す）で表される３−（アミノメチル）−６−クロロピリジン類を工業的に製造するために有利な中間体を鋭意探索した。その結果、３−（アミノメチル）ピリジン類から入手できる一般式［III ］
【化８】

（式中、Ｒ¹ はアルキル基、アリール基またはアルコキシ基を、Ｒ² は水素原子、低級アルキル基またはＲ¹ がアリール基の場合これに結合するカルボニル基を示す）で表される３−（置換アミノメチル）ピリジン １−オキシドから容易に一般式［Ｉ］及び［Ｉ' ］
【化９】

（式中、Ｒ¹ 、Ｒ² 及びＲ²'は前記と同じ意味を示す) で表される３−（置換アミノメチル）−６−クロロピリジンが誘導でき、そしてこの一般式［Ｉ' ］で表される化合物からは効率よく一般式［II］で表される化合物に変換できることを見出し本発明を完成した。即ち、本発明は一般式［Ｉ］及び［Ｉ' ］で表される３−（置換アミノメチル）−６−クロロピリジン及びその製造方法である。
【発明の実施の形態】
Ｒ¹ 、Ｒ² 及びＲ²'について具体的に説明する。Ｒ¹ はアルキル基、アリール基、アラルキル基またはアルコキシ基である。Ｒ¹ は一般式［Ｉ］で表される原料化合物を製造する際の酸化反応とピリジン６位の４級アンモニウム塩化反応の際安定であり、酸存在下でアシルアミノ基が加水分解されるものならばなんでもよく、具体的には、アルキル基としては直鎖状、分岐状、環状のＣ１〜Ｃ１８のアルキル基、アリール基としてはフェニル基またはナフタレン、アントラセンのような縮合環形式の芳香族基も可能であり、更にこれらをメチル、エチル等の低級アルキル基、メトキシ、エトキシ等の低級アルコキシ基またはフッ素、塩素等のハロゲン原子によって置換されているものも使用できる。アラルキル基としては前記したアルキル基とアリール基の任意の組み合わせが可能であり、アルコキシ基はメトキシ、エトキシ、ｉ−プロポキシ等の低級アルコキシ基、ベンジルオキシ基等が例示される。Ｒ² は水素原子またはメチル、エチル等の低級アルキル基またはＲ¹ がアリール基の場合そのオルト位と結合するカルボニル基である。Ｒ²'は水素原子またはメチル、エチル等の低級アルキル基である。
一般式［Ｖ］で表される有機塩基としてはトリメチルアミン、トリエチルアミン、Ｎ，Ｎ−ジメチル−アニリン、ピリジンやＮ，Ｎ−ジメチル−４−アミノピリジン等の３級アミンあるいはメチル、エチル等の低級アルキル基で置換されていてもよいピリジン等が挙げられる。
親電子試剤としてはホスゲン、塩化チオニル、塩化スルフリルなどの塩化物、オキシ塩化リン、五塩化リン、（ジエチルアミド）ホスホン酸ジクロリドのようなリン塩化物、メタンスルホン酸クロリドやトルエンスルホン酸クロリドのようなスルホン酸クロリド類、アセチルクロリドや安息香酸クロリドのような酸クロリド類、クロル蟻酸メチルエステルやクロル蟻酸イソプロピルエステルのようなクロル蟻酸エステル類が挙げられる。
本発明の化合物［Ｉ］及び［Ｉ' ］は次の方法で合成することができる。
【化１０】

Ａ工程
一般式［III ］で表される化合物に一般式［Ｖ］で表される有機塩基及び親電子試剤を作用させて一般式［IV］（式中Ｒ¹ 、Ｒ² 及びＲ' Ｒ''Ｒ''' Ｎは前記と同じ意味を示す）で表されるアンモニウム塩を生成させる。
Ｂ工程
Ａ工程で得たアンモニウム塩［IV］を常圧あるいは加圧下に塩化水素と反応させ一般式［Ｉ］及び［Ｉ' ］で表される３−（置換アミノメチル）−６−クロロピリジンを得る。
Ａ工程の溶媒としては塩化メチレン、クロロホルム、四塩化炭素、クロロベンゼンなどの塩素系あるいはアセトニトリル、ベンゾニトリルなどのニトリル系あるいは酢酸エチル、酢酸メチルなどのエステル系あるいはＴＨＦ、ジエチルエーテルなどのエーテル系あるいはアセトン、ＭＥＫなどのケトン系等の不活性溶媒、もしくはこれらの混合溶媒用、またはこれらの不活性溶媒にヘキサンやトルエン等の炭化水素系溶媒を添加した混合溶媒等が使用できる。一般式［III ］で表される化合物に一般式［Ｖ］で表される塩基を２モル〜６モル等量用い、親電子試剤は一般式［III ］で表される化合物と等モル〜５モル等量使用する。反応は−４０℃〜溶媒の沸点好ましくは−２０℃〜室温で１〜６時間行う。
Ｂ工程はＡ工程の溶媒を使用でき化合物［IV］の単離・精製の要もないため、Ａ工程から連続して行うことができる。反応は塩化水素を３〜２０等量好ましくは５〜１０等量使用し、常圧〜２０ｋｇｆ／ｃｍ² 好ましくは常圧〜１０ｋｇｆ／ｃｍ² の圧力下において、室温〜１２０℃で好ましくは４０〜８０℃で３〜２０時間行う。
こうして得られた一般式［Ｉ' ］で表される３−（置換アミノメチル）−６−クロロピリジンはアシルアミノ基の加水分解が可能であるため、一般式［II］
【化１１】

で表される３−（アミノメチル）−６−クロロピリジン類に導くことができる。即ち、一般式［Ｉ' ］で表される化合物を酸の水溶液またはこれとメタノールなどの低級アルコール系溶媒の混合溶液で希釈し室温〜溶媒の沸点で好ましくは８５〜９５℃で処理することにより一般式［II］で表される化合物が得られる。酸としては塩酸と硫酸が挙げられる。酸濃度は塩酸の場合６〜１２規定が硫酸では５０〜８０％が適当である。また、これらを混合しても使用できる。
原料の一般式［III ］で表される３−（置換アミノメチル）ピリジン １−オキシドは３−（アミノメチル）ピリジン類［VI］からは例えば次のように製造できる。
【化１２】

Ｃ工程
３−（アミノメチル）ピリジン類［VI］に酸ハライド、酸無水物、またはエステル類を反応させて３−（置換アミノメチル）ピリジン［VII ］を得る。
Ｄ工程
［VII ］を酸化し３−（置換アミノメチル）ピリジン １−オキシド［III ］とする。
Ｃ工程は、下記に示す方法に従って行われる。
（１）一般式Ｒ¹ ＣＯＸ［VIII］（式中、Ｒ¹ は前記と同じ意味を示し、Ｘはハロゲン原子を示す）または一般式（Ｒ¹ ＣＯ）₂ Ｏ［IX］（式中、Ｒ¹ は前記と同じ意味を示す）で表される酸ハライド、ハロ蟻酸エステルまたは酸無水物を使用：
一般式［VI］で表される化合物１モルと一般式［VIII］または一般式［IX］で表される化合物１〜１．１モルとを塩化メチレン、クロロホルム、トルエン、キシレン等の有機溶媒中、トリエチルアミン等の有機塩基１〜１．５モルの存在下、−１０〜４０℃で反応させる。
また、有機塩基のかわりに水酸化ナトリウム等の無機塩基の水溶液を用い、必要により４級アンモニウム塩等の相間移動触媒の存在下、室温から５０℃の温度で２相反応を行うことによって製造することもできる。
（２）一般式Ｒ¹'ＣＯＯＹ［Ｘ］（式中、Ｒ¹'はアルキル基、アリール基またはアラルキル基を示し、Ｙは低級アルキル基を示す）で表されるエステル類を使用：
一般式［VI］で表される化合物１モルと一般式［Ｘ］で表されるエステル類１．５〜５．０モルとを塩化水素や硫酸等の酸触媒存在下、（１）と同様の溶媒中、室温から用いる溶媒の沸点までの温度で反応させる。
Ｄ工程は［VII ］を酸化し３−（置換アミノメチル）ピリジン １−オキシド［III ］とする工程で溶媒には低級アルコール類、水、酢酸が使用でき、酸化剤には過酸化水素、過酢酸、メタクロロ過安息香酸等を１〜２等量用い、室温から溶媒の沸点までの温度で反応させる。この際、タングステン酸塩を触媒に使用しても良好な結果が得られる。
こうして得られた一般式［III ］で表される化合物は単離せず、次工程の原料として使用することも可能である。
【実施例】
実施例及び参考例を挙げて詳細に説明する。
実施例１（化合物１）３−（ベンズアミドメチル）−６−クロロピリジンの合成
【化１３】

３−（ベンズアミドメチル）ピリジン １−オキシド（１０．０ｇ，０．０４４ｍｏｌ）とトリメチルアミン（１２．３ｇ，０．２１ｍｏｌ）のクロロホルム溶液（１５０ｍｌ）に−５℃で撹拌しながらホスゲン（１６．０ｇ，０．１６ｍｏｌ）を１時間で吹き込んだ。反応混合液を室温まで加温しさらに２時間撹拌を続けた後、４０℃／４５０ｔｏｒｒでホスゲンを除去した（留出物８０ｍｌ）。次いで反応混合液に塩化水素ガス（２２．４ｇ，０．６１ｍｏｌ）を導入しオートクレーブ中で撹拌下８０〜８５℃、１．８〜２．３ｋｇｆ／ｃｍ² で５時間反応させた。室温まで冷却後、反応混合液を水にあけ抽出・分液し水層はさらにクロロホルムで抽出を繰り返した。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（ベンズアミドメチル）−６−クロロピリジンの結晶９．２ｇ（収率８５％）を得た。
融点：１２４〜１２６℃
実施例２（化合物２）３−（フタルイミドメチル）−６−クロロピリジンの合成
【化１４】

３−（フタルイミドメチル）ピリジン １−オキシド（１２．７ｇ，５０ｍｍｏｌ）とトリメチルアミン（１１．８ｇ，０．２０ｍｏｌ）を塩化メチレン（２５０ｍｌ）に溶解させた溶液に−２０℃で撹拌しながらホスゲン（１６ｇ，０．１６ｍｏｌ）を０．５時間で吹き込んだ。反応混合液を室温まで加温しさらに２時間撹拌を続けた後、溶媒を留去した。残渣を再び塩化メチレン（２００ｍｌ）で希釈し塩化水素ガス（８ｇ，０．２２ｍｏｌ）を導入しオートクレーブ中で撹拌下５５〜６５℃、２．３〜２．６ｋｇｆ／ｃｍ² で７時間反応させた。室温まで冷却後、反応混合液を水にあけ抽出・分液し水層はクロロホルムで抽出を繰り返した。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（フタルイミドメチル）−６−クロロピリジンの結晶１１．３ｇ（収率８３％）を得た。
実施例３（化合物３）３−（アセトアミドメチル）−６−クロロピリジンの合成
【化１５】

３−（アセトアミドメチル）ピリジン １−オキシド（８．３ｇ，５０ｍｏｌ）とトリメチルアミン（１６ｇ，０．２７ｍｏｌ）を塩化メチレン（１５０ｍｌ）に溶解させた。この溶液に−１０℃で撹拌しながらホスゲン（１６ｇ，０．１６ｍｏｌ）を１時間で吹き込んだ。反応混合液を室温まで加温しさらに２時間撹拌を続けた後、溶媒を留去した。残渣を１，２−ジクロロエタン（３００ｍｌ）で希釈し塩化水素ガス（１２．６ｇ，０．３５ｍｏｌ）を導入しオートクレーブ中で撹拌下９０〜１００℃、２．０〜２．４ｋｇｆ／ｃｍ² で５時間反応させた。室温まで冷却後、反応混合液を濃縮し、水にあけｐＨ１２に調整してから塩化メチレンで抽出・分液した。水層は塩化メチレンで抽出を繰り返した。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（アセトアミドメチル）−６−クロロピリジンの結晶４．４ｇ（収率４９％）を得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）：δ ８．２７（ｂｒ，１Ｈ），７．６２（ｄｄ，Ｊ＝７．９２ ａｎｄ ２．４８ Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝７．９２ Ｈｚ，１Ｈ），６．２９（ｂｒｓ，１Ｈ），４．４０（ｄ，Ｊ＝５．９４Ｈｚ，２Ｈ），２．０３（ｓ，３Ｈ）．
実施例４〜１６（化合物４〜１６）
実施例１と同様に以下の化合物４〜１６を合成した。結果を表−１に示した。
【表１】

実施例１７ ３−（アミノメチル）−６−クロロピリジンの合成
【化１６】

３−（ベンズアミドメチル）−６−クロロピリジン（化合物１）の５．０ｇ（２０ｍｍｏｌ）を９Ｎ塩酸１００ｍｌに溶解し撹拌下に１０時間９５℃に保った。室温まで冷却しクロロホルム５０ｍｌで３回抽出し安息香酸を回収した（９５％）。水層にクロロホルム５０ｍｌを添加しｐＨ１３としてから分液し、水層はさらにクロロホルムで抽出を繰り返した。クロロホルム層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（アミノメチル）−６−クロロピリジンの結晶２．７ｇ（収率９５％）を得た。
実施例１８〜２８
実施例１７と同様に化合物４〜１６を処理した。結果を表−２に示した。
【表２】

参考例１ ３−（ベンズアミドメチル）ピリジンの合成
【化１７】

３−ピリジンメタンアミン（１０８ｇ，１．０ｍｏｌ）の水溶液（３００ｍｌ）に２８％苛性ソーダ水溶液（２００ｇ）とトルエン（３００ｍｌ）を添加してから、安息香酸クロリド（１８０ｇ，１．２８ｍｏｌ）を撹拌下０℃、２時間で滴下しさらに３時間撹拌を続けた。その後反応懸濁溶液をろ過し、得られた結晶を冷水で洗浄した。結晶を乾燥し３−（ベンズアミドメチル）ピリジン２０８ｇ（収率９８％）を得た。
参考例２ ３−（ベンズアミドメチル）ピリジン １−オキシドの合成
【化１８】

３−（ベンズアミドメチル）ピリジン（２０５ｇ，０．９５ｍｏｌ）とタングステン酸ソーダ（１ｇ）を氷酢酸（５００ｍｌ）に溶解し撹拌下９５℃で３０％過酸化水素水（１５０ｇ）を１時間で滴下した。１０５℃で１時間反応後、室温に冷却し沃素でんぷん反応が陰性となるまでハイポを加えた。この反応溶液を濃縮し塩化メチレン（３．５Ｌ）と水（２Ｌ）を加え２８％苛性ソーダ水溶液でｐＨ１３に調整し抽出・分液した。水層の抽出を繰り返し有機層をまとめて硫酸マグネシウムで乾燥し、溶媒留去して３−（ベンズアミドメチル）ピリジン １−オキシドの結晶１９０ｇ（収率８８％）を得た。
融点：１１２〜１１３℃
参考例３ ３−（ベンズアミドメチル）ピリジン １−オキシドの合成
【化１９】

３−（ベンズアミドメチル）ピリジン（５．０ｇ，２３．５ｍｍｏｌ）、タングステン酸ソーダ（０．３ｇ）及び３５％塩酸（０．１３ｇ）を水（７．５ｍｌ）に懸濁させた。この懸濁溶液に還流撹拌下３０％過酸化水素水（３．２ｇ）を１５分間で滴下しさらに４時間反応後、室温に冷却し沃素でんぷん反応が陰性となるまでハイポを加えた。この反応溶液をＨＰＬＣで分析したところ、３−（ベンズアミドメチル）ピリジン １−オキシドの生成率は９７％であった。
参考例４ ３−（アセトアミドメチル）ピリジン １−オキシドの合成
【化２０】

３−ピリジンメタンアミン（５０ｇ，０．４６ｍｏｌ）とトリエチルアミン（４６．８ｇ，０．４６ｍｏｌ）の塩化メチレン溶液（２５０ｍｌ）に酢酸クロリド（３６．３ｇ，０．４６ｍｏｌ）のクロロホルム溶液（１００ｍｌ）を撹拌下０〜１０℃、１．５時間で滴下しさらに１時間撹拌を続けた。その後反応溶液に水（２００ｍｌ）を添加し酢酸エチル（６００ｍｌ）で抽出・分液した。水層をイソブタノール（５００ｍｌ×２）で抽出し、有機層を合わせ溶媒１２００ｍｌを留去させた。析出した結晶をろ過し、母液とこの結晶を洗浄した酢酸エチルを合わせ硫酸マグネシウムで乾燥して溶媒留去し３−（アセトアミドメチル）ピリジンの結晶７０ｇ（収率９９％）を得た。次いでこの結晶（３５ｇ，０．２３ｍｏｌ）とタングステン酸ソーダ（０．５ｇ）を氷酢酸（６０ｍｌ）に溶解し撹拌下１００℃で３０％過酸化水素水（４８ｇ）を３時間で滴下した。同温度で３時間反応後、室温に冷却し沃素でんぷん反応が陰性となるまでハイポを加えた。この反応溶液にトルエンを加え共沸脱水後、減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（ＣＨＣｌ₃ ／ＭｅＯＨ＝９／１）によって精製し３−（ベンズアミドメチル）ピリジン １−オキシド１６ｇ（収率４２％）を得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ）：δ ８．４５（ｂｒｓ，１Ｈ），８．１１（ｂｒｓ，２Ｈ），７．３５（ｄｄ，Ｊ＝７．９１ ａｎｄ ７．９１ Ｈｚ，１Ｈ），７．２２（ｄ，Ｊ＝７．９１ Ｈｚ，１Ｈ），４．２２（ｄ，Ｊ＝５．９４Ｈｚ，２Ｈ），１．８９（ｓ，３Ｈ）．
参考例５〜１４
参考例３と同様に以下の化合物１９〜２８を合成した。結果を表−３に示した。
【表３】

参考例１５ ３−（（Ｎ−メチルベンズアミド）メチル）ピリジン １−オキシドの合成
【化２１】

６−（クロロメチル）ピリジン塩酸塩（５．００ｇ，３０．５ｍｍｏｌ）のエタノール（３５ｍｌ）溶液に撹拌下０〜５℃で４０％メチルアミン水溶液（２８．４ｇ，３６６ｍｍｏｌ）を１時間で滴下後３時間還流させ、溶媒を留去した。残渣に２８％苛性ソーダ水溶液（２０ｍｌ）とＴＨＦ（５０ｍｌ）を加え抽出した。分液後水層をさらにＴＨＦで抽出を繰り返し、有機層をまとめて硫酸マグネシウムで乾燥し溶媒留去し３−（メチルアミノメチル）ピリジン（３．６０ｇ，収率９６．８％）を得た。次いで、このピリジン（３．４０ｇ，２７．８ｍｍｏｌ）の塩化メチレン溶液（５５ｍｌ）にトリエチルアミン（２．８１ｇ，２７．８ｍｍｏｌ）を加え、これに安息香酸クロリド（３．９１ｇ，２７．８ｍｍｏｌ）の塩化メチレン溶液（１０ｍｌ）を撹拌下０℃、０．５時間で滴下しさらに１時間撹拌を続けた。その後反応溶液を水（５０ｍｌ）にあけ１時間撹拌してから分液した。水層は酢酸エチル抽出を繰り返し行った。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒留去し３−（（Ｎ−メチルベンズアミド）メチル）ピリジンの白色結晶６．１３ｇ（収率９７．５％）を得た。次いでこの結晶（６．００ｇ，２６．５ｍｍｏｌ）とタングステン酸ソーダ（０．０５ｇ）を酢酸（１２．５ｍｌ）に溶解し撹拌下９０〜１００℃で３０％過酸化水素水（３．６ｇ）を１時間で滴下した。１時間還流後、室温に冷却し沃素でんぷん反応が陰性となるまでハイポを加えた。溶媒留去してから塩化メチレン（５０ｍｌ）と１０％苛性ソーダ水溶液（３０ｍｌ）を加えて抽出した。分液後水層の抽出を繰り返し有機層をまとめて硫酸マグネシウムで乾燥し、溶媒留去して３−（（Ｎ−メチルベンズアミド）メチル）ピリジン １−オキシド６．２１ｇ（収率９６．７％）を得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）：δ ８．３〜８．２（ｍ，２Ｈ），７．４〜７．２（ｍ，７Ｈ），４．６９（ｂｒｓ，２Ｈ），２．９８（ｂｒｓ，３Ｈ）．
参考例１６ ３−（フタルイミドメチル）ピリジン １−オキシドの合成
【化２２】

３−ピリジンメタンアミン（４５．０ｇ，０．４２ｍｏｌ）のトルエン溶液（７００ｍｌ）にトリエチルアミン４．２ｇと無水フタル酸（６１．６ｇ，０．４２ｍｏｌ）を加え撹拌下３時間共沸脱水後、溶媒留去し３−（フタルイミドメチル）ピリジンの結晶８５．０ｇ（収率９８．９％）を得た。次にこの結晶を氷酢酸（２４０ｍｌ）に溶解させ３０％過酸化水素水４１ｍｌとともに３時間還流した。その後室温に冷却し沃素でんぷん反応が陰性となるまでハイポを加えた。この反応溶液を水にあけクロロホルムで抽出・分液し、水層はクロロホルム抽出を繰り返し行った。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒留去し３−（フタルイミドメチル）ピリジン １−オキシドの結晶８０．０ｇ（収率８８％）を得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）：δ ８．２７（ｂｒ，１Ｈ），７．６２（ｄｄ，Ｊ＝７．９２ ａｎｄ ２．４８ Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝７．９２ Ｈｚ，１Ｈ），６．２９（ｂｒｓ，１Ｈ），４．４０（ｄ，Ｊ＝５．９４Ｈｚ，２Ｈ），２．０３（ｓ，３Ｈ）．
実施例２９ ３−（アミノメチル）−６−クロロピリジンの合成
【化２３】

３−ピリジンメタンアミン（１０．８ｇ，０．１０ｍｏｌ）と苛性ソーダ（５．２ｇ）の水溶液（５０ｍｌ）とトルエン（４０ｍｌ）の懸濁溶液に安息香酸クロリド（１４．１ｇ，０．１０ｍｏｌ）を撹拌下０〜１０℃、１時間で滴下しさらに１時間撹拌を続けた。析出した結晶をろ別し冷水（２０ｍｌ）で洗浄した。得られた結晶［３−（ベンズアミドメチル）ピリジン］とタングステン酸ソーダ（０．３ｇ）を水（３０ｍｌ）に懸濁させ、ｐＨ４に調整しつつこの溶液に９５〜１００℃で３０％過酸化水素水（１４．７ｇ）を１時間で滴下した。５時間還流後、室温に冷却し沃素でんぷん反応が陰性となるまでハイポを加えた。この反応溶液のｐＨを９に調整後、溶媒（６０ｇ）を留去し酢酸エチルを添加しつつ共沸脱水を行った。こうして得られた３−（ベンズアミドメチル）ピリジン １−オキシドの酢酸エチル溶液（２００ｍｌ）にトリメチルアミン（２０．０ｇ）のアセトニトリル溶液（１００ｍｌ）を添加してから−５℃で撹拌しながらホスゲン（２０．０ｇ）を１時間で吹き込んだ。反応混合液を室温まで加温しさらに２時間撹拌を続けた後、２３℃／６０ｔｏｒｒ〜５７℃／５５ｔｏｒｒでホスゲンとアセトニトリルを留去した（留出物〜２００ｍｌ）。反応混合液容量を酢酸エチルで３００ｍｌとしてから塩化水素ガス（２２．４ｇ，０．６１ｍｏｌ）を導入しオートクレーブ中で撹拌下７０〜８０℃、２ｋｇｆ／ｃｍ² で５時間反応した。室温まで冷却後、反応混合液を水にあけ抽出・分液し、水層は酢酸エチルで抽出を繰り返した。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒留去して３−（ベンズアミドメチル）−６−クロロピリジンの結晶２０．８ｇを得た。この結晶を９Ｎ塩酸５００ｍｌに懸濁し撹拌下に１０時間９５℃に保った。室温まで冷却しクロロホルム３００ｍｌで３回抽出し安息香酸を回収した（８５％）。水層にクロロホルム５００ｍｌを添加しｐＨ１３としてから分液し、水層はさらにクロロホルムで抽出を繰り返した。クロロホルム層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（アミノメチル）−６−クロロピリジンの結晶１０．９ｇ（収率７６％）を得た。
実施例３０ ３−（アミノメチル）−６−クロロピリジンの合成
【化２４】

３−ピリジンメタンアミン（１０．８ｇ，０．１０ｍｏｌ）を実施例２９と同様に反応を行い、ホスゲン留去後の反応混合溶液の容量を酢酸エチルで４００ｍｌとした。この溶液に常圧で塩化水素ガス（４０ｇ，１．１ｍｏｌ）を撹拌下６０℃で吹き込みながら、１０時間反応した。室温まで冷却後、反応混合液を水にあけ抽出・分液し、水層は酢酸エチルで抽出を繰り返した。有機層をまとめて硫酸マグネシウムで乾燥し、溶媒留去して３−（ベンズアミドメチル）−６−クロロピリジンの結晶２０．４ｇを得た。この結晶を９Ｎ塩酸５００ｍｌに懸濁し撹拌下に１０時間９５℃に保った。室温まで冷却しクロロホルム３００ｍｌで３回抽出し安息香酸を回収した（８３％）。水層を５０℃／２０ｍｍＨｇで１００ｍｌまで濃縮した。クロロホルム５００ｍｌを添加しｐＨ１３としてから分液し、水層をさらにクロロホルムで抽出を繰り返した。クロロホルム層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（アミノメチル）−６−クロロピリジンの結晶１０．４ｇ（収率７３％）を得た。
実施例３１ ３−（ピバロイルアミノメチル）ピリジン １−オキシドから３−（アミノメチル）−６−クロロピリジンの合成
【化２５】

３−（ピバロイルアミノ）ピリジン １−オキシド（２０．８ｇ，０．１ｍｏｌ）のクロロホルム溶液（１１０ｍｌ）にトリメチルアミン（１５．９ｇ，０．２７ｍｏｌ）を加え、−５℃で撹拌しながらホスゲン（１３．４ｇ，０．１３５ｍｏｌ）を３０分で吹き込んだ。次いで、この反応溶液をオートクレーブに移し、塩化水素ガス（４０．２ｇ，１．１ｍｏｌ）を導入し撹拌下６０℃（５ｋｇｆ／ｃｍ² ）で５時間反応した後、室温まで冷却した。反応溶液を水洗しさらに有機層をｐＨ２で水洗してから、有機層を濃縮・乾固して３−（ビバロイルアミノメチル）−６−クロロピリジン（化合物１３）の結晶を得た（２０．８ｇ，収率９２％）。この結晶を９Ｎ塩酸（３００ｍｌ）に溶解し９０〜９５％で９時間加熱した。室温まで冷却し５０％苛性ソーダ水溶液を加え、溶液のｐＨを１３．５とした。この溶液にクロロホルム（１００ｍｌ）を加え分液し、水層は更にクロロホルムで抽出を繰り返した。クロロホルム層をまとめて硫酸マグネシウムで乾燥し、溶媒を留去し３−（アミノメチル）−６−クロロピリジンの結晶１２．６ｇ（０．０８８ｍｏｌ）収率８８％を得た。
実施例３２ ３−（ｉ−プロポキシカルボニルアミノメチル）ピリジン １−オキシドから３−（アミノメチル）−６−クロロピリジンの合成
【化２６】

３−（ｉ−プロポキシカルボニルアミノメチル）ピリジン １−オキシド（４２．０ｇ，０．２ｍｏｌ）のクロロホルム溶液（２５０ｍｌ）にトリメチルアミン（２９．６ｇ，０．５ｍｏｌ）を加え、−５℃で撹拌しながらホスゲン（２４．０ｇ，０．２４ｍｏｌ）を１時間で吹き込んだ。次いで、この反応溶液をオートクレーブに移し、塩化水素ガス（６７．０ｇ，１．８ｍｏｌ）を導入し撹拌下５０℃（５ｋｇｆ／ｃｍ² ）で５時間反応した後、室温まで冷却した。反応溶液をＨＰＬＣにて分析したところ３−（ｉ−プロポキシカルボニルアミノメチル）−６−クロロピリジン（化合物２５）３６．６ｇ（収率８０％）と３−（アミノメチル）−６−クロロピリジン４．３ｇ（収率１５％）が含まれていた。この反応溶液に３５％塩酸（２００ｍｌ）を加え抽出・分液を行い、得られた塩酸水溶液を９０〜９５℃で３．５時間加熱した。室温まで冷却し２８％苛性ソーダ水溶液を加え溶液のｐＨを１３．５に調整した。この溶液にクロロホルム（１５０ｍｌ）を加え分液し、水層は更にクロロホルムで抽出を繰り返した。クロロホルム層をまとめて硫酸マグネシウムで乾燥した。この溶液をＨＰＬＣにて分析したところ、３−（アミノメチル）−６−クロロピリジン２５．７ｇ（０．１８ｍｏｌ，収率９０％）が含まれていた。
【発明の効果】
一般式［Ｉ］で表される本発明化合物は下記反応式に従って殺虫剤として有用な一般式［IX］で表される化合物に導くことが出来る。
【化２７】

また、下記反応式に従って一般式［II］で表される化合物を経由せずに工程を短縮して一般式［IX］で表される化合物を合成することができることから一般式［Ｉ］で表される化合物は非常に有用な中間体である。
【化２８】

[Industrial application fields]
The present invention relates to substituted aminomethylpyridines useful as production precursors for important raw materials in the production of agricultural chemicals.
[Prior art]
General formula [II]
[Chemical 6]

(Wherein R ² Since 3- (aminomethyl) -6-chloropyridines represented by 'represents a hydrogen atom or a lower alkyl group) is an important raw material for the production of agricultural chemical insecticides, various production methods have been proposed.
Many methods for obtaining 3- (aminomethyl) -6-chloropyridines from 6-chloro-3- (chloromethyl) pyridine as a raw material have been reported (EP42530, EP391205, EP302389, EP366085, EP376279, JP52886936). However, this method has a problem that a by-product such as a dimer is produced by a reaction of replacing chlorine on the methyl group with an amino group. There was also a problem with the method for producing the starting 6-chloro-3- (chloromethyl) pyridine. The raw material pyridine can be produced by (1) a method of chlorinating the methyl group of 6-chloro-3-methylpyridine produced by the method described in EP556668 (DE3630046, DE4016175), (2) 6-chloro. -3- (Trichloromethyl) pyridine reduction method (EP512463, JP5320132), (3) 3- (polychloromethyl) pyridine derived from nicotinic acid or β-picoline through a rearrangement, hydrolysis, chlorination step, etc. Although many methods are reported (EP373464, JP221247, EP2292622) or (4) a method using 6-hydroxynicotinic acid, 6-chloronicotinic acid and its ester as starting materials (EP559947, 42530, 256990) The method of (1) Is insufficient in selectivity and yield of chlorination to the 3-position methyl group of the pyridine ring, (2) is unsatisfactory in the reduction yield of trichloromethyl group to monochloromethyl group, (3) (4 ) Has a large number of steps and a low overall yield, so that none of the production methods was practical.
A method of reducing the cyano group of this compound to an aminomethyl group using 6-chloro-3-cyanopyridine as a precursor is also known (DE42222152, WO9213840). However, in this method, there is a problem that chlorine elimination, dimer and the like are by-produced in the cyano group reduction step, and in the production of the raw material, a regioisomer is produced during the 6-position chlorination of 3-cyanopyridine. There was a problem that chloro-3-cyanopyridine could not be obtained efficiently.
Thus, although various methods for producing 3- (aminomethyl) -6-chloropyridines represented by the general formula [II] have been proposed, an industrial production method has not yet been established.
[Means for Solving the Problems]
We have general formula [II]
[Chemical 7]

(Wherein R ² In order to industrially produce 3- (aminomethyl) -6-chloropyridines represented by the formula ('represents the same meaning as described above), an advantageous intermediate was sought. As a result, the general formula [III] available from 3- (aminomethyl) pyridines
[Chemical 8]

(Wherein R ¹ Represents an alkyl group, an aryl group or an alkoxy group, R ² Is a hydrogen atom, a lower alkyl group or R ¹ A carbonyl group bonded to this when it is an aryl group) from a 3- (substituted aminomethyl) pyridine 1-oxide can be easily represented by the general formulas [I] and [I ′]
[Chemical 9]

(Wherein R ¹ , R ² And R ² Can be derived from 3- (substituted aminomethyl) -6-chloropyridine represented by the general formula [II ′], and from the compound represented by the general formula [I ′], the general formula [II The present invention was completed. That is, the present invention is 3- (substituted aminomethyl) -6-chloropyridine represented by the general formulas [I] and [I ′] and a method for producing the same.
DETAILED DESCRIPTION OF THE INVENTION
R ¹ , R ² And R ² 'Will be explained in detail. R ¹ Is an alkyl group, an aryl group, an aralkyl group or an alkoxy group. R ¹ Is stable during the oxidation reaction and the quaternary ammonium chloride reaction at the 6-position of pyridine in the production of the raw material compound represented by the general formula [I], and any acylamino group can be hydrolyzed in the presence of an acid. Specifically, the alkyl group may be a linear, branched or cyclic C1-C18 alkyl group, and the aryl group may be a phenyl group or a condensed ring type aromatic group such as naphthalene or anthracene. Further, those substituted with a lower alkyl group such as methyl or ethyl, a lower alkoxy group such as methoxy or ethoxy, or a halogen atom such as fluorine or chlorine can also be used. As the aralkyl group, any combination of the above-described alkyl group and aryl group is possible, and examples of the alkoxy group include lower alkoxy groups such as methoxy, ethoxy and i-propoxy, benzyloxy groups and the like. R ² Is a hydrogen atom or a lower alkyl group such as methyl or ethyl, or R ¹ When is an aryl group, it is a carbonyl group bonded to the ortho position. R ² 'Is a hydrogen atom or a lower alkyl group such as methyl or ethyl.
The organic base represented by the general formula [V] includes trimethylamine, triethylamine, N, N-dimethyl-aniline, tertiary amines such as pyridine and N, N-dimethyl-4-aminopyridine, or lower alkyl such as methyl and ethyl. Examples thereof include pyridine which may be substituted with a group.
Electrophilic reagents include chlorides such as phosgene, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorous chlorides such as (diethylamido) phosphonic dichloride, methanesulfonic acid chloride and toluenesulfonic acid chloride Examples thereof include sulfonic acid chlorides, acid chlorides such as acetyl chloride and benzoic acid chloride, and chloroformic acid esters such as chloroformate methyl ester and chloroformate isopropyl ester.
Compounds [I] and [I ′] of the present invention can be synthesized by the following method.
[Chemical Formula 10]

Process A
An organic base represented by the general formula [V] and an electrophilic reagent are allowed to act on the compound represented by the general formula [III] to form the general formula [IV] (wherein R ¹ , R ² And R ′ R ″ R ′ ″ N has the same meaning as described above).
Process B
The ammonium salt [IV] obtained in Step A is reacted with hydrogen chloride under normal pressure or under pressure to obtain 3- (substituted aminomethyl) -6-chloropyridine represented by the general formulas [I] and [I ′]. .
Solvents in step A include chlorinated solvents such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, nitrile solvents such as acetonitrile and benzonitrile, ester solvents such as ethyl acetate and methyl acetate, ether solvents such as THF and diethyl ether, and acetone. Inert solvents such as ketones such as MEK, mixed solvents thereof, or mixed solvents obtained by adding hydrocarbon solvents such as hexane and toluene to these inert solvents can be used. The compound represented by the general formula [III] is used in an amount of 2 to 6 mole equivalent of the base represented by the general formula [V], and the electrophilic reagent is equimolar to 5 moles of the compound represented by the general formula [III]. Use molar equivalents. The reaction is carried out at -40 ° C to the boiling point of the solvent, preferably -20 ° C to room temperature for 1 to 6 hours.
Step B can be carried out continuously from Step A because the solvent of Step A can be used and there is no need for isolation and purification of compound [IV]. The reaction uses 3 to 20 equivalents of hydrogen chloride, preferably 5 to 10 equivalents, and normal pressure to 20 kgf / cm. ² Preferably normal pressure to 10 kgf / cm ² Under the pressure of room temperature to room temperature to 120 ° C., preferably 40 to 80 ° C. for 3 to 20 hours.
Since the 3- (substituted aminomethyl) -6-chloropyridine represented by the general formula [I ′] thus obtained can hydrolyze an acylamino group, the general formula [II]
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To 3- (aminomethyl) -6-chloropyridines represented by That is, the compound represented by the general formula [I ′] is diluted with an aqueous acid solution or a mixed solution of a lower alcohol solvent such as methanol and treated at room temperature to the boiling point of the solvent, preferably at 85 to 95 ° C. A compound represented by the general formula [II] is obtained. Examples of the acid include hydrochloric acid and sulfuric acid. The acid concentration is suitably 6 to 12 N for hydrochloric acid and 50 to 80% for sulfuric acid. Moreover, it can be used even if these are mixed.
The 3- (substituted aminomethyl) pyridine 1-oxide represented by the general formula [III] of the raw material can be produced from 3- (aminomethyl) pyridines [VI], for example, as follows.
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Process C
3- (Aminomethyl) pyridines [VI] are reacted with acid halides, acid anhydrides, or esters to give 3- (substituted aminomethyl) pyridines [VII].
D process
[VII] is oxidized to 3- (substituted aminomethyl) pyridine 1-oxide [III].
C process is performed according to the method shown below.
(1) General formula R ¹ COX [VIII] (wherein R ¹ Represents the same meaning as described above, X represents a halogen atom) or a general formula (R ¹ CO) ₂ O [IX] (wherein R ¹ Represents the same meaning as described above), and an acid halide, haloformate or acid anhydride represented by
1 mol of the compound represented by the general formula [VI] and 1 to 1.1 mol of the compound represented by the general formula [VIII] or the general formula [IX] in an organic solvent such as methylene chloride, chloroform, toluene and xylene. In the presence of 1 to 1.5 mol of an organic base such as triethylamine, the reaction is carried out at −10 to 40 ° C.
In addition, an aqueous solution of an inorganic base such as sodium hydroxide is used in place of the organic base, and a two-phase reaction is carried out at a temperature of room temperature to 50 ° C. in the presence of a phase transfer catalyst such as a quaternary ammonium salt if necessary. You can also.
(2) General formula R ¹ 'COOY [X] (where R ¹ 'Represents an alkyl group, an aryl group or an aralkyl group, and Y represents a lower alkyl group).
In the presence of an acid catalyst such as hydrogen chloride or sulfuric acid, 1 mol of the compound represented by the general formula [VI] and 1.5 to 5.0 mol of the ester represented by the general formula [X] are the same as in (1). In the solvent at room temperature to the boiling point of the solvent used.
In step D, [VII] is oxidized to 3- (substituted aminomethyl) pyridine 1-oxide [III], and lower alcohols, water, and acetic acid can be used as the solvent. Hydrogen peroxide, hydrogen peroxide is used as the oxidizing agent. The reaction is carried out at a temperature from room temperature to the boiling point of the solvent using 1 to 2 equivalents of acetic acid, metachloroperbenzoic acid and the like. In this case, good results can be obtained even when tungstate is used as a catalyst.
The compound represented by the general formula [III] thus obtained can be used as a raw material for the next step without being isolated.
【Example】
Examples and reference examples will be described in detail.
Example 1 (Compound 1) Synthesis of 3- (benzamidomethyl) -6-chloropyridine
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While stirring at −5 ° C. in a chloroform solution (150 ml) of 3- (benzamidomethyl) pyridine 1-oxide (10.0 g, 0.044 mol) and trimethylamine (12.3 g, 0.21 mol), phosgene (16.0 g, 0.16 mol) was blown in 1 hour. The reaction mixture was warmed to room temperature and further stirred for 2 hours, after which phosgene was removed at 40 ° C./450 torr (80 ml of distillate). Next, hydrogen chloride gas (22.4 g, 0.61 mol) was introduced into the reaction mixture, and the mixture was stirred in an autoclave at 80 to 85 ° C. and 1.8 to 2.3 kgf / cm. ² For 5 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted and separated, and the aqueous layer was further extracted with chloroform. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 9.2 g (yield 85%) of 3- (benzamidomethyl) -6-chloropyridine crystals.
Melting point: 124-126 ° C
Example 2 (Compound 2) Synthesis of 3- (phthalimidomethyl) -6-chloropyridine
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While stirring at −20 ° C. in a solution of 3- (phthalimidomethyl) pyridine 1-oxide (12.7 g, 50 mmol) and trimethylamine (11.8 g, 0.20 mol) in methylene chloride (250 ml), phosgene (16 g , 0.16 mol) was blown in 0.5 hours. The reaction mixture was warmed to room temperature and further stirred for 2 hours, after which the solvent was distilled off. The residue was diluted again with methylene chloride (200 ml), hydrogen chloride gas (8 g, 0.22 mol) was introduced, and the mixture was stirred in an autoclave at 55-65 ° C., 2.3-2.6 kgf / cm. ² For 7 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted and separated, and the aqueous layer was repeatedly extracted with chloroform. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 11.3 g (yield 83%) of 3- (phthalimidomethyl) -6-chloropyridine crystals.
Example 3 (Compound 3) Synthesis of 3- (acetamidomethyl) -6-chloropyridine
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3- (acetamidomethyl) pyridine 1-oxide (8.3 g, 50 mol) and trimethylamine (16 g, 0.27 mol) were dissolved in methylene chloride (150 ml). While stirring at −10 ° C., phosgene (16 g, 0.16 mol) was blown into this solution for 1 hour. The reaction mixture was warmed to room temperature and further stirred for 2 hours, after which the solvent was distilled off. The residue was diluted with 1,2-dichloroethane (300 ml), hydrogen chloride gas (12.6 g, 0.35 mol) was introduced, and the mixture was stirred at 90-100 ° C., 2.0-2.4 kgf / cm in an autoclave. ² For 5 hours. After cooling to room temperature, the reaction mixture was concentrated, poured into water, adjusted to pH 12, and extracted and separated with methylene chloride. The aqueous layer was extracted repeatedly with methylene chloride. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 4.4 g (yield 49%) of 3- (acetamidomethyl) -6-chloropyridine crystals.
¹ H-NMR (CDCl _Three ): Δ 8.27 (br, 1H), 7.62 (dd, J = 7.92 and 2.48 Hz, 1H), 7.28 (d, J = 7.92 Hz, 1H), 6. 29 (brs, 1H), 4.40 (d, J = 5.94 Hz, 2H), 2.03 (s, 3H).
Examples 4 to 16 (compounds 4 to 16)
The following compounds 4 to 16 were synthesized in the same manner as in Example 1. The results are shown in Table-1.
[Table 1]

Example 17 Synthesis of 3- (aminomethyl) -6-chloropyridine
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5.0 g (20 mmol) of 3- (benzamidomethyl) -6-chloropyridine (Compound 1) was dissolved in 100 ml of 9N hydrochloric acid and kept at 95 ° C. for 10 hours with stirring. The mixture was cooled to room temperature and extracted three times with 50 ml of chloroform to recover benzoic acid (95%). 50 ml of chloroform was added to the aqueous layer to adjust the pH to 13, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 2.7 g of 3- (aminomethyl) -6-chloropyridine crystals (yield 95%).
Examples 18-28
Compounds 4 to 16 were treated in the same manner as Example 17. The results are shown in Table-2.
[Table 2]

Reference Example 1 Synthesis of 3- (benzamidomethyl) pyridine
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A 28% aqueous sodium hydroxide solution (200 g) and toluene (300 ml) were added to an aqueous solution (300 ml) of 3-pyridinemethanamine (108 g, 1.0 mol), and then benzoic chloride (180 g, 1.28 mol) was added with stirring. The solution was added dropwise at 2 ° C. for 2 hours and stirring was continued for 3 hours. Thereafter, the reaction suspension solution was filtered, and the obtained crystals were washed with cold water. The crystals were dried to obtain 208 g (yield 98%) of 3- (benzamidomethyl) pyridine.
Reference Example 2 Synthesis of 3- (benzamidomethyl) pyridine 1-oxide
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3- (Benzamidomethyl) pyridine (205 g, 0.95 mol) and sodium tungstate (1 g) were dissolved in glacial acetic acid (500 ml), and 30% hydrogen peroxide (150 g) was added dropwise at 95 ° C. over 1 hour with stirring. . After reacting at 105 ° C. for 1 hour, the mixture was cooled to room temperature and hypo was added until the iodine starch reaction was negative. The reaction solution was concentrated, methylene chloride (3.5 L) and water (2 L) were added, adjusted to pH 13 with 28% aqueous sodium hydroxide solution, and extracted and separated. The extraction of the aqueous layer was repeated, the organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to obtain 190 g (yield 88%) of 3- (benzamidomethyl) pyridine 1-oxide crystals.
Melting point: 112-113 ° C
Reference Example 3 Synthesis of 3- (benzamidomethyl) pyridine 1-oxide
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3- (benzamidomethyl) pyridine (5.0 g, 23.5 mmol), sodium tungstate (0.3 g) and 35% hydrochloric acid (0.13 g) were suspended in water (7.5 ml). To this suspension solution, 30% hydrogen peroxide (3.2 g) was added dropwise over 15 minutes with stirring under reflux. After further reaction for 4 hours, the mixture was cooled to room temperature and hypo was added until the iodine starch reaction was negative. When this reaction solution was analyzed by HPLC, the production rate of 3- (benzamidomethyl) pyridine 1-oxide was 97%.
Reference Example 4 Synthesis of 3- (acetamidomethyl) pyridine 1-oxide
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Stirring a chloroform solution (100 ml) of acetic chloride (36.3 g, 0.46 mol) into a methylene chloride solution (250 ml) of 3-pyridinemethanamine (50 g, 0.46 mol) and triethylamine (46.8 g, 0.46 mol). The temperature was dropped at 0 to 10 ° C. for 1.5 hours, and stirring was further continued for 1 hour. Thereafter, water (200 ml) was added to the reaction solution, followed by extraction and liquid separation with ethyl acetate (600 ml). The aqueous layer was extracted with isobutanol (500 ml × 2), the organic layers were combined, and 1200 ml of the solvent was distilled off. The precipitated crystals were filtered, the mother liquor and ethyl acetate washed with the crystals were combined, dried over magnesium sulfate and evaporated to give 70 g (yield 99%) of 3- (acetamidomethyl) pyridine crystals. Next, the crystals (35 g, 0.23 mol) and sodium tungstate (0.5 g) were dissolved in glacial acetic acid (60 ml), and 30% aqueous hydrogen peroxide (48 g) was added dropwise at 100 ° C. over 3 hours with stirring. After reacting at the same temperature for 3 hours, the mixture was cooled to room temperature and hypo was added until the iodine starch reaction was negative. Toluene was added to the reaction solution, azeotropic dehydration was performed, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (CHCl 3). _Three / MeOH = 9/1) to obtain 16 g (42% yield) of 3- (benzamidomethyl) pyridine 1-oxide.
¹ H-NMR (DMSO): δ 8.45 (brs, 1H), 8.11 (brs, 2H), 7.35 (dd, J = 7.91 and 7.91 Hz, 1H), 7.22 ( d, J = 7.91 Hz, 1H), 4.22 (d, J = 5.94 Hz, 2H), 1.89 (s, 3H).
Reference Examples 5-14
The following compounds 19 to 28 were synthesized in the same manner as in Reference Example 3. The results are shown in Table-3.
[Table 3]

Reference Example 15 Synthesis of 3-((N-methylbenzamido) methyl) pyridine 1-oxide
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To a solution of 6- (chloromethyl) pyridine hydrochloride (5.00 g, 30.5 mmol) in ethanol (35 ml) was added dropwise 40% aqueous methylamine solution (28.4 g, 366 mmol) at 0 to 5 ° C. with stirring over 1 hour. The mixture was refluxed for 3 hours, and the solvent was distilled off. The residue was extracted by adding 28% aqueous sodium hydroxide (20 ml) and THF (50 ml). After separation, the aqueous layer was further extracted with THF. The organic layers were combined, dried over magnesium sulfate and evaporated to give 3- (methylaminomethyl) pyridine (3.60 g, yield 96.8%). . Next, triethylamine (2.81 g, 27.8 mmol) was added to a methylene chloride solution (55 ml) of this pyridine (3.40 g, 27.8 mmol), and benzoic acid chloride (3.91 g, 27.8 mmol) was salified. Methylene solution (10 ml) was added dropwise at 0 ° C. with stirring for 0.5 hour, and stirring was continued for another hour. Thereafter, the reaction solution was poured into water (50 ml) and stirred for 1 hour, followed by liquid separation. The aqueous layer was repeatedly extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to obtain 6.13 g of white crystals of 3-((N-methylbenzamido) methyl) pyridine (yield 97.5%). Next, this crystal (6.00 g, 26.5 mmol) and sodium tungstate (0.05 g) were dissolved in acetic acid (12.5 ml), and 30% hydrogen peroxide solution (3.6 g) was added at 90-100 ° C. with stirring. It was dripped in 1 hour. After refluxing for 1 hour, the mixture was cooled to room temperature and hypo was added until the iodine starch reaction was negative. After the solvent was distilled off, methylene chloride (50 ml) and 10% aqueous sodium hydroxide solution (30 ml) were added for extraction. After separation, the aqueous layer was extracted repeatedly, the organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to give 6.21 g of 3-((N-methylbenzamido) methyl) pyridine 1-oxide (yield 96.7%). )
¹ H-NMR (CDCl _Three ): Δ 8.3-8.2 (m, 2H), 7.4-7.2 (m, 7H), 4.69 (brs, 2H), 2.98 (brs, 3H).
Reference Example 16 Synthesis of 3- (phthalimidomethyl) pyridine 1-oxide
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To a toluene solution (700 ml) of 3-pyridinemethanamine (45.0 g, 0.42 mol), 4.2 g of triethylamine and phthalic anhydride (61.6 g, 0.42 mol) were added, and after azeotropic dehydration with stirring for 3 hours, Distilled off to obtain 85.0 g (yield 98.9%) of 3- (phthalimidomethyl) pyridine crystals. Next, the crystals were dissolved in glacial acetic acid (240 ml) and refluxed with 41 ml of 30% aqueous hydrogen peroxide for 3 hours. Thereafter, the mixture was cooled to room temperature, and a hypo was added until the iodine starch reaction became negative. The reaction solution was poured into water, extracted and separated with chloroform, and the aqueous layer was repeatedly extracted with chloroform. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off to obtain 80.0 g (yield 88%) of 3- (phthalimidomethyl) pyridine 1-oxide crystals.
¹ H-NMR (CDCl _Three ): Δ 8.27 (br, 1H), 7.62 (dd, J = 7.92 and 2.48 Hz, 1H), 7.28 (d, J = 7.92 Hz, 1H), 6. 29 (brs, 1H), 4.40 (d, J = 5.94 Hz, 2H), 2.03 (s, 3H).
Example 29 Synthesis of 3- (aminomethyl) -6-chloropyridine
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Stir benzoic acid chloride (14.1 g, 0.10 mol) into a suspension of 3-pyridinemethanamine (10.8 g, 0.10 mol), caustic soda (5.2 g) in water (50 ml) and toluene (40 ml). The temperature was dropped at 0 to 10 ° C. for 1 hour, and stirring was continued for 1 hour. The precipitated crystals were separated by filtration and washed with cold water (20 ml). The obtained crystals [3- (benzamidomethyl) pyridine] and sodium tungstate (0.3 g) were suspended in water (30 ml) and adjusted to pH 4 with 30% hydrogen peroxide at 95-100 ° C. Water (14.7 g) was added dropwise over 1 hour. After refluxing for 5 hours, the mixture was cooled to room temperature and hypo was added until the iodine starch reaction was negative. After adjusting the pH of the reaction solution to 9, the solvent (60 g) was distilled off, and azeotropic dehydration was performed while adding ethyl acetate. Triethylamine (20.0 g) in acetonitrile (100 ml) was added to the ethyl acetate solution (200 ml) of 3- (benzamidomethyl) pyridine 1-oxide thus obtained, and phosgene (20.20) was stirred at -5 ° C. 0 g) was blown in 1 hour. After the reaction mixture was warmed to room temperature and further stirred for 2 hours, phosgene and acetonitrile were distilled off at 23 ° C./60 torr / 57 ° C./55 torr (distillate to 200 ml). The reaction mixture volume was adjusted to 300 ml with ethyl acetate, hydrogen chloride gas (22.4 g, 0.61 mol) was introduced, and the mixture was stirred in an autoclave at 70-80 ° C., 2 kgf / cm 2. ² For 5 hours. After cooling to room temperature, the reaction mixture was poured into water, extracted and separated, and the aqueous layer was repeatedly extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and evaporated to give 20.8 g of 3- (benzamidomethyl) -6-chloropyridine crystals. The crystals were suspended in 500 ml of 9N hydrochloric acid and kept at 95 ° C. for 10 hours with stirring. The mixture was cooled to room temperature and extracted three times with 300 ml of chloroform to recover benzoic acid (85%). Chloroform 500 ml was added to the aqueous layer to adjust the pH to 13, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 10.9 g (yield 76%) of 3- (aminomethyl) -6-chloropyridine crystals.
Example 30 Synthesis of 3- (aminomethyl) -6-chloropyridine
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3-Pyridinemethanamine (10.8 g, 0.10 mol) was reacted in the same manner as in Example 29, and the volume of the reaction mixture solution after distilling off phosgene was adjusted to 400 ml with ethyl acetate. The solution was reacted for 10 hours while blowing hydrogen chloride gas (40 g, 1.1 mol) at 60 ° C. with stirring at normal pressure. After cooling to room temperature, the reaction mixture was poured into water, extracted and separated, and the aqueous layer was repeatedly extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and evaporated to give 20.4 g of 3- (benzamidomethyl) -6-chloropyridine crystals. The crystals were suspended in 500 ml of 9N hydrochloric acid and kept at 95 ° C. for 10 hours with stirring. The mixture was cooled to room temperature and extracted three times with 300 ml of chloroform to recover benzoic acid (83%). The aqueous layer was concentrated to 100 ml at 50 ° C./20 mmHg. Chloroform 500 ml was added to adjust the pH to 13, followed by liquid separation. The aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 10.4 g (yield 73%) of 3- (aminomethyl) -6-chloropyridine crystals.
Example 31 Synthesis of 3- (aminomethyl) -6-chloropyridine from 3- (pivaloylaminomethyl) pyridine 1-oxide
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Trimethylamine (15.9 g, 0.27 mol) was added to a chloroform solution (110 ml) of 3- (pivaloylamino) pyridine 1-oxide (20.8 g, 0.1 mol), and phosgene (13.4 g) was stirred at −5 ° C. , 0.135 mol) was blown in 30 minutes. The reaction solution was then transferred to an autoclave, hydrogen chloride gas (40.2 g, 1.1 mol) was introduced, and the mixture was stirred at 60 ° C. (5 kgf / cm ² ) For 5 hours, and then cooled to room temperature. The reaction solution was washed with water and the organic layer was washed with water at pH 2. Then, the organic layer was concentrated and dried to obtain crystals of 3- (bivaloylaminomethyl) -6-chloropyridine (Compound 13) (20. 8 g, yield 92%). The crystals were dissolved in 9N hydrochloric acid (300 ml) and heated at 90-95% for 9 hours. After cooling to room temperature, 50% aqueous sodium hydroxide solution was added to adjust the pH of the solution to 13.5. Chloroform (100 ml) was added to the solution and the phases were separated, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over magnesium sulfate, and the solvent was distilled off to obtain 12.6 g (0.088 mol) crystals of 3- (aminomethyl) -6-chloropyridine at a yield of 88%.
Example 32 Synthesis of 3- (aminomethyl) -6-chloropyridine from 3- (i-propoxycarbonylaminomethyl) pyridine 1-oxide
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Trimethylamine (29.6 g, 0.5 mol) was added to a chloroform solution (250 ml) of 3- (i-propoxycarbonylaminomethyl) pyridine 1-oxide (42.0 g, 0.2 mol) and stirred at −5 ° C. Phosgene (24.0 g, 0.24 mol) was blown in over 1 hour. The reaction solution was then transferred to an autoclave, hydrogen chloride gas (67.0 g, 1.8 mol) was introduced, and the mixture was stirred at 50 ° C. (5 kgf / cm ² ) For 5 hours, and then cooled to room temperature. The reaction solution was analyzed by HPLC. 3- (i-propoxycarbonylaminomethyl) -6-chloropyridine (Compound 25) 36.6 g (yield 80%) and 3- (aminomethyl) -6-chloropyridine 4 0.3 g (15% yield) was included. 35% hydrochloric acid (200 ml) was added to this reaction solution for extraction and liquid separation, and the resulting aqueous hydrochloric acid solution was heated at 90 to 95 ° C. for 3.5 hours. After cooling to room temperature, 28% aqueous sodium hydroxide solution was added to adjust the pH of the solution to 13.5. Chloroform (150 ml) was added to the solution and the phases were separated, and the aqueous layer was further extracted with chloroform. The chloroform layers were combined and dried over magnesium sulfate. When this solution was analyzed by HPLC, 25.7 g (0.18 mol, yield 90%) of 3- (aminomethyl) -6-chloropyridine was contained.
【The invention's effect】
The compound of the present invention represented by the general formula [I] can be led to a compound represented by the general formula [IX] useful as an insecticide according to the following reaction formula.
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Further, since the compound represented by the general formula [IX] can be synthesized by shortening the process without passing through the compound represented by the general formula [II] according to the following reaction formula, the compound represented by the general formula [I] is represented. The compounds that are obtained are very useful intermediates.
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Claims (2)

Formula [III]

(Wherein R ¹ represents an alkyl group, an aryl group, an aralkyl group or an alkoxy group; R ² represents a hydrogen atom or a lower alkyl group when R ¹ is an alkyl group, an aralkyl group or an alkoxy group; ^{When 1} is an aryl group, it represents a carbonyl group bonded to this group). 3- (Substituted aminomethyl) pyridine-1-oxide is represented by the general formula [V]: R′R ″ R ′ ″ N ( In the formula, R ′, R ″ and R ′ ″ are the same or different and represent a lower alkyl group or an aromatic group, or R′R ″ R ′ ″ N together have a substituent. A general formula [I], characterized by reacting an organic base represented by (II) and an electrophilic reagent having at least one chlorine atom, and further reacting with hydrogen chloride.

(In formula, R < ¹ >, R < ² > shows the same meaning as the above.) The manufacturing method of 3- (substituted aminomethyl) -6-chloropyridine represented. Formula [I ']

(Wherein R ¹ represents the same meaning as described in claim 1, and R ² ′ represents a hydrogen atom or an alkyl group.) 3- (substituted aminomethyl) -6-chloropyridine represented by acid In the presence of water, it is treated with water and is represented by the general formula [II]

(In the formula, R ² ′ has the same meaning as described above.)
The manufacturing method of 3- (aminomethyl) -6-chloropyridine represented by these.