JP4556241B2 - Novel 6-fluoroalkyl-2 (1H) -pyridinone, 6-fluoroalkylpyridine compound and process for producing the same - Google Patents
Novel 6-fluoroalkyl-2 (1H) -pyridinone, 6-fluoroalkylpyridine compound and process for producing the same Download PDFInfo
- Publication number
- JP4556241B2 JP4556241B2 JP2005502987A JP2005502987A JP4556241B2 JP 4556241 B2 JP4556241 B2 JP 4556241B2 JP 2005502987 A JP2005502987 A JP 2005502987A JP 2005502987 A JP2005502987 A JP 2005502987A JP 4556241 B2 JP4556241 B2 JP 4556241B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- pyridinone
- methyl
- represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
Description
技術分野：
本発明は、農医薬、特に殺菌剤の製造中間体として有用な、６位に少なくとも１個のフッ素原子が置換したハロアルキル基を有する新規２（１Ｈ）−ピリジノン化合物またはその誘導体である２位に置換基を有する新規ピリジン化合物およびそれらの製造方法に関する。
背景技術：
本発明に係る６−ハロアルキル−２（１Ｈ）−ピリジノン類およびその製造方法は、例えば２（１Ｈ）−ピリジノンの６位をブロモトリフルオロメタンによりトリフルオロメチル化する方法で６−トリフルオロメチル−２（１Ｈ）−ピリジノンを製造している例がＥＰ０２０６９５１号公報等に、
６−トリフルオロメチル−２−ハロピリジン類を加水分解することにより６−トリフルオロメチル−２（１Ｈ）−ピリジノンを製造する例がＷＯ９８／４０３５５号公報等に、
６−ハロアルキル−２−ヒドロキシニコチン酸類を脱炭酸することにより６−ハロアルキル−２（１Ｈ）−ピリジノン類を製造する例がＧＢ２３０５１７４号公報等に記載されている。
しかし、いずれの場合もピリジン環の４位にアルキル基が置換している化合物を製造した例は記載されていない。
また、本発明における６−ハロアルキル−２（１Ｈ）−ピリジノン類の中間原料である６−ハロアルキル−２−ピロン類の合成法は例えばＨｅｌｖ．Ｃｈｉｍ．Ａｃｔａ Ｖｏｌ．５３（８），２１５９−２１５７（１９７０）にトリクロロアセチルクロライドとアクリル酸クロライドを塩基存在下に反応させ６−トリクロロ−２−ピロン類を製造する例が報告されている。
しかし、フッ素原子を有するハロアルキルカルボン酸無水物を用いる例および得られた６−ハロアルキル−２−ピロン類を６−ハロアルキル−２（１Ｈ）−ピリジノン類へ変換する例は記載されていない。
本発明に係る６−ハロアルキル−２−ハロピリジン類およびその製造方法は、例えば２−ピコリン類にハロゲンガスを作用させ２位メチル基および６位をハロゲン化した後、フッ化水素ガスなどのフッ素化剤でハロゲン化されたメチル基をフッ素化することにより製造する方法が、公開特許公報昭和５８−２０６５６３などに記載されている。
しかし、ピリジン環の４位にアルキル基が置換している化合物を製造した例は記載されていない。
発明の開示：
本発明は、有用な６位に少なくとも１個のフッ素原子が置換したハロアルキル基を有する新規２（１Ｈ）−ピリジノン化合物またはその誘導体である２位に置換基を有する新規ピリジン化合物を工業的に有利に製造する方法を提供することを課題とする。
本発明は、第１に、式（１）
（式中、Ｒ１は、水素原子またはＣ１〜６アルキル基を表す。Ｘは塩素原子または臭素原子などのハロゲン原子を表す。）で表される化合物と
式（２）
（式中、Ｒ２およびＲ３はそれぞれ独立して水素原子、ハロゲン原子、Ｃ１〜６アルキル基、またはＣ１〜６ハロアルキル基を表す。）で表される酸無水物または、
式（２´）
（式中、Ｒ２およびＲ３はそれぞれ独立して水素原子、ハロゲン原子、Ｃ１〜６アルキル基、またはＣ１〜６ハロアルキル基を表す。Ｘ´はハロゲン原子を表す。）
で表される酸ハライドを塩基存在下に反応させることにより
式（３）
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。）で表される化合物を得る工程と、
得られた式（３）で表される化合物とアンモニアまたはアンモニウム塩を反応させる工程とを有する、
式（４）
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。）で表される化合物の製造方法であり、
第２に前記式（４）で表される化合物とオキシ臭化リンなどのハロゲン化剤またはスルホニル化剤を反応させることによる、
式（５）
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。Ｙ１はハロゲン原子、Ｃ１〜６アルキルスルホニルオキシ基、置換されても良いベンゼンスルホニルオキシ基またはＣ１ 〜６ハロアルキルスルホニルオキシ基を表す。）で表される化合物の製造方法であり、
第３に、前記式（５）で表わされる化合物とアルキル化剤を反応させることによる、
式（６）
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。Ｙ２はＣ１〜６アルキル基を表わす。）
で表される化合物の製造方法であり、
さらに、式（７）
（式中、Ｒ１´は、Ｃ１〜６アルキル基を表す。Ｒ２およびＲ３は前記と同じ意味を表す。）
で表される化合物および、式（８）
（式中、Ｒ１´、Ｒ２およびＲ３は前記と同じ意味を表す。Ｙは前記Ｙ１またはＹ２を表す。）
で表される化合物を提供する。
以下本発明を詳細に説明する
前記式（１）〜（８）の定義において、Ｒ１は、水素原子、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、イソブチル、ｔ−ブチル、ペンチルおよびその異性体、ヘキシルおよびその異性体等のＣ１−６アルキル基が挙げられる。
これらの中でも、水素原子、メチル基が好ましい。
Ｒ２、Ｒ３はそれぞれ独立して水素原子、フッ素、塩素、臭素、ヨウ素等のハロゲン原子、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、イソブチル、ｔ−ブチル、ペンチルおよびその異性体、ヘキシルおよびその異性体等のＣ１−６アルキル基、クロロメチル、フルオロメチル、ブロモメチル、ジクロロメチル、ジフルオロメチル、ジブロモメチル、トリクロロメチル、トリフルオロメチル、トリブロモメチル、トリクロロエチル、トリフルオロエチル、ペンタフルオロエチル等のＣ１−６ハロアルキル基が挙げられる。この中でも、水素原子、フッ素原子、塩素原子、トリフルオロメチル基が好ましい。
Ｙ１はフッ素、塩素、臭素、ヨウ素等のハロゲン原子、メタンスルホニルオキシ、エタンスルホニルオキシ、プロパンスルホニルオキシなどのＣ１−６アルキル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、トリクロロメタンスルホニルオキシ基、ペンタフルオロエタンスルホニルオキシ等のＣ１−６ハロアルキルスルホニルオキシ基、ベンゼンスルホニルオキシ、２−メチルベンゼンスルホニルオキシ、３−メチルベンゼンスルホニルオキシ、４−メチルベンゼンスルホニル等の置換されてもよいベンゼンスルホニルオキシ基が挙げられる。この中でも、塩素原子、臭素原子、メタンスルホニル基、トリフルオロメタンスルホニルオキシ基、４−メチルベンゼンスルホニルオキシ基が好ましい。
Ｙ２はメチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、イソブチル、ｔ−ブチル、ペンチルおよびその異性体、ヘキシルおよびその異性体等のＣ１−６アルキル基を表す。この中でも、メチル基、エチル基が好ましい。
Ｒ１´はメチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ−ブチル、イソブチル、ｔ−ブチル、ペンチルおよびその異性体、ヘキシルおよびその異性体等のＣ１−６アルキル基が挙げられる。この中でも、メチル基、エチル基が好ましい。
Ｘはフッ素、塩素、臭素、ヨウ素等のハロゲン原子が挙げられる。この中でも、塩素原子、臭素原子が好ましい。
Ｘ´は、フッ素、塩素、臭素、ヨウ素等のハロゲン原子が挙げられる。この中でも、塩素原子、臭素原子が好ましい。
次に本発明の製造方法について説明する。
（１）製造方法１−１
（式中、Ｒ１、Ｒ２、Ｒ３、ＸおよびＸ´は前記と同じ意味を表す。）
本発明のなかで式（１）で表される酸ハロゲン化物と式（２）で表される酸無水物または式（２’）で表される酸ハロゲン化物とを有機溶媒中、塩基存在下に反応させて式（３）で表されるピロン類へ誘導する製造法において、反応溶媒としては、ジクロロメタン、クロロホルムなどのハロゲン炭化水素類、ジエチルエーテル、ジオキサンなどのエーテル系溶媒、酢酸エチルなどのカルボン酸エステル系溶媒、アセトニトリルなどのニトリル系溶媒、トルエンなどの芳香族炭化水素系溶媒、または、場合によってはこれらの混合溶媒が使用できる。これらの中でも、ジクロロメタン、クロロホルムなどのハロゲン炭化水素類の使用が好ましい。
塩基としてはトリエチルアミン、ジイソプロピルエチルアミン、ピリジン、１，４−ジアザビシクロ［２，２，２］オクタン（ＤＡＢＣＯ）、４−ジメチルアミノピリジン（ＤＭＡＰ）、１，４−ジアザビシクロ［５，４，０］ウンデ−７−エン（ＤＢＵ）などの有機塩基の使用が可能である。塩基の使用量は式（１）で表される酸ハロゲン化物に対し、２−３当量の範囲から適宜選択して使用することができる。
反応温度は通常室温から使用する溶媒の沸点まで可能である。
（２）製造方法１−２
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。）
式（３）で表されるピロン類とアンモニアまたはアンモニウム塩を水あるいは有機溶媒中で反応させて式（４）で表される２（１Ｈ）−ピリジノン類を得る製造法において、反応溶媒としては、水、メタノール、エタノール等のアルコール類、酢酸等のカルボン酸類、ジクロロメタン、クロロホルム等のハロゲン炭化水素類、アセトニトリル等のニトリル系溶媒、テトラヒドロフラン（ＴＨＦ）、ジオキサンなどのエーテル系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、ジメチルホルムアミド（ＤＭＦ）等のアミド系溶媒等または、場合によってはこれらの混合溶媒が使用できる。この中で水、アルコール類、カルボン酸類の使用が好ましい。
使用できるアンモニウム塩としては炭酸アンモニウム、酢酸アンモニウム等の有機酸塩、塩化アンモニウム等の無機塩が挙げられる。この中で炭酸アンモニウム、酢酸アンモニウム等の有機酸塩の使用が望ましい。アンモニアまたはアンモニウム塩の使用量は、式（３）で表されるピロン類に対し、１−１０当量の範囲から適宜選択して使用することができる。
反応温度は通常室温から使用する溶媒の沸点まで可能である。アンモニアガスを用いる場合はオートクレーブ中、１−１００気圧下で反応させることがより好ましい。
（３）製造方法２−１
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。Ｘは前記Ｙ１のうちハロゲン原子を表す。）
式（４）で表される２（１Ｈ）−ピリジノン類に無溶媒または有機溶媒中、場合によっては塩基性触媒存在下でハロゲン化剤を反応させて式（５−１）で表される化合物を得る製造方法において、反応溶媒としては、ジクロロメタン、クロロホルム等のハロゲン炭化水素系溶媒、トルエン等の芳香族炭化水素系溶媒、ジメチルホルムアミド等のアミド系溶媒または、場合によってはこれらの混合溶媒が使用できる。
反応に用いることのできるハロゲン化剤としては、三塩化リン、三臭化リン、五塩化リン、五臭化リン等のハロゲン化リン化合物、オキシ塩化リン、オキシ臭化リン等のオキシハロゲン化リン化合物、トリフェニルジクロロホスフィン、トリフェニルジブロモホスフィン、ジフェニルペンタクロロホスフィン等の芳香族ハロゲン化リン化合物等が挙げられる。
ハロゲン化剤の使用量としては、式（４）で表される２（１Ｈ）−ピリジノン類に対して、１−１０当量の範囲から適宜選択して使用することができる。
また、この反応においては、ＤＭＡＰ、ジメチルアニリン等の塩基性触媒を用いることにより、反応を迅速に効率良く進行させることができる。触媒の使用量は、反応が効率良く進行する程度の範囲で適宜選択できるが、通常、式（４）で表される２（１Ｈ）−ピリジノン類に対して、０．００１〜１当量の範囲である。反応は室温〜２００℃で円滑に進行する。
（４）製造方法２−２
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。Ｚは前記Ｙ１のうちＣ１〜６アルキルスルホニルオキシ基、置換されても良いベンゼンスルホニルオキシ基またはＣ１〜６ハロアルキルスルホニル基を表す。）
式（４）で表される２（１Ｈ）−ピリジノン類に、無溶媒または有機溶媒中、好ましくは塩基存在下、スルフォニル化剤を反応させることにより、式（５−２）で表される化合物を得る。反応溶媒としてはジクロロメタン、クロロホルム等のハロゲン炭化水素系溶媒、トルエン等の芳香族炭化水素系溶媒、酢酸エチル等のカルボン酸エステル系溶媒、ＴＨＦ、ジオキサン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒、ジメチルホルムアミド等のアミド系溶媒または、場合によってはこれらの混合溶媒が使用できる。
使用できるスルホニル化剤としては、メタンスルホニルクロライド、４−メチルベンゼンスルホニルクロライド等のスルホン酸ハライド類、トリフルオロメタンスルホン酸無水物等のスルホン酸無水物等が挙げられる。
スルホニル化剤の使用量としては、式（４）で表される２（１Ｈ）−ピリジノン類に対して、１−１０当量の範囲から適宜選択して使用することができる。
反応時、系中に発生するハロゲン化水素を捕獲する塩基を必ずしも存在させる必要はないが、必要に応じてハロゲン化水素を除去するためトリエチルアミンのような有機塩基や重炭酸ソーダのような無機塩基を使用しても良い。
反応は−２０℃〜２００℃で円滑に進行する。
（５）製造方法３
（式中、Ｒ１、Ｒ２、Ｒ３、Ｙ１およびＹ２は前記と同じ意味を表す。）
式（５）で表されるピリジン類に、有機溶媒中、触媒存在下、アルキル化剤を反応させることにより一般式（５−３）で表される化合物を得る製造方法において、反応溶媒としては、ジエチルエーテル、ＴＨＦ等のエーテル系溶媒を用いることができる。
使用できるアルキル化剤としては、メチルリチウム等のアルキルリチウム類、メチルマグネシウムブロマイド等のグリニヤール試薬、メチルジンククロライド等のアルキル亜鉛化合物等が挙げられる。アルキル化剤の使用量としては、式（５）で表されるピリジン類に対して、１−１０当量の範囲から適宜選択して使用することができる。反応は−２０℃〜反応溶媒の還流温度で進行するが、２０℃〜反応溶媒の還流温度で行うのが好ましい。
使用できる触媒としてはＮｉＣｌ２（ｄｐｐｐ）等の適当な配位子を有するニッケル化合物、ＰｄＣｌ２（ＰＰｈ３）２等の適当な配位子を有するパラジウム化合物等が挙げられる。触媒の使用量は、反応が効率良く進行する程度の範囲で適宜選択できるが、通常、式（５）で表されるピリジン類に対して、０．００１〜１当量の範囲である。
反応終了後は、通常の後処理を行うことにより、目的とする化合物を得ることができる。
以下にこれら合成法により製造できる化合物を示す。
このようにして得られる化合物のうち式（８）で表される化合物は、ＷＯ０１／３４５６８、ＷＯ０２／６４５６６、ＷＯ０２／６６４３４等に記載されている方法で殺菌剤として有用なオキシムエーテル化合物へと誘導することができる。
発明を実施するための最良の形態：
次に製造例で本発明を詳しく説明するが、本発明は下記の製造例のみに限定されるものではない。Technical field:
The present invention provides a novel 2 (1H) -pyridinone compound having a haloalkyl group substituted with at least one fluorine atom at the 6-position, or a derivative thereof, which is useful as an intermediate for producing agricultural medicine, particularly a fungicide. The present invention relates to a novel pyridine compound having a substituent and a method for producing the same.
Background technology:
The 6-haloalkyl-2 (1H) -pyridinones according to the present invention and the method for producing the 6-trifluoroalkyl-2 are obtained by, for example, trifluoromethylating 6-position of 2 (1H) -pyridinone with bromotrifluoromethane. An example of producing (1H) -pyridinone is disclosed in EP0206951 and the like.
An example of producing 6-trifluoromethyl-2 (1H) -pyridinone by hydrolyzing 6-trifluoromethyl-2-halopyridines is disclosed in WO98 / 40355, etc.
An example of producing 6-haloalkyl-2 (1H) -pyridinones by decarboxylation of 6-haloalkyl-2-hydroxynicotinic acids is described in GB2305174.
However, in any case, no example of producing a compound in which an alkyl group is substituted at the 4-position of the pyridine ring is described.
A method for synthesizing 6-haloalkyl-2-pyrones, which are intermediate raw materials for 6-haloalkyl-2 (1H) -pyridinones in the present invention, is described in, for example, Helv. Chim. Acta Vol. 53 (8), 2159-2157 (1970) reports an example of producing 6-trichloro-2-pyrones by reacting trichloroacetyl chloride and acrylic acid chloride in the presence of a base.
However, an example using a haloalkylcarboxylic anhydride having a fluorine atom and an example of converting the obtained 6-haloalkyl-2-pyrones to 6-haloalkyl-2 (1H) -pyridinones are not described.
The 6-haloalkyl-2-halopyridines and the method for producing the same according to the present invention include, for example, halogenation of 2-picolines to halogenate the 2-position methyl group and the 6-position, followed by fluorination of hydrogen fluoride gas or the like. A method for producing a methyl group halogenated with an agent by fluorination is described in, for example, Japanese Patent Application Laid-Open No. 58-206563.
However, an example in which a compound in which an alkyl group is substituted at the 4-position of the pyridine ring is not described.
Disclosure of the invention:
INDUSTRIAL APPLICABILITY The present invention is industrially advantageous to a novel 2 (1H) -pyridinone compound having a haloalkyl group substituted with at least one fluorine atom at the 6-position, or a novel pyridine compound having a substituent at the 2-position, which is a derivative thereof. It is an object of the present invention to provide a manufacturing method.
The present invention firstly provides the formula (1)
(Wherein R 1 represents a hydrogen atom or a C 1-6 alkyl group, X represents a halogen atom such as a chlorine atom or a bromine atom) and a formula (2)
(Wherein R2 and R3 each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 haloalkyl group) or
Formula (2 ')
(In the formula, R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group. X ′ represents a halogen atom.)
By reacting an acid halide represented by the formula (3)
(Wherein R1, R2 and R3 represent the same meaning as described above),
A step of reacting the obtained compound represented by formula (3) with ammonia or an ammonium salt,
Formula (4)
(Wherein R 1, R 2 and R 3 represent the same meaning as described above),
Second, by reacting the compound represented by the formula (4) with a halogenating agent or sulfonylating agent such as phosphorus oxybromide,
Formula (5)
(Wherein, R1, .Y1 R2 and R3 represent the same meanings as described above is a halogen atom, C 1 to 6 alkylsulfonyloxy group, an optionally substituted benzenesulfonyloxy group or a C 1 to 6 haloalkylsulfonyl group And a method for producing a compound represented by:
Third, by reacting the compound represented by the formula (5) with an alkylating agent,
Formula (6)
(Wherein R1, R2 and R3 represent the same meaning as described above. Y2 represents a C1-6 alkyl group.)
A method for producing a compound represented by:
Furthermore, Formula (7)
(In the formula, R1 ′ represents a C 1-6 alkyl group. R2 and R3 have the same meaning as described above.)
A compound represented by formula (8):
(In the formula, R1 ′, R2 and R3 have the same meaning as above. Y represents Y1 or Y2.)
The compound represented by these is provided.
Hereinafter, the present invention will be described in detail. In the definitions of the formulas (1) to (8), R1 represents a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl and the like. Examples thereof include C 1-6 alkyl groups such as isomers, hexyl and isomers thereof.
Among these, a hydrogen atom and a methyl group are preferable.
R2 and R3 are each independently a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine or iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl and its isomer, hexyl And C 1-6 alkyl groups such as isomers thereof, chloromethyl, fluoromethyl, bromomethyl, dichloromethyl, difluoromethyl, dibromomethyl, trichloromethyl, trifluoromethyl, tribromomethyl, trichloroethyl, trifluoroethyl, pentafluoro And C 1-6 haloalkyl groups such as ethyl. Among these, a hydrogen atom, a fluorine atom, a chlorine atom, and a trifluoromethyl group are preferable.
Y1 is a halogen atom such as fluorine, chlorine, bromine or iodine, C 1-6 alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, trichloromethanesulfonyloxy group, pentafluoroethane C 1-6 haloalkylsulfonyloxy groups such as sulfonyloxy, benzenesulfonyloxy, 2-methylbenzenesulfonyloxy, 3-methylbenzenesulfonyloxy, 4-methylbenzenesulfonyl and the like may be substituted benzenesulfonyloxy groups. . Among these, a chlorine atom, a bromine atom, a methanesulfonyl group, a trifluoromethanesulfonyloxy group, and a 4-methylbenzenesulfonyloxy group are preferable.
Y 2 represents a C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl and its isomer, hexyl and its isomer, and the like. Among these, a methyl group and an ethyl group are preferable.
Examples of R1 ′ include C 1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, pentyl and its isomer, hexyl and its isomer. Among these, a methyl group and an ethyl group are preferable.
X includes halogen atoms such as fluorine, chlorine, bromine and iodine. Among these, a chlorine atom and a bromine atom are preferable.
Examples of X ′ include halogen atoms such as fluorine, chlorine, bromine and iodine. Among these, a chlorine atom and a bromine atom are preferable.
Next, the manufacturing method of this invention is demonstrated.
(1) Manufacturing method 1-1
(Wherein R1, R2, R3, X and X ′ represent the same meaning as described above.)
In the present invention, the acid halide represented by the formula (1) and the acid anhydride represented by the formula (2) or the acid halide represented by the formula (2 ′) are contained in an organic solvent in the presence of a base. In the production method in which a pyrone represented by the formula (3) is obtained by reacting with the reaction solvent, the reaction solvent includes halogen hydrocarbons such as dichloromethane and chloroform, ether solvents such as diethyl ether and dioxane, and ethyl acetate. A carboxylic acid ester solvent, a nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, or in some cases, a mixed solvent thereof can be used. Of these, the use of halogen hydrocarbons such as dichloromethane and chloroform is preferred.
Examples of the base include triethylamine, diisopropylethylamine, pyridine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [5,4,0] unde- Organic bases such as 7-ene (DBU) can be used. The usage-amount of a base can be suitably selected from the range of 2-3 equivalent with respect to the acid halide represented by Formula (1), and can be used.
The reaction temperature is usually from room temperature to the boiling point of the solvent used.
(2) Manufacturing method 1-2
(Wherein R1, R2 and R3 have the same meaning as described above.)
In the production method for obtaining 2 (1H) -pyridinones represented by the formula (4) by reacting the pyrones represented by the formula (3) with ammonia or an ammonium salt in water or an organic solvent, Water, alcohols such as methanol and ethanol, carboxylic acids such as acetic acid, halogen hydrocarbons such as dichloromethane and chloroform, nitrile solvents such as acetonitrile, ether solvents such as tetrahydrofuran (THF) and dioxane, benzene, toluene, etc. Aromatic hydrocarbon solvents, amide solvents such as dimethylformamide (DMF), and the like, or in some cases, a mixed solvent thereof can be used. Of these, the use of water, alcohols and carboxylic acids is preferred.
Examples of ammonium salts that can be used include organic acid salts such as ammonium carbonate and ammonium acetate, and inorganic salts such as ammonium chloride. Of these, the use of organic acid salts such as ammonium carbonate and ammonium acetate is desirable. The amount of ammonia or ammonium salt used can be appropriately selected from the range of 1-10 equivalents to the pyrones represented by formula (3).
The reaction temperature is usually from room temperature to the boiling point of the solvent used. When using ammonia gas, it is more preferable to make it react at 1-100 atmospheres in an autoclave.
(3) Manufacturing method 2-1
(Wherein R1, R2 and R3 represent the same meaning as described above. X represents a halogen atom in Y1.)
Compound represented by Formula (5-1) by reacting 2 (1H) -pyridinone represented by Formula (4) with a halogenating agent in the absence of a solvent or in an organic solvent, optionally in the presence of a basic catalyst. As a reaction solvent, a halogen hydrocarbon solvent such as dichloromethane or chloroform, an aromatic hydrocarbon solvent such as toluene, an amide solvent such as dimethylformamide, or in some cases a mixed solvent thereof may be used as a reaction solvent. it can.
Examples of halogenating agents that can be used in the reaction include phosphorus halides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus pentabromide, and phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide. Examples thereof include aromatic phosphorous compounds such as compounds, triphenyldichlorophosphine, triphenyldibromophosphine, and diphenylpentachlorophosphine.
As a usage-amount of a halogenating agent, it can select suitably from the range of 1-10 equivalent with respect to 2 (1H) -pyridinone represented by Formula (4), and can use it.
In this reaction, a basic catalyst such as DMAP or dimethylaniline can be used to advance the reaction quickly and efficiently. The amount of the catalyst used can be appropriately selected within a range where the reaction proceeds efficiently, but is usually in the range of 0.001 to 1 equivalent with respect to 2 (1H) -pyridinones represented by the formula (4). It is. The reaction proceeds smoothly at room temperature to 200 ° C.
(4) Manufacturing method 2-2
(Wherein R1, R2 and R3 represent the same meaning as described above. Z represents a C 1-6 alkylsulfonyloxy group, an optionally substituted benzenesulfonyloxy group or a C 1-6 haloalkylsulfonyl group in Y1). To express.)
A compound represented by the formula (5-2) by reacting the 2 (1H) -pyridinone represented by the formula (4) with a sulfonylating agent in the absence of a solvent or in an organic solvent, preferably in the presence of a base. Get. Reaction solvents include halogen hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, carboxylic acid ester solvents such as ethyl acetate, ether solvents such as THF and dioxane, and nitrile solvents such as acetonitrile. An amide solvent such as dimethylformamide or a mixed solvent thereof may be used in some cases.
Examples of the sulfonylating agent that can be used include sulfonic acid halides such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, and sulfonic acid anhydrides such as trifluoromethanesulfonic acid anhydride.
As a usage-amount of a sulfonylating agent, it can select suitably from the range of 1-10 equivalent with respect to 2 (1H) -pyridinone represented by Formula (4), and can use it.
During the reaction, it is not always necessary to have a base that captures the hydrogen halide generated in the system, but if necessary, an organic base such as triethylamine or an inorganic base such as sodium bicarbonate is used to remove the hydrogen halide. You may do it.
The reaction proceeds smoothly at -20 ° C to 200 ° C.
(5) Manufacturing method 3
(In the formula, R1, R2, R3, Y1 and Y2 represent the same meaning as described above.)
In the production method for obtaining the compound represented by the general formula (5-3) by reacting the pyridine represented by the formula (5) with an alkylating agent in an organic solvent in the presence of a catalyst, , Ether solvents such as diethyl ether and THF can be used.
Examples of the alkylating agent that can be used include alkyllithiums such as methyllithium, Grignard reagents such as methylmagnesium bromide, and alkylzinc compounds such as methylzinc chloride. As the usage-amount of an alkylating agent, it can select suitably from the range of 1-10 equivalent with respect to the pyridine represented by Formula (5), and can use it. The reaction proceeds at −20 ° C. to the reflux temperature of the reaction solvent, but is preferably performed at 20 ° C. to the reflux temperature of the reaction solvent.
Examples of the catalyst that can be used include nickel compounds having an appropriate ligand such as NiCl2 (dppp), palladium compounds having an appropriate ligand such as PdCl2 (PPh3) 2, and the like. Although the usage-amount of a catalyst can be suitably selected in the range in which reaction advances efficiently, it is the range of 0.001-1 equivalent normally with respect to pyridines represented by Formula (5).
After completion of the reaction, the desired compound can be obtained by carrying out ordinary post-treatment.
The compounds that can be produced by these synthesis methods are shown below.
Among the compounds thus obtained, the compound represented by the formula (8) is derived into an oxime ether compound useful as a fungicide by the method described in WO01 / 34568, WO02 / 64566, WO02 / 66434, or the like. can do.
Best Mode for Carrying Out the Invention:
Next, the present invention will be described in detail with reference to production examples, but the present invention is not limited to the following production examples.
４−メチル−６−トリフルオロメチル−２（１Ｈ）−ピリジノン（化合物番号１−１２）の製造
ｉ）４−メチル−６−トリフルオロメチル−２−ピロンの製造
１０ｇ（８４．３８ミリモル）の３，３−ジメチルアクリルクロリドと２１．２６ｇ（１０１．２６ミリモル）の無水トリフルオロ酢酸を１７０ｍｌの脱エタノール処理したクロロホルムに溶解し、この溶液に１０℃以下で１８．７４ｇ（１８５．６３ミリモル）のトリエチルアミンを添加した。１０℃以下で１時間攪拌後、さらに室温で２０時間撹拌した後、反応液を水で処理し、有機層を２回水洗、飽和炭酸ナトリウム水溶液で中和、１回水洗、さらに飽和食塩水で洗浄後、無水硫酸マグネシウム乾燥、減圧濃縮し、４−メチル−６−トリフルオロメチル−２−ピロンの粗生成物を得た。
ｉｉ）４−メチル−６−トリフルオロメチル−２（１Ｈ）−ピリジノンの製造
得られた４−メチル−６−トリフルオロメチル−２−ピロンの粗生成物の全量を１７０ｍｌの酢酸中に溶解し、この溶液に室温で１３．００ｇ（１６８．７６ミリモル）の酢酸アンモニウムを加えた。添加後、還流温度まで昇温し、同温度で２４時間撹拌した。酢酸を留去し、残査を飽和炭酸ナトリウム水溶液で中和後、酢酸エチルで抽出した。有機層を水洗後、無水硫酸マグネシウム乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ヘキサン：酢酸エチル＝１０：１（ｖ／ｖ））にて精製して、目的物８．７４ｇを得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．３４（ｓ，３Ｈ），６．７０（ｓ，１Ｈ），６．７９（ｓ，１Ｈ）
同様の方法で以下の化合物を製造した。
４−メチル−６−クロロジフルオロメチル−２（１Ｈ）−ピリジノン（化合物番号１−１１）
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．３２（ｓ，３Ｈ），６．６５（ｓ，１Ｈ），６．７１（ｓ，１Ｈ）
４−メチル−６−ペンタフルオロエチル−２（１Ｈ）−ピリジノン（化合物番号１−１３）
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．３４（ｓ，３Ｈ），６．６９（ｓ，１Ｈ），６．７５（ｓ，１Ｈ）Preparation of 4-methyl-6-trifluoromethyl-2 (1H) -pyridinone (Compound No. 1-12) i) Preparation of 4-methyl-6-trifluoromethyl-2-pyrone
10 g (84.38 mmol) of 3,3-dimethylacrylic chloride and 21.26 g (101.26 mmol) of trifluoroacetic anhydride were dissolved in 170 ml of deethanol-treated chloroform. .74 g (185.63 mmol) of triethylamine was added. After stirring at 10 ° C. or lower for 1 hour and further stirring at room temperature for 20 hours, the reaction solution is treated with water, and the organic layer is washed twice with water, neutralized with a saturated sodium carbonate aqueous solution, once with water, and further with saturated saline. After washing, anhydrous magnesium sulfate was dried and concentrated under reduced pressure to obtain a crude product of 4-methyl-6-trifluoromethyl-2-pyrone.
ii) Preparation of 4-methyl-6-trifluoromethyl-2 (1H) -pyridinone
The total amount of the resulting crude product of 4-methyl-6-trifluoromethyl-2-pyrone was dissolved in 170 ml of acetic acid, and 13.00 g (168.76 mmol) of ammonium acetate was added to this solution at room temperature. It was. After the addition, the temperature was raised to the reflux temperature, and the mixture was stirred at the same temperature for 24 hours. Acetic acid was distilled off, and the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1 (v / v)), 8.74 g of the target product was obtained.
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.34 (s, 3H), 6.70 (s, 1H), 6.79 (s, 1H)
The following compounds were prepared in a similar manner.
4-Methyl-6-chlorodifluoromethyl-2 (1H) -pyridinone (Compound No. 1-11)
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.32 (s, 3H), 6.65 (s, 1H), 6.71 (s, 1H)
4-Methyl-6-pentafluoroethyl-2 (1H) -pyridinone (Compound No. 1-13)
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.34 (s, 3H), 6.69 (s, 1H), 6.75 (s, 1H)
４−メチル−６−ヘプタトリフルオロプロピル−２−ピロンの製造
２．５４ｇ（２１，１５ミリモル）の３，３−ジメチルアクリルクロリドと５．０ｇ（２１，１５ミリモル）のヘプタフルオロブタン酸クロリドを４５ｍｌの脱エタノール処理したクロロホルムに溶解し、この溶液に１０℃以下で４．５６ｇ（４５．１５ミリモル）のトリエチルアミンを添加した。１０℃以下で１時間攪拌後、さらに室温で２０時間撹拌した後、反応液を水に注ぎ、有機層を２回水洗した。さらに有機層を飽和炭酸ナトリウム水溶液、水、飽和食塩水で１回ずつ洗浄した。分液後、有機層を無水硫酸マグネシウム乾燥、減圧濃縮し、４−メチル−６−ヘプタフルオロプロピル−２−ピロンの粗生成物５．９ｇを得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．２６（ｓ，３Ｈ），６．２８（ｓ，１Ｈ），６．５２（ｓ，１Ｈ）Preparation of 4-methyl-6-heptatrifluoropropyl-2-pyrone
2.54 g (21,15 mmol) of 3,3-dimethylacrylic chloride and 5.0 g (21,15 mmol) of heptafluorobutanoic acid chloride were dissolved in 45 ml of deethanol-treated chloroform. Below 4.56 g (45.15 mmol) of triethylamine was added. After stirring at 10 ° C. or lower for 1 hour and further at room temperature for 20 hours, the reaction solution was poured into water, and the organic layer was washed twice with water. Further, the organic layer was washed once with a saturated aqueous sodium carbonate solution, water and saturated brine. After liquid separation, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 5.9 g of a crude product of 4-methyl-6-heptafluoropropyl-2-pyrone.
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.26 (s, 3H), 6.28 (s, 1H), 6.52 (s, 1H)
２−ブロモ−４−メチル−６−トリフルオロメチルピリジンの製造（化合物番号２−６６）
８．７４ｇ（４９．３７ミリモル）の４−メチル−６−トリフルオロメチル−２（１Ｈ）−ピリジノンと１５．６ｇ（５４．３１ミリモル）のオキシ臭化燐を混ぜ、混合物を１１０℃まで昇温し、同温度で２時間撹拌した。熱時に反応混合物を水中に注ぎ、水酸化ナトリウム水溶液で中和後、エーテルで抽出した。有機層を水洗後、無水硫酸マグネシウム乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ヘキサン：酢酸エチル＝１０：１（ｖ／ｖ））にて精製して、目的物９．６ｇを得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．４４（ｓ，３Ｈ），７．４５（ｓ，１Ｈ），７．５１（ｓ，１Ｈ）
同様の方法で以下の化合物を製造した。
２−ブロモ−４−メチル−６−クロロジフルオロメチルピリジン（化合物番号２−６５）
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．４３（ｓ，３Ｈ），７．４３（ｓ，１Ｈ），７．４７（ｓ，１Ｈ）
２−ブロモ−４−メチル−６−ペンタフルオロエチルピリジン（化合物番号２−６７）
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．４４（ｓ，３Ｈ），７．４７（ｓ，１Ｈ），７．５２（ｓ，１Ｈ）Preparation of 2-bromo-4-methyl-6-trifluoromethylpyridine (Compound No. 2-66)
8.74 g (49.37 mmol) 4-methyl-6-trifluoromethyl-2 (1H) -pyridinone and 15.6 g (54.31 mmol) phosphorus oxybromide were mixed and the mixture was raised to 110 ° C. Warm and stir at the same temperature for 2 hours. When hot, the reaction mixture was poured into water, neutralized with aqueous sodium hydroxide solution, and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1 (v / v)), 9.6 g of the target product was obtained.
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.44 (s, 3H), 7.45 (s, 1H), 7.51 (s, 1H)
The following compounds were prepared in a similar manner.
2-Bromo-4-methyl-6-chlorodifluoromethylpyridine (Compound No. 2-65)
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.43 (s, 3H), 7.43 (s, 1H), 7.47 (s, 1H)
2-Bromo-4-methyl-6-pentafluoroethylpyridine (Compound No. 2-67)
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.44 (s, 3H), 7.47 (s, 1H), 7.52 (s, 1H)
２−クロロ−４−メチル−６−トリフルオロメチルピリジンの製造（化合物番号２−５８）
１．５ｇ（８．４７ミリモル）の４−メチル−６−トリフルオロメチル−２（１Ｈ）−ピリジノンと２．０６ｇ（１０．５９ミリモル）のフェニルホスホン酸ジクロリドを混ぜ、混合物を１６０℃まで昇温し、同温度で３時間撹拌した。熱時に反応混合物を水中に注ぎ、飽和炭酸ナトリウム水溶液で中和後、エーテルで抽出した。有機層を水洗後、無水硫酸マグネシウム乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ヘキサン：酢酸エチル＝１０：１（ｖ／ｖ））にて精製して、目的物０．７５ｇを得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．４５（ｓ，３Ｈ），７．３５（ｓ，１Ｈ），７．４３（ｓ，１Ｈ）Production of 2-chloro-4-methyl-6-trifluoromethylpyridine (Compound No. 2-58)
1.5 g (8.47 mmol) of 4-methyl-6-trifluoromethyl-2 (1H) -pyridinone and 2.06 g (10.59 mmol) of phenylphosphonic dichloride are mixed and the mixture is raised to 160 ° C. Warm and stir at the same temperature for 3 hours. When heated, the reaction mixture was poured into water, neutralized with a saturated aqueous sodium carbonate solution, and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1 (v / v)), 0.75 g of the target product was obtained.
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.45 (s, 3H), 7.35 (s, 1H), 7.43 (s, 1H)
４−メチル−２−トリフルオロメタンスルフォニルオキシ−６−トリフルオロメチルピリジン（化合物番号２−８２）の製造
４−メチル−６−トリフルオロメチル−２−ピリジノン５．３１ｇ（３０ｍｍｏｌ）を５０ｍＬのジクロロメタンに溶解し、１〜４℃に冷却下にピリジン５．２１ｇ（６６ｍｍｏｌ）を加えた後、−６℃〜０℃に冷却下、トリフルオロメタンスルフォン酸無水物１０．１６ｇ（３６ｍｍｏｌ）を滴下した。反応液を室温まで徐々に昇温し、室温でさらに４時間撹拌した。
反応液を冷水に注ぎ、分液を行い、得られた有機層を水洗した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去することにより目的物１２．０ｇが得られた。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．５５（ｓ，３Ｈ），７．２０（ｓ，１Ｈ），７．６０（ｓ，１Ｈ）
同様の方法で以下の化合物を製造した。
４−メチル−２−（４−メチルベンゼンスルフォニルオキシ）−６−トリフルオロメチルピリジン（化合物番号２−９０）
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．４２（ｓ，３Ｈ），２．４６（ｓ，３Ｈ），７．１２（ｓ，１Ｈ），７．３３（ｓ，１Ｈ），７．３５（ｄ，２Ｈ），７．９２（ｄ，２Ｈ）
４−メチル−２−メタンスルフォニルオキシ−６−トリフルオロメチルピリジン（化合物番号２−７４）
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．５０（ｓ，３Ｈ），３．５５（ｓ，３Ｈ），７．１５（ｓ，１Ｈ），７．５０（ｓ，１Ｈ）Production of 4-methyl-2-trifluoromethanesulfonyloxy-6-trifluoromethylpyridine (Compound No. 2-82)
After dissolving 5.31 g (30 mmol) of 4-methyl-6-trifluoromethyl-2-pyridinone in 50 mL of dichloromethane, and adding 5.21 g (66 mmol) of pyridine under cooling to 1-4 ° C., −6 ° C. While cooling to ˜0 ° C., 10.16 g (36 mmol) of trifluoromethanesulfonic anhydride was added dropwise. The reaction solution was gradually warmed to room temperature and further stirred at room temperature for 4 hours.
The reaction solution was poured into cold water and separated, and the resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 12.0 g of the desired product.
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.55 (s, 3H), 7.20 (s, 1H), 7.60 (s, 1H)
The following compounds were prepared in a similar manner.
4-Methyl-2- (4-methylbenzenesulfonyloxy) -6-trifluoromethylpyridine (Compound No. 2-90)
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.42 (s, 3H), 2.46 (s, 3H), 7.12 (s, 1H), 7.33 (s, 1H), 7.35 (d, 2H), 7.92 (d, 2H)
4-Methyl-2-methanesulfonyloxy-6-trifluoromethylpyridine (Compound No. 2-74)
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.50 (s, 3H), 3.55 (s, 3H), 7.15 (s, 1H), 7.50 (s, 1H)
２，４−ジメチル−６−トリフルオロメチルピリジン（化合物番号２−９７）の製造
４−メチル−２−トリフルオロメタンスルフォニルオキシ−６−トリフルオロメチルピリジン０．６３ｇ（１．８８ｍｍｏｌ）、ＮｉＣｌ２（ｄｐｐｐ）０．０３ｇ（０．０５５ｍｍｏｌ）を脱水したＴＨＦ５ｍＬに溶解し、窒素雰囲気下、室温にてメチルマグネシウムブロマイド（１．４Ｍ ＴＨＦ溶液）２．７ｍＬ（３．７８ｍｍｏｌ）を滴下した。室温で１時間撹拌した後、加熱還流下、７時間撹拌した。反応液を室温まで冷却後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水洗後、無水硫酸マグネシウム乾燥、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ヘキサン：ベンゼン＝１：１（ｖ／ｖ））にて精製して、目的物０．０８ｇを得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３，ＴＭＳ，δｐｐｍ）データ：２．４０（ｓ，３Ｈ），２．５９（ｓ，３Ｈ），７．１６（ｓ，１Ｈ），７．３１（ｓ，１Ｈ）
産業上の利用可能性：
以上説明した様に、本発明方法によれば、殺菌剤の製造中間体として有用な６−フルオロアルキル−２（１Ｈ）−ピリジノン及び６−フルオロアルキルピリジン化合物を工業的に有利に製造することができる。Production of 2,4-dimethyl-6-trifluoromethylpyridine (Compound No. 2-97)
4-methyl-2-trifluoromethanesulfonyloxy-6-trifluoromethylpyridine (0.63 g, 1.88 mmol) and NiCl2 (dppp) (0.03 g, 0.055 mmol) were dissolved in dehydrated THF (5 mL). At room temperature, 2.7 mL (3.78 mmol) of methylmagnesium bromide (1.4 M THF solution) was added dropwise. After stirring at room temperature for 1 hour, the mixture was stirred for 7 hours while heating under reflux. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: benzene = 1: 1 (v / v)) to obtain the target. 0.08 g of product was obtained.
1 H-NMR (CDCl 3 , TMS, δ ppm) data: 2.40 (s, 3H), 2.59 (s, 3H), 7.16 (s, 1H), 7.31 (s, 1H)
Industrial applicability:
As described above, according to the method of the present invention, 6-fluoroalkyl-2 (1H) -pyridinone and 6-fluoroalkylpyridine compound useful as intermediates for producing a bactericide can be produced industrially advantageously. it can.
Claims (2)
（式中、Ｒ１は、水素原子またはＣ１〜６アルキル基を表す。Ｘはハロゲン原子を表す。）
で表される化合物と
式（２）
（式中、Ｒ２およびＲ３はそれぞれ独立して水素原子、ハロゲン原子、Ｃ１〜６アルキル基、またはＣ１〜６ハロアルキル基を表す。）
で表される酸無水物または、
式（２´）
（式中、Ｒ２およびＲ３はそれぞれ独立して水素原子、ハロゲン原子、Ｃ１〜６アルキル基、またはＣ１〜６ハロアルキル基を表す。Ｘ´はハロゲン原子を表す。）
で表される酸ハライドを塩基存在下に反応させることにより
式（３）
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。）
で表される化合物を得る工程と、得られた式（３）で表される化合物とアンモニアまたはアンモニウム塩を反応させる工程とを有する、
式（４）
（式中、Ｒ１、Ｒ２およびＲ３は前記と同じ意味を表す。）
で表される化合物の製造方法。Formula (1)
(In the formula, R 1 represents a hydrogen atom or a C 1-6 alkyl group. X represents a halogen atom.)
And a compound represented by formula (2)
(In the formula, R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group.)
An acid anhydride represented by
Formula (2 ')
(In the formula, R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 haloalkyl group. X ′ represents a halogen atom.)
By reacting an acid halide represented by formula (3) in the presence of a base.
(Wherein R1, R2 and R3 have the same meaning as described above.)
And a step of reacting the obtained compound represented by the formula (3) with ammonia or an ammonium salt.
Formula (4)
(Wherein R1, R2 and R3 have the same meaning as described above.)
The manufacturing method of the compound represented by these.
（式中、Ｒ１´は、Ｃ１〜６アルキル基を表す。Ｒ２およびＲ３は請求項１と同じ意味を表す。）
で表される化合物。Formula (7)
(In the formula, R1 ′ represents a C 1-6 alkyl group. R2 and R3 represent the same meaning as in claim 1.)
A compound represented by
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003028552 | 2003-02-05 | ||
| JP2003028552 | 2003-02-05 | ||
| PCT/JP2004/001046 WO2004078727A1 (en) | 2003-02-05 | 2004-02-03 | Novel 6-fluoroalkyl-2(1h)-pyridinones and 6-fluoro- alkylpyridines and processes for the production thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010129703A Division JP5197677B2 (en) | 2003-02-05 | 2010-06-07 | Novel 6-fluoroalkylpyridine compound and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2004078727A1 JPWO2004078727A1 (en) | 2006-06-08 |
| JP4556241B2 true JP4556241B2 (en) | 2010-10-06 |
Family
ID=32955993
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005502987A Expired - Fee Related JP4556241B2 (en) | 2003-02-05 | 2004-02-03 | Novel 6-fluoroalkyl-2 (1H) -pyridinone, 6-fluoroalkylpyridine compound and process for producing the same |
| JP2010129703A Expired - Fee Related JP5197677B2 (en) | 2003-02-05 | 2010-06-07 | Novel 6-fluoroalkylpyridine compound and method for producing the same |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010129703A Expired - Fee Related JP5197677B2 (en) | 2003-02-05 | 2010-06-07 | Novel 6-fluoroalkylpyridine compound and method for producing the same |
Country Status (2)
| Country | Link |
|---|---|
| JP (2) | JP4556241B2 (en) |
| WO (1) | WO2004078727A1 (en) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EG10850A (en) * | 1972-03-25 | 1976-06-30 | Hoechst Ag | Process for the preparation of 1-hydroxy-pyridones |
| US4249009A (en) * | 1979-01-29 | 1981-02-03 | Reilly Tar & Chemical Corp. | Processes for preparing 2-chloro-5-trifluoromethylpyridine |
| JP2628053B2 (en) * | 1987-12-09 | 1997-07-09 | 日本ケミファ株式会社 | Novel amino acid derivative and method for producing the same |
| FR2687674B1 (en) * | 1992-02-07 | 1995-05-19 | Roussel Uclaf | NEW PYRIDONE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| US5674883A (en) * | 1992-02-07 | 1997-10-07 | Roussel Uclaf | Derivatives of pyridone, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them |
| GB9602623D0 (en) * | 1996-02-09 | 1996-04-10 | Zeneca Ltd | Fungicides |
| GB0016338D0 (en) * | 2000-07-03 | 2000-08-23 | Zeneca Ltd | Chemical process |
-
2004
- 2004-02-03 WO PCT/JP2004/001046 patent/WO2004078727A1/en active Application Filing
- 2004-02-03 JP JP2005502987A patent/JP4556241B2/en not_active Expired - Fee Related
-
2010
- 2010-06-07 JP JP2010129703A patent/JP5197677B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2004078727A1 (en) | 2006-06-08 |
| JP5197677B2 (en) | 2013-05-15 |
| JP2010235619A (en) | 2010-10-21 |
| WO2004078727A1 (en) | 2004-09-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI629262B (en) | A method for producing 2,3-dichloro-5-(trichloromethyl)pyridine | |
| JP2002338516A (en) | Method of production for 2-halogenated benzoic acids | |
| TWI695824B (en) | Process for preparing 3-chloro-2-vinylphenylsulfonates | |
| JP5077969B2 (en) | Process for the preparation of 2-substituted 5- (1-alkylthio) alkylpyridines | |
| JP6174161B2 (en) | Method for producing 2-aminonicotinic acid benzyl ester derivative | |
| JP6239003B2 (en) | Process for the preparation of 4-amino-5-fluoro-3-chloro-6- (substituted) picolinate | |
| JP2007230963A (en) | Method for producing 2,4-disubstituted pyridine | |
| JP4556241B2 (en) | Novel 6-fluoroalkyl-2 (1H) -pyridinone, 6-fluoroalkylpyridine compound and process for producing the same | |
| JP2020172469A (en) | Method for Producing Condensed Heterocyclic Compound | |
| JP4026233B2 (en) | Method for producing 4,5-dichloro-6- (α-fluoroalkyl) pyrimidine | |
| EP1873145B1 (en) | Method for producing nicotinic acid derivative or salt thereof | |
| JP2002284768A (en) | Method for producing phenylpyrimidine derivative | |
| JP5647673B2 (en) | Process for the preparation of bromo-substituted quinolines | |
| JP3533567B2 (en) | A new synthetic method to produce substituted quinolines from substituted anilines | |
| KR20150032539A (en) | Production of n-substituted sulfoximine pyridine n-oxides | |
| JP4239473B2 (en) | Process for producing pyridone compounds and intermediates thereof | |
| CN107406394B (en) | Process for the preparation of substituted phenylisoxazoline derivatives | |
| TWI752129B (en) | Method for preparing 3-substituted 2-vinylphenyl sulfonates | |
| JP2719604B2 (en) | Fluorine-substituted pyridine derivatives | |
| JP4198278B2 (en) | Process for producing 2-substituted tetrahydrothiophen-3-one derivatives | |
| JPH1077270A (en) | 2-(1-chlorovinyl)pyridine derivative and its production | |
| BR112020019277B1 (en) | PROCESS FOR PRODUCING 2,6-DIALKYLPHENYL ACETIC ACIDS, AND THEIR INTERMEDIATES | |
| JP2004300058A (en) | Method for producing pyridines containing trifluoromethyl group | |
| JP4432376B2 (en) | Method for producing 2-pyridone compound substituted with phenoxy group | |
| CA3162102A1 (en) | Process for synthesis of a 2-thioalkyl pyrimidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20061222 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100524 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100607 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20100628 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100711 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 4556241 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130730 Year of fee payment: 3 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |