JP2004002324A - Herbicide composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a herbicide composition excellent in weeding effects and in selectivity between crops and weeds. <P>SOLUTION: The herbicide composition comprises an isoxazoline derivative represented by general formula [I] or a salt thereof and at least one herbicide selected from the group A. In the general formula [I], Q is a group represented by -S(O)<SB>n</SB>-(CR<SB>5</SB>CR<SB>6</SB>)m-; n is an integer of 0-2; m is an integer of 1-3; R<SB>5</SB>and R<SB>6</SB>are each a hydrogen atom or a 1-6C alkyl group; R<SB>1</SB>and R<SB>2</SB>are each a hydrogen atom or a 1-8C alkyl group; R<SB>3</SB>and R<SB>4</SB>are each a hydrogen atom or a 1-8C alkyl group; and Y is a hydrogen atom, a 1-10C alkyl group or an optionally substituted phenyl group. The group A includes atrazine, simagine, cyanazine, isoxaflutole, flumetsulam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfron, halosulfuron methyl, rimsulfuron, bentazone and the like. <P>COPYRIGHT: (C)2004,JPO

Description

【０００８】
｛式中、Ｑは基−Ｓ（Ｏ）_ｎ−（ＣＲ_５Ｒ_６）_ｍ−を表し、ｎは０〜２の整数を表し、ｍは１〜３の整数を表し、Ｒ_５及びＲ_６は互いに独立して、水素原子、シアノ基、アルコキシカルボニル基又はＣ１〜Ｃ６アルキル基を表し、
Ｒ_１及びＲ_２は水素原子、［Ｃ３〜Ｃ８シクロアルキル基、Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ６アルキルカルボニル基、Ｃ１〜Ｃ６アルキルチオ基、Ｃ１〜Ｃ６アルキルスルフィニル基、Ｃ１〜Ｃ６アルキルスルホニル基、Ｃ１〜Ｃ６アルキルアミノ基、ジ（Ｃ１〜Ｃ６アルキル）アミノ基、シアノ基、Ｃ１〜Ｃ６アルコキシカルボニル基、Ｃ１〜Ｃ６アルキルアミノカルボニル基、ジ（Ｃ１〜Ｃ６アルキル）アミノカルボニル基、（Ｃ１〜Ｃ６アルキルチオ）カルボニル基、カルボキシル基、（置換されていてもよい）ベンジルオキシ基、（置換されていてもよい）フェノキシ基若しくは（置換されていてもよい）フェニル基で置換されていてもよい］Ｃ１〜Ｃ８アルキル基、Ｃ３〜Ｃ８シクロアルキル基、Ｃ１〜Ｃ６アルコキシカルボニル基、Ｃ１〜Ｃ６アルキルアミノカルボニル基、ジ（Ｃ１〜Ｃ６アルキル）アミノカルボニル基、Ｃ１〜Ｃ６アルキルチオカルボニル基、カルボキシル基又は（置換されていてもよい）フェニル基を表し、或いはＲ_１及びＲ_２はこれらの結合した炭素原子と共にＣ３〜Ｃ７のスピロ環を形成してもよく、
Ｒ_３及びＲ_４は水素原子、（同一若しくは相異なる１〜３個のハロゲン原子、Ｃ３〜Ｃ８シクロアルキル基又はＣ１〜Ｃ６アルコキシ基で置換されていてもよい）Ｃ１〜Ｃ８アルキル基又はＣ３〜Ｃ８シクロアルキル基を表し、Ｒ_３及びＲ_４はこれらの結合した炭素原子と共にＣ３〜Ｃ７のスピロ環を形成してもよく、或いはＲ_１，Ｒ_２，Ｒ_３及びＲ_４はこれらの結合した炭素原子と共に５〜８員環を形成してもよく、
Ｙは水素原子、Ｃ１〜Ｃ６アルコキシカルボニル基、カルボキシル基、Ｃ２〜Ｃ６アルケニル基、［同一若しくは相異なる１〜３個のハロゲン原子、Ｃ１〜Ｃ６アルコキシ基、Ｃ２〜Ｃ６アルケニルオキシ基、Ｃ２〜Ｃ６アルキニルオキシ基、（置換されていてもよい）ベンジルオキシ基、Ｃ１〜Ｃ６アルコキシカルボニル基、カルボキシル基、水酸基又はホルミル基で置換されていてもよい］Ｃ１〜Ｃ１０アルキル基或いは（１〜５個の同一若しくは相異なるＲ_７で置換された）フェニル基を表し、
Ｒ_７は水素原子、［同一若しくは相異なる１〜３個のハロゲン原子、Ｃ１〜Ｃ６アルコキシ基、水酸基、Ｃ１〜Ｃ６アルキルチオ基、Ｃ１〜Ｃ６アルキルスルフィニル基、Ｃ１〜Ｃ６アルキルスルホニル基、Ｃ１〜Ｃ６アルキルアミノ基、Ｃ１〜Ｃ６ジアルキルアミノ基、シアノ基又は（置換されていてもよい）フェノキシで置換されていてもよい］Ｃ１〜Ｃ６アルキル基、（同一若しくは相異なる１〜３個のハロゲン原子、Ｃ１〜Ｃ６アルコキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ２〜Ｃ６アルキニル基、Ｃ１〜Ｃ６アルコキシカルボニル基、Ｃ１〜Ｃ６アルキルカルボニル基又はＣ３〜Ｃ８シクロアルキル基で置換されていてもよい）Ｃ１〜Ｃ６アルコキシ基、Ｃ２〜Ｃ６アルケニル基、Ｃ３〜Ｃ８シクロアルキルオキシ基、（同一若しくは相異なる１〜３個のハロゲン原子又はＣ１〜Ｃ６アルコキシ基で置換されていてもよい）Ｃ１〜Ｃ６アルキルチオ基、（同一若しくは相異なる１〜３個のハロゲン原子又はＣ１〜Ｃ６アルコキシ基で置換されていてもよい）Ｃ１〜Ｃ６アルキルスルフィニル基、（同一若しくは相異なる１〜３個のハロゲン原子又はＣ１〜Ｃ６アルコキシ基で置換されていてもよい）Ｃ１〜Ｃ６アルキルスルホニル基、（置換されていてもよい）ベンジルオキシ基、（Ｃ１〜Ｃ６アルキル基、Ｃ１〜Ｃ６アルキルスルホニル基、Ｃ１〜Ｃ６アルキルカルボニル（Ｃ１〜Ｃ６アルキル）基又はＣ１〜Ｃ６アルキルスルホニル（Ｃ１〜Ｃ６アルキル）基で置換されていてもよい）アミノ基、ハロゲン原子、シアノ基、ニトロ基、Ｃ１〜Ｃ６アルコキシカルボニル基、Ｃ３〜Ｃ８シクロアルキルオキシカルボニル基、カルボキシル基、Ｃ２〜Ｃ６アルケニルオキシカルボニル基、Ｃ２〜Ｃ６アルキニルオキシカルボニル基、（置換されていてもよい）ベンジルオキシカルボニル基、（置換されていてもよい）フェノキシカルボニル基或いはＣ１〜Ｃ６アルキルカルボニルオキシ基を表す。｝で示されるイソオキサゾリン誘導体又はその塩と次に示したＡ群から選ばれる少なくとも一種を含有することを特徴とする除草剤組成物である。
Ａ群：アトラジン、シマジン、シアナジン、イソキサフルトール、フルメツラム、イマゼタピル、イマザピル、ジカンバ、クロピラリド、プロスルフロン、ハロスルフロン・メチル、リムスルフロン、ベンタゾン、カルフェントラゾン・エチル、メトリブジン、チフェンスルフロン・メチル、ニコスルフロン、プリミスルフロン、グルホシネート、グリホセート及びスルホセート
尚、本明細書において、用いられる用語の定義を以下に示す。
【０００９】
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を示す。
【００１０】
アルキル基とは、特に限定しない限り、炭素数が１〜１０の直鎖又は分岐鎖状のアルキル基を示し、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基、イソペンチル基、ネオペンチル基、ｎ−ヘキシル基、イソヘキシル基、３，３−ジメチルブチル基、ヘプチル基又はオクチル基等を挙げることができる。
【００１１】
シクロアルキル基とは、炭素数が３〜８のシクロアルキル基を示し、例えばシクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基等を挙げることができる。
【００１２】
アルコキシ基とは、アルキル部分が上記の意味である（アルキル）−Ｏ−基を示し、例えばメトキシ基又はエトキシ基等を挙げることができる。
【００１３】
アルキルチオ基、アルキルスルフィニル基及びアルキルスルホニル基とは、アルキル部分が上記の意味である（アルキル）−Ｓ−基、（アルキル）−ＳＯ−基、（アルキル）−ＳＯ_２−基を示し、例えばメチルチオ基、エチルチオ基、メチルスルフィニル基、メチルスルホニル基又はエチルスルホニル基等を挙げることができる。
【００１４】
アルケニル基とは、炭素数が２〜６の直鎖又は分岐鎖のアルケニル基を示し、例えばエテニル基、１−プロペニル基、２−プロペニル基、イソプロペニル基、１−ブテニル基、２−ブテニル基、３−ブテニル基又は２−ペンテニル基等を挙げることができる。
【００１５】
アルキニル基とは、炭素数が２〜６の直鎖又は分岐鎖のアルキニル基を示し、例えばエチニル基、２−プロピニル基、２−ブチニル基、３−ブチニル基等を挙げることができる。
【００１６】
アルケニルオキシ基及びアルキニルオキシ基とは、アルケニル又はアルキニル部分が上記の意味である（アルケニル）−Ｏ−基、（アルキニル）−Ｏ−基を示し、例えば２−プロペニルオキシ基、２−プロピニルオキシ基等を挙げることができる。
【００１７】
アルキルアミノ基及びジアルキルアミノ基とは、アルキル部分が上記の意味である（アルキル）−ＮＨ−基、（アルキル）_２Ｎ−基を示し、例えばメチルアミノ基、エチルアミノ基、ジメチルアミノ基等を挙げることができる。
【００１８】
アルキルカルボニル基、（アルキルチオ）カルボニル基、アルコキシカルボニル基、アルキルアミノカルボニル基及びジアルキルアミノカルボニル基とは、アルキル、アルキルチオ、アルコキシ、アルキルアミノ又はジアルキルアミノ部分が上記の意味である（アルキル）−ＣＯ−基、（アルキルチオ）−ＣＯ−基、（アルコキシ）−ＣＯ−基、（アルキルアミノ）−ＣＯ−基、（ジアルキルアミノ）−ＣＯ−基を示し、例えばアセチル基、メチルチオカルボニル基、エトキシカルボニル基、メトキシカルボニル基、メチルアミノカルボニル基、ジメチルアミノカルボニル基等を挙げることができる。
【００１９】
アルキルアミノカルボニルアミノ基、ジアルキルアミノカルボニルアミノ基及びアルコキシカルボニルアミノ基とは、アルキルアミノカルボニル、ジアルキルアミノカルボニル又はアルコキシカルボニル部分が上記の意味である（アルキルアミノカルボニル）−ＮＨ−基、（ジアルキルアミノカルボニル）−ＮＨ−基、（アルコキシカルボニル）−ＮＨ−基を示し、例えばメチルアミノカルボニルアミノ基、ジメチルアミノカルボニルアミノ基、メトキシカルボニルアミノ基等を挙げることができる。
【００２０】
置換されていてもよいフェニル基とはフェニル環上にハロゲン原子、Ｃ１〜Ｃ６アルキル基又はＣ１〜Ｃ６アルコキシ基等の置換基を１〜５個有するフェニル基を挙げることができる。
【００２１】
置換されていてもよいフェノキシ基とはフェニル環上にハロゲン原子、Ｃ１〜Ｃ６アルキル基又はＣ１〜Ｃ６アルコキシ基等の置換基を１〜５個有するフェノキシ基を挙げることができる。
【００２２】
置換されていてもよいベンジルオキシ基とはフェニル環上及びベンジル位にハロゲン原子、Ｃ１〜Ｃ６アルキル基又はＣ１〜Ｃ６アルコキシ基等の置換基を１〜７個有するベンジルオキシ基を挙げることができる。
【００２３】
置換されていてもよいフェノキシカルボニル基とはフェニル環上にハロゲン原子、Ｃ１〜Ｃ６アルキル基又はＣ１〜Ｃ６アルコキシ基等の置換基を１〜５個有するフェノキシカルボニル基を挙げることができる。
【００２４】
塩とは、一般式［Ｉ］で表される化合物において、水酸基、カルボキシル基又はアミノ基等がその構造中に存在する場合に、これらと金属もしくは有機塩基との塩又は鉱酸もしくは有機酸との塩であり、金属としてはナトリウム又はカリウム等のアルカリ金属或いはマグネシウム又はカルシウム等のアルカリ土類金属を挙げることができ、有機塩基としてはトリエチルアミン又はジイソプロピルアミン等を挙げることができ、鉱酸としては塩酸又は硫酸等を挙げることができ、有機酸としては酢酸、メタンスルホン酸又はｐ−トルエンスルホン酸等を挙げることができる。
【００２５】
前記一般式［Ｉ］において、好ましい化合物群としては、Ｑは基−Ｓ（Ｏ）_ｎ−（ＣＲ_５Ｒ_６）_ｍ−を表し、ｎは２を表し、ｍは１を表し、Ｒ_５及びＲ_６は水素原子を表し、Ｒ_１及びＲ_２はＣ１〜Ｃ４アルキル基を表し、Ｒ_３及びＲ_４は水素原子を表し、Ｙは（１〜５個の同一又は相異なるＲ_７で置換された）フェニル基を表し、Ｒ_７は水素原子、（同一若しくは相異なる１〜３個のハロゲン原子で置換されていてもよい）Ｃ１〜Ｃ６アルキル基、（同一若しくは相異なる１〜３個のハロゲン原子で置換されていてもよい）Ｃ１〜Ｃ６アルコキシ基、Ｃ１〜Ｃ６アルコキシカルボニル基、Ｃ２〜Ｃ６アルキニルオキシ基、ハロゲン原子、ニトロ基又はシアノ基で表される化合物群が挙げられる。
【００２６】
【発明の実施の形態】
本発明組成物は、各成分の相対的活性にもよるが、一般的には、次に示したＡ群から選ばれる少なくとも一種の化合物１重量部当り、上記式［Ｉ］で表される化合物を、０．００１〜５０重量部、好ましくは、０．００１〜１０重量部含んでいる。
Ａ群：アトラジン、シマジン、シアナジン、イソキサフルトール、フルメツラム、イマゼタピル、イマザピル、ジカンバ、クロピラリド、プロスルフロン、ハロスルフロン・メチル、リムスルフロン、ベンタゾン、カルフェントラゾン・エチル、メトリブジン、チフェンスルフロン・メチル、ニコスルフロン、プリミスルフロン、グルホシネート、グリホセート及びスルホセート
本発明組成物の一つの活性成分は、式［Ｉ］で表される化合物であり、それ自体単独でも優れた除草活性を有する。
【００２７】
特に、イネ、コムギ、オオムギ、トウモロコシ、グレインソルガム、ダイズ、ワタ、テンサイ、芝、果樹等に薬害が少なく、畑地において問題となる種々の雑草、例えばイヌビエ、メヒシバ、エノコログサ、スズメノカタビラ、ジョンソングラス、ノスズメノテッポウ、野生エンバク等のイネ科雑草をはじめ、オオイヌタデ、アオビユ、シロザ、ハコベ、イチビ、アメリカキンゴジカ、アメリカツノクサネム、ブタクサ、アサガオの広葉雑草、ハマスゲ、キハマスゲ、ヒメクグ、カヤツリグサ、コゴメガヤツリ等の多年生および１年生カヤツリグサ科雑草の発芽前から生育期の広い範囲にわたって優れた除草効果を発揮する。
【００２８】
更に、水田に発生するタイヌビエ、タマガヤツリ、コナギ、アゼナ等の１年生雑草及びミズガヤツリ、クログワイ、ホタルイ等の多年生雑草についても発芽前から生育期の広い範囲にわたって低薬量で防除することができる。
【００２９】
本発明組成物の一つの活性成分である、一般式［Ｉ］で表される化合物の代表例はＷＯ０１／０１２６１３号公報に記載のイソオキサゾリン誘導体又はその塩の中から選ばれる化合物であり、それらの代表例を表１及び表２に示す。
【００３０】
【表１】

【００３１】
【表２】

【００３２】
本発明組成物に使用することができる、式［Ｉ］で表される化合物の製造例は以下の製造例に示す方法により製造することができるが、これらに限定されるものではない。
【００３３】
＜製造例１＞
３−ベンジルチオ−５，５−ジメチル−２−イソオキサゾリン（化合物番号１）の製造
ベンジルメルカプタン２．８ｇ（２２．５ミリモル）のＮ，Ｎ−ジメチルホルムアミド５０ｍｌ溶液に、窒素気流下、無水炭酸カリウム３．２ｇ（２３．２ミリモル）及び３−クロロ−５，５−ジメチル−２−イソオキサゾリン３．０ｇ（２２．５ミリモル）を加え、１００℃で２時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、黄色油状物質（屈折率ｎ_Ｄ ^２０＝１．５５２１）の３−ベンジルチオ−５，５−ジメチル−２−イソオキサゾリン３．１ｇ（収率６２．０％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．２４−７．３９（５Ｈ，ｍ）、４．２６（２Ｈ，ｓ）、２．７７（２Ｈ，ｓ）、１．４０（６Ｈ，ｓ）
【００３４】
＜製造例２＞
５−エチル−３−（２，６−ジフルオロベンジルスルフィニル）−５−メチル−２−イソオキサゾリン（化合物番号２）の製造
５−エチル−３−（２，６−ジフルオロベンジルチオ）−５−メチル−２−イソオキサゾリン４．１ｇ（１５．０ミリモル）のクロロホルム５０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸４．６ｇ（純度７０％、１８．８ミリモル）を加え１時間攪拌し、さらに室温で１２時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機相を亜硫酸水素ナトリウム水溶液、炭酸カリウム水溶液、水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶媒系ヘキサン−酢酸エチル）で精製し、白色粉末（融点３０℃以下）の５−エチル−３−（２，６−ジフルオロベンジルスルフィニル）−５−メチル−２−イソオキサゾリン１．５ｇ（収率３４．８％）を得た
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．３９−７．２８（１Ｈ，ｍ）、７．０３−６．９４（２Ｈ，ｍ）、４．３８（２Ｈ，ｓ）、３．０４（１Ｈ，ＡＢｑ，Ｊ＝１７．２，Δν＝８５．７Ｈｚ）＋３．１２（１Ｈ，ｓ）、１．７５（２Ｈ，ｍ）、１．４４（３Ｈ，ｓ）＋１．４１（３Ｈ，ｓ）、０．９７（３Ｈ，ｍ）
【００３５】
＜製造例３＞
５−エチル−３−（２，６−ジフルオロベンジルスルホニル）−５−メチル−２−イソオキサゾリン（化合物番号３）の製造
５−エチル−３−（２，６−ジフルオロベンジルスルフィニル）−５−メチル−２−イソオキサゾリン０．８ｇ（２．８ミリモル）のクロロホルム５０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．０ｇ（純度７０％、４．１ミリモル）を加え１時間攪拌し、さらに室温で１２時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸カリウム水溶液、水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶媒系：ヘキサン−酢酸エチル）で精製し、白色粉末（融点６４〜６５℃）の５−エチル−３−（２，６−ジフルオロベンジルスルホニル）−５−メチル−２−イソオキサゾリン０．６ｇ（収率７５％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．３６−７．４６（１Ｈ，ｍ）、６．９８−７．０４（２Ｈ，ｍ）、４．７３（２Ｈ，ｓ）、３．０４（２Ｈ，ＡＢｑ，Ｊ＝１７．２，Δν＝５１．１Ｈｚ）、１．７７（２Ｈ，ｑ）、１．４６（３Ｈ，ｓ）、０．９７（３Ｈ，ｔ）
【００３６】
＜製造例４＞
３−（２，６−ジフルオロベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号４）の製造
３−（２，６−ジフルオロベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン３．９ｇ（１５．２ミリモル）のクロロホルム５０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸８．５ｇ（純度７０％、３４．５ミリモル）を加え１時間攪拌し、さらに室温で１２時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸カリウム水溶液、水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をジイソプロピルエーテルで洗浄し、白色粉末（融点１１０〜１１１℃）の３−（２，６−ジフルオロベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン３．４ｇ（収率７７％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．３５−７．４５（１Ｈ，ｍ）、６．９８−７．０３（２Ｈ，ｍ）、４．７２（２Ｈ，ｓ）、３．０６（２Ｈ，ｓ）、１．５１（６Ｈ，ｓ）
【００３７】
＜製造例５＞
３−（２，６−ジフルオロベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン（化合物番号５）の製造
３−メチルスルホニル−５，５−ジメチル−２−イソオキサゾリン５．０ｇ（２８．２ミリモル）のＮ，Ｎ−ジメチルホルムアミド５０ｍｌ溶液に、氷冷下、水硫化ナトリウム水和物４．５ｇ（純度７０％、５６．１ミリモル）、無水炭酸カリウム７．８ｇ（５６．４ミリモル）及びロンガリット８．７ｇ（５６．５ミリモル）を加え２時間攪拌した。その後、２，６−ジフルオロベンジルベンジルブロマイド５．８ｇ（２８．０ミリモル）を加え、さらに室温で１２時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、白色粉末（融点７７〜８０℃）の３−（２，６−ジフルオロベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン５．８ｇ（収率８０％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．２０−７．２８（１Ｈ，ｍ）、６．８６−６．９３（２Ｈ，ｍ）、４．３５（２Ｈ，ｓ）、２．８１（２Ｈ，ｓ）、１．４３（６Ｈ，ｓ）
【００３８】
＜製造例６＞
３−メチルスルホニル−５，５−ジメチル−２−イソオキサゾリン（化合物番号６）の製造
３−クロル−５，５−ジメチル−２−イソオキサゾリン１４３．０ｇ（１．０７モル）のＮ，Ｎ−ジメチルホルムアミド５００ｍｌ溶液に、氷冷下、メチルメルカプタンナトリウム水溶液１０００ｇ（含量１５％、２．１４モル）を滴下し、その後室温で１２時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、３−メチルチオ−５，５−ジメチル−２−イソオキサゾリンの粗生成物を１１５．０ｇ（収率７４％）得た。そして３−メチルチオ−５，５−ジメチル−２−イソオキサゾリンの粗生成物１１５．０ｇ（７４１．２ミリモル相当）をクロロホルム１ｌに溶解し、氷冷下、ｍ−クロロ過安息香酸（純度７０％）３９２．０ｇ（１．５９モル）を加え１時間攪拌した。その後、さらに室温で１２時間攪拌した。反応終了後、析出したｍ−クロロ安息香酸を濾別し、濾液を亜硫酸水素ナトリウム水溶液、水、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をジイソプロピルエーテルで洗浄し、白色粉末（融点８２〜８４℃）の３−メチルスルホニル−５，５−ジメチル−２−イソオキサゾリン７７．６ｇ（収率５９．１％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：３．２６（３Ｈ，ｓ）、３．１２（２Ｈ，ｓ）、１．５１（６Ｈ，ｓ）
【００３９】
＜製造例７＞
３−（５−クロロ−２−ジフルオロメトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１２）の製造
【００４０】
（１）５−クロロ−２−ジフルオロメトキシトルエンの製造
４−クロロ−２−メチルフェノール７．１ｇ（５０．０ミリモル）のＮ，Ｎ−ジメチルホルムアミド１００ｍｌ溶液中に、無水炭酸カリウム１０．４ｇ（７５．０ミリモル）を加えた。反応溶液を攪拌しながら、５０℃でクロロジフルオロメタンを導入した。原料消失を確認した後、クロロジフルオロメタンの導入を停止し、反応溶液を室温まで冷却した。その後反応溶液を水中に注ぎ、ジイソプロピルエーテルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、無色透明結晶の５−クロロ−２−ジフルオロメトキシトルエン５．４ｇ（収率５６．６％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．２１（１Ｈ，　ｄ）　，　７．１５（１Ｈ，　ｑ）　，　７．０１（１Ｈ，　ｄ）　，　６．４７（１Ｈ，　ｔ，　Ｊ＝７３．８Ｈｚ）　，　２．２６（３Ｈ，　ｓ）
【００４１】
（２）５−クロロ−２−ジフルオロメトキシベンジルブロミドの製造
５−クロロ−２−ジフルオロメトキシトルエン２．４ｇ（１２．５ミリモル）の四塩化炭素３０ｍｌ溶液中に、Ｎ−ブロモこはく酸イミド２．２ｇ（１２．５ミリモル）及び２，２’−アゾビス（イソブチロニトリル）０．２ｇ（１．３ミリモル）を加え、光照射下、２時間加熱環流した。反応終了後、室温まで冷却し不溶物を濾別した。溶媒を減圧下留去し、５−クロロ−２−ジフルオロメトキシベンジルブロミドの粗生成物を得た。
【００４２】
（３）３−（５−クロロ−２−ジフルオロメトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン１．９ｇ（１０．０ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物１．６ｇ（純度７０％、２０．０ミリモル）を加え１時間攪拌した。その後、無水炭酸カリウム１．４ｇ（１０．０ミリモル）、ロンガリット１．６ｇ（１０．０ミリモル）及び（２）で得られた５−クロロ−２−ジフルオロメトキシベンジルブロミドの粗生成物（１２．５ミリモル相当）を加え、さらに室温で１時間攪拌した。反応終了後、反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−（５−クロロ−２−ジフルオロメトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン２．４ｇ（収率７４．５％）を得た。
【００４３】
（４）３−（５−クロロ−２−ジフルオロメトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１２）の製造
３−（５−クロロ−２−ジフルオロメトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン２．４ｇ（７．５ミリモル）のクロロホルム１５ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸４．６ｇ（純度７０％、１８．６ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、析出した結晶をｎ−ヘキサンで洗浄し、白色結晶（融点５３〜５４℃）の３−（５−クロロ−２−ジフルオロメトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン１．９ｇ（収率７２．２％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　７．５１（１Ｈ，　ｄ）　，　７．３９（１Ｈ，　ｑ）　，　７．１９（１Ｈ，　ｄ）　，　６．５２（１Ｈ，　ｔ，　Ｊ＝７３．２Ｈｚ）　，　４．６９（２Ｈ，　ｓ）　，　３．０２（２Ｈ，　ｓ）　，　１．４９（６Ｈ，　ｓ）
【００４４】
＜製造例８＞
３−（２−ジフルオロメトキシ−５−メチルベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１６）の製造
【００４５】
（１）２−ヒドロキシ−５−メチル安息香酸メチルエステルの製造
５−メチルサリチル酸２５．０ｇ（１６４．３ミリモル）のＮ，Ｎ−ジメチルホルムアミド２００ｍｌ溶液に、室温で無水炭酸カリウム１１．９ｇ（８６．３ミリモル）及びヨウ化メチル２４．５ｇ（１７２．５ミリモル）を加え一夜攪拌した。反応溶液を水中に注ぎ、酢酸エチルで抽出し、得られた有機層を水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、２−ヒドロキシ−５−メチル安息香酸メチルエステル２７．３ｇ（収率１００％）を得た。
【００４６】
（２）２−ジフルオロメトキシ−５−メチル安息香酸メチルエステルの製造
２−ヒドロキシ−５−メチル安息香酸メチルエステル２７．３ｇ（１６４．３ミリモル）のＮ，Ｎ−ジメチルホルムアミド２００ｍｌ溶液に、無水炭酸カリウム３４．０ｇ（２４６．５ミリモル）を室温で加えた。反応溶液を攪拌しながら、１００℃でクロロジフルオロメタンを導入した。原料消失を確認した後（約４時間後）、クロロジフルオロメタンの導入を停止し、反応溶液を室温まで冷却した。反応溶液を水中に注ぎ、酢酸エチルで抽出し、得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、黄色液体の２−ジフルオロメトキシ−５−メチル安息香酸　メチルエステル２５．３ｇ（収率７１．３％）を得た。
【００４７】
（３）２−ジフルオロメトキシ−５−メチルフェニルメタノールの製造
水素化リチウムアルミニウム０．６ｇ（１５ミリモル）のテトラヒドロフラン３０ｍｌ溶液中に、室温で２−ジフルオロメトキシ−５−メチル安息香酸メチルエステル３．２ｇ（１５ミリモル）のテトラヒドロフラン１０ｍｌ溶液を滴下した。反応終了確認後、反応溶液中に飽和塩化アンモニウム水溶液を加え、この溶液を水中にあけ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥して、溶媒を減圧下留去し、２−ジフルオロメトキシ−５−メチルフェニルメタノールの粗生成物を得た。
【００４８】
（４）２−ジフルオロメトキシ−５−メチルベンジルクロリドの製造
（３）で得られた２−ジフルオロメトキシ−５−メチルフェニルメタノールの粗生成物（１５ミリモル相当）のクロロホルム３０ｍｌ溶液に、室温で塩化チオニル５．４ｇ（４５ミリモル）を加え３時間攪拌した。その後溶媒を減圧下留去し、２−ジフルオロメトキシ−５−メチルベンジルクロリドの粗生成物を得た。
【００４９】
（５）３−（２−ジフルオロメトキシ−５−メチルベンジルチオ）−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン１．０ｇ（５ミリモル）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液に、水硫化ナトリウム水和物０．８ｇ（純度７０％、１０ミリモル）を加え、１時間攪拌した。その後、無水炭酸カリウム０．７ｇ（５ミリモル）、ロンガリット０．７ｇ（５ミリモル）及び（４）で得られた２−ジフルオロメトキシ−５−メチルベンジルクロリドの粗生成物（１５ミリモル相当）を加え、さらに室温で１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−（２−ジフルオロメトキシ−５−メチルベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン１．５ｇ（収率：定量的）を得た。
【００５０】
（６）３−（２−ジフルオロメトキシ−５−メチルベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１６）の製造
３−（２−ジフルオロメトキシ−５−メチルベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン１．５ｇ（５．０ミリモル）のクロロホルム３０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸３．１ｇ（純度７０％、１２．５ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、淡黄色結晶（融点７１〜７３℃）の３−（２−ジフルオロメトキシ−５−メチルベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン１．１ｇ（収率６６．０％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　７．３１（１Ｈ，　ｄ）　，　７．２１（１Ｈ，　ｑ）　，　７．１１（１Ｈ，　ｄ）　，　６．５０（１Ｈ，　ｔ，　Ｊ＝７３．９Ｈｚ）　，　４．６７（２Ｈ，　ｓ）　，　２．９９（２Ｈ，　ｓ）　，　２．３６（３Ｈ，　ｓ），１．４７（６Ｈ，　ｓ）
【００５１】
＜製造例９＞
３−（２−ジフルオロメトキシ−５−メトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１７）の製造
【００５２】
（１）２−ヒドロキシ−５−メトキシ安息香酸メチルエステルの製造
５−メトキシサリチル酸２５．０ｇ（１４８．７ミリモル）のＮ，Ｎ−ジメチルホルムアミド２００ｍｌ溶液に、室温で無水炭酸カリウム１０．８ｇ（７８．１ミリモル）及びヨウ化メチル２１．１ｇ（１４８．７ミリモル）を加え一夜攪拌した。反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、２−ヒドロキシ−５−メトキシ安息香酸メチルエステル１４．６ｇ（収率５３．９％）を得た。
【００５３】
（２）２−ジフルオロメトキシ−５−メトキシ安息香酸メチルエステルの製造２−ヒドロキシ−５−メトキシ安息香酸メチルエステル１４．６ｇ（８０．１ミリモル）のＮ，Ｎ−ジメチルホルムアミド１００ｍｌ溶液に、室温で無水炭酸カリウム１３．３ｇ（９６．２ミリモル）を加えた。反応溶液を攪拌しながら、１００℃でクロロジフルオロメタンを導入した。原料消失を確認した後（約６時間後）、クロロジフルオロメタンの導入を停止し反応溶液を室温まで冷却した。その後反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マクネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、黄色液体の２−ジフルオロメトキシ−５−メトキシ安息香酸メチルエステル３．５ｇ（収率１８．８％）を得た。
【００５４】
（３）２−ジフルオロメトキシ−５−メトキシフェニルメタノールの製造
水素化リチウムアルミニウム０．６ｇ（１５．１ミリモル）のテトラヒドロフラン３０ｍｌ溶液中に、室温で２−ジフルオロメトキシ−５−メトキシ安息香酸メチルエステル３．５ｇ（１５．１ミリモル）のテトラヒドロフラン１０ｍｌ溶液を滴下した。反応終了確認後、反応溶液中に飽和塩化アンモニウム水溶液を加え、この溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マクネシウムで乾燥した。溶媒を減圧下留去し、２−ジフルオロメトキシ−５−メトキシフェニルメタノールの粗生成物を得た。
【００５５】
（４）２−ジフルオロメトキシ−５−メトキシベンジルクロリドの製造
（３）で得られた２−ジフルオロメトキシ−５−メトキシフェニルメタノールの粗生成物（１５．１ミリモル相当）のクロロホルム３０ｍｌ溶液に、室温で塩化チオニル５．４ｇ（４５．３ミリモル）を加え３時間攪拌した。その後溶媒を減圧下留去し、２−ジフルオロメトキシ−５−メトキシベンジルクロリドの粗生成物を得た。
【００５６】
（５）３−（２−ジフルオロメトキシ−５−メトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン２．９ｇ（１５．１ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物２．４ｇ（純度７０％、３０．２ミリモル）を加え１時間攪拌した。その後、無水炭酸カリウム２．０８ｇ（１５．１ミリモル）及び（４）で得られた２−ジフルオロメトキシ−５−メトキシベンジルクロリドの粗生成物（１５．１ミリモル相当）を加え、さらに室温で１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−（２−ジフルオロメトキシ−５−メトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン２．３ｇ（収率４８．０％）を得た。
【００５７】
（６）３−（２−ジフルオロメトキシ−５−メトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１７）の製造
３−（２−ジフルオロメトキシ−５−メトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン０．５ｇ（１．６ミリモル）のクロロホルム１０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．０ｇ（純度７０％、３．８ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をｎ−ヘキサンで洗浄し、白色結晶（融点７０〜７１℃）の３−（２−ジフルオロメトキシ−５−メトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン０．４ｇ（収率６３．４％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　７．１７（１Ｈ，　ｄ）　，　７．０４（１Ｈ，　ｄ）　，　６．９３（１Ｈ，　ｑ）　，　６．４７（１Ｈ，　ｔ，　Ｊ＝７４．１Ｈｚ）　，　４．６８（２Ｈ，　ｓ）　，　３．８１（３Ｈ，　ｓ）　，　２．９９（２Ｈ，　ｓ），１．４７（６Ｈ，　ｓ）
【００５８】
＜製造例１０＞
３−［２，３−ビス（ジフルオロメトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン（化合物番号１８）の製造
【００５９】
（１）２，３−ビス（ジフルオロメトキシ）トルエンの製造
３−メチルカテコール５．０ｇ（４０．３ミリモル）のＮ，Ｎ−ジメチルホルムアミド１００ｍｌ溶液中に、無水炭酸カリウム１２．３ｇ（８９．０ミリモル）を加えた。反応溶液を攪拌しながら、室温でクロロジフルオロメタンを導入した。７０℃で２時間攪拌した。原料消失を確認した後、クロロジフルオロメタンの導入を停止し、反応溶液を室温まで冷却した。その後反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、２，３−ビス（ジフルオロメトキシ）トルエン０．８２ｇ（収率９．１％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ）δ（ｐｐｍ））：　　７．１７−７．０９（３Ｈ，　ｍ）　，　６．５２（１Ｈ，　ｔ，Ｊ＝７５．０Ｈｚ），　６．５０（１Ｈ，　ｔ，Ｊ＝７３．６Ｈｚ）　，　２．３５（３Ｈ，　ｓ）
【００６０】
（２）２，３−ビス（ジフルオロメトキシ）ベンジルブロミドの製造
２，３−ビス（ジフルオロメトキシ）トルエン０．８２ｇ（３．６６ミリモル）の四塩化炭素２０ｍｌ溶液中に、Ｎ−ブロモこはく酸イミド０．６８ｇ（３．８２ミリモル）及び２，２’−アゾビス（イソブチロニトリル）０．０６ｇ（０．３７ミリモル）を加え、反応溶液を光照射で３時間環流した。反応終了後、室温まで冷却し不溶物を濾別した。溶媒を減圧下留去し、２，３−ビス（ジフルオロメトキシ）ベンジルブロミドの粗生成物を得た。
【００６１】
（３）３−［２，３−ビス（ジフルオロメトキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン０．７３ｇ（３．８２ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物０．６０ｇ（純度７０％、７．４９ミリモル）を加え２時間攪拌した。その後、無水炭酸カリウム０．５３ｇ（３．８２ミリモル）、ロンガリット０．５９ｇ（３．８２ミリモル）及び２）で得られた２，３−ビスジフルオロメトキシベンジルブロミドの粗生成物（３．６６ミリモル相当）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液を加え、さらに室温で１１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−［２，３−ビス（ジフルオロメトキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．８７ｇ（収率６７．３％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ）δ（ｐｐｍ））：　７．４６（１Ｈ，　ｄｄ）　，　７．２４−７．１６（２Ｈ，　ｍ）　，　６．６０（１Ｈ，　ｔ，Ｊ＝７４．３Ｈｚ），　６．５２（１Ｈ，　ｔ，Ｊ＝７３．２Ｈｚ）　，　４．３５（２Ｈ，　ｓ）　，　２．７８（２Ｈ，　ｓ）　，　１．４１（６Ｈ，　ｓ）
【００６２】
（４）３−［２，３−ビス（ジフルオロメトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン（化合物番号１８）の製造
３−（２，３−ビス（ジフルオロメトキシ）ベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン０．８７ｇ（２．４６ミリモル）のクロロホルム３０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．５２ｇ（純度７０％、６．１７ミリモル）を加え、室温で１４時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、析出した結晶をｎ−ヘキサンで洗浄し、白色結晶（融点８４〜８６℃）の３−［２，３−ビス（ジフルオロメトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン０．８４ｇ（収率８８．５％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ）δ（ｐｐｍ））：　７．５０−７．４６（１Ｈ，　ｍ）　，　７．３４−７．３２（２Ｈ，　ｍ）　，　６．６０（１Ｈ，　ｔ，Ｊ＝７３．６Ｈｚ），　６．５２（１Ｈ，　ｔ，Ｊ＝７２．８Ｈｚ）　，　４．７４（２Ｈ，　ｓ）　，　３．０６（２Ｈ，　ｓ）　，１．４９（６Ｈ，　ｓ）
【００６３】
＜製造例１１＞
３−（４−クロロ−２−ジフルオロメトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１９）の製造
【００６４】
（１）４−クロロサリチル酸メチルエステルの製造
４−クロロサリチル酸５．０ｇ（２９．０ミリモル）のエタノール５０ｍｌ溶液に硫酸１ｍｌを加えた。反応溶液を８時間還流した。反応終了後エタノールを減圧下留去し、残渣を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、４−クロロサリチル酸メチルエステル３．０５ｇ（収率５２％）を得た。
【００６５】
（２）４−クロロ−２−ジフルオロメトキシ安息香酸メチルエステルの製造
４−クロロサリチル酸メチルエステル３．０５ｇ（１５．０ミリモル）のテトラヒドロフラン３０ｍｌ溶液に粉末状にした水酸化カリウム１．７１ｇ（３０．０ミリモル）とテトラブチルアンモニウムブロミド０．１０ｇ（０．３１ミリモル）を加えた。反応溶液を攪拌しながら室温でクロロジフルオロメタンを導入した。原料消失を確認した後、導入を停止した。反応溶液はそのまま室温で一夜攪拌を続けた。不溶物を濾別し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィーで精製し、４−クロロ−２‐ジフルオロメトキシ安息香酸メチルエステル１．３３ｇ（収率３５％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．８６　（１Ｈ，　ｄ）　，　７．２９（２Ｈ，　ｍ）　，　６．５７（１Ｈ，ｔ，Ｊ＝７４．２Ｈｚ）　，　４．３８（２Ｈ，　ｑ），１．３８（３Ｈ，ｔ）
【００６６】
（３）４−クロロ−２−ジフルオロメトキシフェニルメタノールの製造
水素化リチウムアルミニウム０．２ｇ（５．３ミリモル）のテトラヒドロフラン２０ｍｌ溶液中に、室温で４−クロロ−２‐ジフルオロメトキシ安息香酸メチルエステル１．３３ｇ（５．３ミリモル）のテトラヒドロフラン５ｍｌ溶液を滴下した。反応終了確認後、反応溶液中に飽和塩化アンモニウム水溶液を加えた。その溶液を水中にあけ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、４−クロロ−２−ジフルオロメトキシフェニルメタノールの粗生成物を得た。
【００６７】
（４）４−クロロ−２−ジフルオロメトキシベンジルクロリドの製造
（３）で得られた４−クロロ−２−ジフルオロメトキシフェニルメタノールの粗生成物（５．３ミリモル相当）のジクロロメタン溶液に、室温で塩化チオニル０．６３ｇ（５．３ミリモル）を加え２時間攪拌した。その後溶媒を減圧下留去し、４−クロロ−２−ジフルオロメトキシベンジルクロリドの粗生成物を得た。
【００６８】
（５）３−（４−クロロ−２−ジフルオロメトキシベンジチオ）−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン０．８９ｇ（４．７ミリモル）のＮ，Ｎ−ジメチルホルムアミド１５ｍｌ溶液に、水硫化ナトリウム水和物０．７５ｇ（純度７０％、９．３ミリモル）を加え、１時間攪拌した。その後、無水炭酸カリウム０．６５ｇ（４．７ミリモル）、ロンガリット０．７２ｇ（４．７ミリモル）及び４）で得られた４−クロロ−２−ジフルオロメトキシベンジルクロリドの粗生成物（５．３ミリモル相当）を加え、さらに室温で１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーで精製し、３−（４−クロロ−２−ジフルオロメトキシベンジチオ）−５，５−ジメチル−２−イソオキサゾリン０．８５ｇ（収率５７％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．４７　（１Ｈ，　ｄ）　，　７．１６（２Ｈ，　ｍ）　，　６．５５（１Ｈ，ｔ，　Ｊ＝７３．１Ｈｚ）　，　４．２５（２Ｈ，　ｓ），２．７５（２Ｈ，　ｓ）　，　１．４０（６Ｈ，　ｓ）
【００６９】
（６）３−（４−クロロ−２−ジフルオロメトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号１９）の製造
３−（４−クロロ−２−ジフルオロメトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン０．８５ｇ　（２．６ミリモル）のクロロホルム２０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．６３ｇ（純度７０％、６．６ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎ、クロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、白色結晶（融点８０〜８２℃）の３−（４−クロロ−２−ジフルオロメトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン０．８０ｇ（収率８６％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．４７　（１Ｈ，　ｄ）　，　７．２８（２Ｈ，　ｍ）　，　６．５４（１Ｈ，ｔ，　Ｊ＝７３．１Ｈｚ）　，　４．７０（２Ｈ，　ｓ），３．０２（２Ｈ，　ｓ）　，　１．４８（６Ｈ，　ｓ）
【００７０】
＜製造例１２＞
２−（５，５−ジメチルイソオキサゾリン−３−イルスルホニルメチル）−３−フルオロベンゾニトリル（化合物番号２２）の製造
【００７１】
（１）３−フルオロ−２−メチル安息香酸メチルエステルの製造
３−フルオロ−２−メチル安息香酸４．８ｇ（３１．１ミリモル）のＮ，Ｎ−ジメチルホルムアミド５０ｍｌ溶液に、室温で無水炭酸カリウム４．３ｇ（３１．１ミリモル）、ヨウ化メチル４．４ｇ（３１．１ミリモル）を加え一夜攪拌した。反応終了確認後、反応溶液を水中に注ぎ酢酸エチルで抽出し、得られた有機層を水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、３−フルオロ−２−メチル安息香酸　メチルエステル５．２ｇ（収率９９．４％）を得た。
【００７２】
（２）２−ブロモメチル−３−フルオロ安息香酸メチルエステルの製造
３−フルオロ−２−メチル安息香酸メチルエステル８．５ｇ（５０．５ミリモル）の四塩化炭素１００ｍｌ溶液に、室温でＮ−ブロモこはく酸イミド９．５ｇ（５３．１ミリモル）及び２，２’−アゾビス（イソブチロニトリル）０．９ｇ（５．３ミリモル）を加えた。反応溶液を２．５時間環流した。反応終了後、室温まで冷却し不溶物を濾別した。溶媒を減圧下留去し、２−ブロモメチル−３−フルオロ安息香酸メチルエステルの粗生成物を得た。
【００７３】
（３）２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）３−フルオロ安息香酸メチルエステルの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン９．６ｇ（５０ミリモル）のＮ、Ｎ−ジメチルホルムアミド１００ｍｌ溶液に、水硫化ナトリウム水和物８．０ｇ（純度７０％、１００ミリモル）を加え、１時間攪拌した。その後、氷冷下無水炭酸カリウム６．９ｇ（５０ミリモル）、ロンガリット７．９ｇ（５０ミリモル）及び（４）で得られた２−ブロモメチル−３−フルオロ安息香酸メチルエステルの粗生成物（５０．５ミリモル相当）を加え、さらに室温で３時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーで精製し、２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロ安息香酸メチルエステル７．３ｇ（収率４９．９％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．７２　（１Ｈ，　ｄ）　，　７．３７〜７．２１（２Ｈ，　ｍ）　，　４．６９（２Ｈ，　ｓ）　，　３．９４（３Ｈ，　ｓ），２．７８（２Ｈ，　ｓ）　，　１．４０（６Ｈ，　ｓ）
【００７４】
（４）２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロ安息香酸の製造
２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロ安息香酸メチルエステル１４．３ｇ（４８．１ミリモル）のテトラヒドロフラン１００ｍｌ溶液中に、室温で水酸化ナトリウム２．３ｇ（５７．７ミリモル）を溶解した水溶液１０ｍｌを加え、一夜攪拌した。反応終了確認後、反応溶液を水中に注ぎ、ｐＨを４に調整した後、酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロ安息香酸１０．６ｇ（収率７７．９％）を得た。
【００７５】
（５）２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロベンズアミドの製造
２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロ安息香酸０．８５ｇ（３．０ミリモル）のテトラヒドロフラン１０ｍｌ溶液中に、室温でＮ，Ｎ’−カルボニルジイミダゾール０．７３ｇ（４．５ミリモル）を加え１時間攪拌した。さらに反応溶液中に２８％アンモニア水１０ｍｌを加え、一夜攪拌した。反応終了確認後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロベンズアミド０．８４ｇ（収率９９．３％）を得た。
【００７６】
（６）２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロベンゾニトリルの製造
２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロベンズアミド０．８４ｇ（２．９８ミリモル）の１，４−ジオキサン１０ｍｌ溶液に、室温でピリジン０．４７ｇ（５．９５ミリモル）を加え、氷冷下で無水トリフルオロ酢酸０．７５ｇ（３．５７ミリモル）を加え、さらに室温で４時間攪拌した。反応終了確認後、反応溶液を水中に注ぎ、酢酸エチルで抽出し、得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーで精製し、白色粉末の２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロベンゾニトリル０．６４ｇ（収率：８１．０％）を得た。
【００７７】
（７）２−（５，５−ジメチルイソオキサゾリン−３−イルスルホニルメチル）−３−フルオロベンゾニトリル（化合物番号２２）の製造
２−（５，５−ジメチルイソオキサゾリン−３−イルチオメチル）−３−フルオロベンゾニトリル０．６４ｇ（２．４２ミリモル）のクロロホルム２０ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．４９ｇ（純度７０％、６．０５ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、白色結晶（融点１１２〜１１４℃）の２−（５，５−ジメチルイソオキサゾリン−３−イルスルホニルメチル）−３−フルオロベンゾニトリル０．５１ｇ（収率７１．１％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．６１〜７．４１　（３Ｈ，　ｍ）　，　４．８９（２Ｈ，　ｓ），３．１６（２Ｈ，　ｓ）　，　１．５４（６Ｈ，　ｓ）
【００７８】
＜製造例１３＞
３−［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン（化合物番号３０）の製造
【００７９】
（１）３，４−ジクロロ−２−ヒドロキシメチルフェノールの製造
３，４−ジクロロフェノール１０．０ｇ（６１．０ミリモル）とパラホルムアルデヒド１８．４ｇ（６１０．０ミリモル）を水５０ｍｌに懸濁させ、そこに水酸化ナトリウム２５％水溶液４９ｇ（３１０．０ミリモル）を加えた。反応溶液を６０℃で１２時間攪拌した。反応溶液を室温まで冷却し、その後反応溶液を水中に注ぎ、クエン酸水溶液で酸性にした後、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、白色結晶の３，４−ジクロロ−２−ヒドロキシメチルフェノール２．５ｇ（収率２１％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　８．４２（１Ｈ，　ｓ）　，　７．２５（１Ｈ，　ｄ）　，　６．７５（１Ｈ，　ｄ）　，　５．１５（２Ｈ，ｓ）　，　２．５８（１Ｈ，　ｓ）
【００８０】
（２）［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）フェニル］メタノールの製造
３，４−ジクロロ−２−ヒドロキシメチルフェノール１．０ｇ（５．２ミリモル）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液中に、無水炭酸カリウム０．７２ｇ（５．２ミリモル）とトリフルオロメタンスルホン酸２，２，２−トリフルオロエチル１．２１ｇ（５．２ミリモル）を加えた。反応溶液を室温で一晩攪拌した。原料消失を確認した後、反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）フェニル］メタノールを得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．４１（１Ｈ，　ｄ）　，　６．７８（１Ｈ，　ｄ）　，　４．９２（２Ｈ，ｓ）　，　４．４１（２Ｈ，　ｑ）
【００８１】
（３）２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルブロミドの製造
［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）フェニル］メタノール１．４３ｇ（５．２ミリモル相当）のジエチルエーテル２０ｍｌ溶液に、三臭化りん０．７１ｇ（２．６ミリモル）を加え１時間攪拌した。反応終了後、反応溶液を水中に注ぎ、ジエチルエーテルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルブロミドの粗生成物を得た。
【００８２】
（４）３−［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン１．００ｇ（５．２ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物０．８４ｇ（純度７０％、１０．０ミリモル）を加え２時間攪拌した。その後、無水炭酸カリウム０．７２ｇ（５．２ミリモル）、ロンガリット（ＣＨ_２（ＯＨ）ＳＯ_２Ｎａ・２Ｈ_２Ｏ）０．８０ｇ（５．２ミリモル）及び（３）で得られた２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルブロミドの粗生成物（５．２ミリモル相当）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液を加え、さらに室温で１１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）］ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．７０ｇ（収率３４％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ）δ（ｐｐｍ））：　７．３８（１Ｈ，　ｄｄ）　，　６．７６（１Ｈ，　ｄ）　，　４．５５（２Ｈ，　ｓ），　４．４０（２Ｈ，　ｑ）　，　２．８２（２Ｈ，　ｓ）　，　１．４３（６Ｈ，　ｓ）
【００８３】
（５）３−［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン（化合物番号３０）の製造
３−［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）］ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．７０ｇ（１．８ミリモル）のクロロホルム１５ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．１１ｇ（純度７０％、４．５ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、析出した結晶をｎ−ヘキサンで洗浄し、白色結晶（融点１３５〜１３７℃）の３−［２，３−ジクロロ−６−（２，２，２−トリフルオロエトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン０．６２ｇ（収率８２％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　７．５１（１Ｈ，　ｄ）　，　６．８７（１Ｈ，　ｄ）　，　５．０６（２Ｈ，　ｓ）　，　４．４５（２Ｈ，　ｑ）　，　３．０８（２Ｈ，　ｓ）　，　１．５２（６Ｈ，　ｓ）
【００８４】
＜製造例１４＞
３−［２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン（化合物番号３２）の製造
【００８５】
（１）［２，３−ジクロロ−６−（２−プロピニルオキシ）フェニル］メタノールの製造
３，４−ジクロロ−２−ヒドロキシメチルフェノール１．０ｇ（５．２ミリモル）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液中に、無水炭酸カリウム０．７２ｇ（５．２ミリモル）と３−ブロモプロピン０．６２ｇ（５．２ミリモル）を加えた。反応溶液を室温で一晩攪拌した。原料消失を確認した後、反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、［２，３−ジクロロ−６−（２−プロピニルオキシ）フェニル］メタノールを得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．３８（１Ｈ，　ｄ）　，　６．９２（１Ｈ，　ｄ）　，　４．９０（２Ｈ，　ｓ）　，　４．７６（２Ｈ，ｄ），２．５５（１Ｈ，ｔ），２．２７（１Ｈ、ｓ）
【００８６】
（２）２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルブロミドの製造
［２，３−ジクロロ−６−（２−プロピニルオキシ）フェニル］メタノール１．２０ｇ（５．２ミリモル相当）のジエチルエーテル２０ｍｌ溶液に、三臭化りん０．７１ｇ（２．６ミリモル）を加え１時間攪拌した。反応終了後、反応溶液を水中に注ぎ、ジエチルエーテルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルブロミドの粗生成物を得た。
【００８７】
（３）３−［２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン１．００ｇ（５．２ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物０．８４ｇ（純度７０％、１０．０ミリモル）を加え２時間攪拌した。その後、無水炭酸カリウム０．７２ｇ（５．２ミリモル）、ロンガリット（ＣＨ_２（ＯＨ）ＳＯ_２Ｎａ・２Ｈ_２Ｏ）０．８０ｇ（５．２ミリモル）及び（２）で得られた２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルブロミドの粗生成物（５．２ミリモル相当）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液を加え、さらに室温で１１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−［２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．８１ｇ（収率４６％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ）δ（ｐｐｍ））：　７．３８（１Ｈ，　ｄ）　，　６．９３（１Ｈ，　ｄ）　，　４．７６（２Ｈ，　ｄ），　４．５４（２Ｈ，　ｓ）　，　２．８３（２Ｈ，　ｓ）　，　１．４３（６Ｈ，　ｓ）
【００８８】
（４）３−［２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン（化合物番号３２）の製造
３−［２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．８１ｇ（２．４ミリモル）のクロロホルム１５ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸１．４５ｇ（純度７０％、５．９ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、析出した結晶をｎ−ヘキサンで洗浄し、白色結晶（融点１１３〜１１５℃）の３−［２，３−ジクロロ−６−（２−プロピニルオキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．６７ｇ（収率７５％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　７．４７（１Ｈ，　ｄ）　，７．０２（１Ｈ，　ｄ）　，　５．０３（２Ｈ，　ｓ），　４．７７（２Ｈ，　ｄ）　，　３．０５（２Ｈ，　ｓ），　２．５６（１Ｈ，ｓ），　１．５０（６Ｈ，　ｓ）
【００８９】
＜製造例１５＞
３−［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン（化合物番号３３）の製造
【００９０】
（１）メタンスルホン酸２，２−ジフルオロエチルの製造
２，２−ジフロロエタノール０．５ｇ（６．１ミリモル）とトリエチルアミン０．６８ｇ（６．７ミリモル）のジクロロメタン１５ｍｌ溶液に、氷冷下メタンスルホニルクロリド０．７７ｇ（６．７ミリモル）のジクロロメタン溶液５ｍｌを滴下した。滴下終了後、反応溶液を１０℃以下で１時間攪拌した。反応溶液を水中に注ぎ、ジクロロメタンで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、メタンスルホン酸２，２−ジフルオロエチルの粗生成物を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：６．０１（１Ｈ，ｔｔ，Ｊ＝３．６８、Ｊ＝５４．５９），４．３８（２Ｈ，ｔｔ，Ｊ＝３．９２，Ｊ＝１３．１９），３．１２（２Ｈ，ｓ）
【００９１】
（２）［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）フェニル］メタノールの製造
３，４−ジクロロ−２−ヒドロキシメチルフェノール１．０ｇ（５．２ミリモル）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液中に、無水炭酸カリウム０．７２ｇ（５．２ミリモル）と（１）で得られたメタンスルホン酸２，２−ジフルオロエチル０．９８ｇ（６．１ミリモル相当）を加えた。反応溶液を７０℃で１８時間攪拌した。原料消失を確認した後、反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）フェニル］メタノールの粗生成物を得た。
【００９２】
（３）２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルブロミドの製造
［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）フェニル］メタノール１．５７ｇ（６．１ミリモル相当）のジエチルエーテル２０ｍｌ溶液に、三臭化りん０．８３ｇ（３．１ミリモル）を加え１時間攪拌した。反応終了後、反応溶液を水中に注ぎ、ジエチルエーテルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルブロミドの粗生成物を得た。
【００９３】
（４）３−［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン１．１７ｇ（６．１ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物０．９８ｇ（純度７０％、１２．０ミリモル）を加え２時間攪拌した。その後、無水炭酸カリウム０．８４ｇ（６．１ミリモル）、ロンガリット０．９４ｇ（６．１ミリモル）及び（３）で得られた２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルブロミドの粗生成物（６．１ミリモル相当）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液を加え、さらに室温で１１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）］ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．４０ｇ（収率１８％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．３８（１Ｈ，ｄ），６．７６（１Ｈ，ｄ），６．１５（１Ｈ，ｔｔ，Ｊ＝４．０２，Ｊ＝５４．８８），４．５５（１Ｈ，ｓ），４．２２（２Ｈ，ｔｔ，Ｊ＝４．０２，Ｊ＝１２．６２），２．８１（１Ｈ，ｓ），１．４３（６Ｈ，ｓ）
【００９４】
（５）３−［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン（化合物番号３３）の製造
３−［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）］ベンジルチオ］−５，５−ジメチル−２−イソオキサゾリン０．４０ｇ（１．１ミリモル）のクロロホルム１５ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸０．６７ｇ（純度７０％、２．７ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、析出した結晶をｎ−ヘキサンで洗浄し、白色結晶（融点１１８〜１２０℃）の３−［２，３−ジクロロ−６−（２，２−ジフルオロエトキシ）ベンジルスルホニル］−５，５−ジメチル−２−イソオキサゾリン０．４１ｇ（収率９５％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：７．４８（１Ｈ，ｓ），６．８５（１Ｈ，ｄ），６．１６（１Ｈ，ｔｔ，Ｊ＝４．２１，Ｊ＝５５．０６），５．０５（１Ｈ，ｓ），４．２５（２Ｈ，ｔｔ，Ｊ＝４．２０，Ｊ＝１２．８３），２．８１（１Ｈ，ｓ），１．４３（６Ｈ，ｓ）
【００９５】
＜製造例１６＞
３−（２，５−ジクロロ−４−エトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号４７）の製造
【００９６】
（１）２，５−ジクロロ−４−ヒドロキシメチルフェノールの製造
２，５−ジクロロフェノール５．０ｇ（３１．０ミリモル）とパラホルムアルデヒド９．２１ｇ（３１０，０ミリモル）を水３０ｍｌに懸濁させ、そこに水酸化ナトリウム２５％水溶液２５ｇ（１５０．０ミリモル）加えた。反応溶液を７０℃で１２時間攪拌した。反応溶液を室温まで冷却し、その後反応溶液を水中に注ぎ、クエン酸水溶液で酸性にした後、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、白色結晶の２，５−ジクロロ−４−ヒドロキシメチルフェノール２．４５ｇ（収率４１％）を得た。
（^１Ｈ−ＮＭＲ値（ＤＭＳＯ−ｄ_６　δ（ｐｐｍ））：　　１０．５１（１Ｈ，ｓ），７．４１（１Ｈ，ｓ），６．９６（１Ｈ，ｓ），５．３０（１Ｈ，ｓ），４．４１（２Ｈ，ｓ）
【００９７】
（２）（２，５−ジクロロ−４−エトキシフェニル）メタノールの製造
２，５−ジクロロ−４−ヒドロキシメチルフェノール１．２３ｇ（６．３ミリモル）のＮ，Ｎ−ジメチルホルムアミド２５ｍｌ溶液中に、無水炭酸カリウム０．８８ｇ（６．３ミリモル）とヨードエタン０．９９ｇ（６．３ミリモル）を加えた。反応溶液を室温で一晩攪拌した。原料消失を確認した後、反応溶液を水中に注ぎ、酢酸エチルで抽出した。得られた有機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、（２，５−ジクロロ−４−エトキシフェニル）メタノールを得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　　７．４７（１Ｈ，　ｓ）　，　６．９２（１Ｈ，　ｓ）　，　４．６８（２Ｈ，ｓ）　，　４．０８（２Ｈ，　ｑ），１．４７（３Ｈ，ｔ）
【００９８】
（３）（２，５−ジクロロ−４−エトキシ）ベンジルブロミドの製造
（２，５−ジクロロ−４−エトキシフェニル）メタノール１．４０ｇ（６．３ミリモル相当）のジエチルエーテル２０ｍｌ溶液に、三臭化りん０．８５ｇ（３．２ミリモル）を加え１時間攪拌した。反応終了後、反応溶液を水中に注ぎ、ジエチルエーテルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、（２，５−ジクロロ−４−エトキシ）ベンジルブロミドの粗生成物を得た。
【００９９】
（４）３−（２，５−ジクロロ−４−エトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリンの製造
５，５−ジメチル−３−エチルスルホニル−２−イソオキサゾリン１．２０ｇ（６．３ミリモル）のＮ，Ｎ−ジメチルホルムアミド３０ｍｌ溶液に、水硫化ナトリウム水和物１．０１ｇ（純度７０％、１３．０ミリモル）を加え２時間攪拌した。その後、無水炭酸カリウム０．８７ｇ（６．３ミリモル）、ロンガリット（ＣＨ_２（ＯＨ）ＳＯ_２Ｎａ・２Ｈ_２Ｏ）０．９７ｇ（６．３ミリモル）及び（３）で得られた（２，５−ジクロロ−４−エトキシ）ベンジルブロミドの粗生成物（６．３ミリモル相当）のＮ，Ｎ−ジメチルホルムアミド２０ｍｌ溶液を加え、さらに室温で１１時間攪拌した。反応終了後、反応溶液を水中に注ぎ酢酸エチルで抽出した。得られた有機層を水及び食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、３−（２，５−ジクロロ−４−エトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン１．５３ｇ（収率７３％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ）δ（ｐｐｍ））：　７．５１（１Ｈ，　ｓ）　，　６．９２（１Ｈ，　ｓ）　，　４．２９（２Ｈ，　ｓ），　４．０８（２Ｈ，　ｑ）　，　２．７７（２Ｈ，　ｓ）　，　１．４６（３Ｈ，ｔ），１．４１（６Ｈ，　ｓ）
【０１００】
（５）３−（２，５−ジクロロ−４−エトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン（化合物番号４７）の製造
３−（２，５−ジクロロ−４−エトキシベンジルチオ）−５，５−ジメチル−２−イソオキサゾリン１．５３ｇ（４．６ミリモル）のクロロホルム１５ｍｌ溶液に、氷冷下、ｍ−クロロ過安息香酸２．８２ｇ（純度７０％、１１．０ミリモル）を加え、室温で２０時間攪拌した。反応終了後、反応溶液を水中に注ぎクロロホルムで抽出した。得られた有機層を亜硫酸水素ナトリウム水溶液、炭酸水素ナトリウム水溶液及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、析出した結晶をｎ−ヘキサンで洗浄し、白色結晶（融点１５５〜１５６℃）の３−（２，５−ジクロロ−４−エトキシベンジルスルホニル）−５，５−ジメチル−２−イソオキサゾリン１．３９ｇ（収率８３％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：　７．５１（１Ｈ，　ｓ）　，　６．９２（１Ｈ，　ｓ）　，　４．２９（２Ｈ，　ｓ）　，　４．０７（２Ｈ，　ｑ）　，　２．７７（２Ｈ，　ｓ）　，　１．４７（３Ｈ，ｔ），１．４１（６Ｈ，　ｓ）
【０１０１】
（中間体の製造例）
＜参考例１＞
３−クロロ−５，５−ジメチル−２−イソオキサゾリンの製造
グリオキシル酸アルドオキシム１８２．７ｇ（２．０５モル）のジメトキシエタン２ｌ溶液に、６５〜７０℃でＮ−クロロこはく酸イミド５３４．０ｇ（４．０モル）を徐々に加えた後、１時間加熱還流した。氷冷下、炭酸水素カリウム１４４０．０ｇ（１４．４モル）及び水１０ｍｌを加えた後、２−メチルプロペン３６０．０ｇ（６．４モル）を反応溶液に加え、室温で２４時間攪拌した。反応溶液を水中に注ぎイソプロピルエーテルで抽出した。得られた有機層を水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、黄色粘調性液体の３−クロロ−５，５−ジメチル−２−イソオキサゾリン１０７．７ｇ（収率４０．０％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：２．９３（２Ｈ，ｓ）、１．４７（６Ｈ，ｓ）
【０１０２】
＜参考例２＞
３−クロロ−５−エチル−５−メチル−２−イソオキサゾリンの製造
グリオキシル酸アルドオキシム２０．６ｇ（２３１．７ミリモル）のジメトキシエタン５００ｍｌ溶液に、６０℃でＮ−クロロコハク酸イミド６１．９ｇ（４６３．４ミリモル）を徐々に加えた。加え終わった後、１０分間加熱還流した。次に、氷冷下、２−メチル−１−ブテン５０ｍｌ（４６３．４ミリモル）、炭酸水素カリウム９８．９ｇ（１６２２ミリモル）及び水１０ｍｌを加え１２時間攪拌した。反応溶液を水中に注ぎｎ−ヘキサンで抽出した。得られた有機層を水及び食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、淡黄色粘調性液体の３−クロロ−５−エチル−５−メチル−２−イソオキサゾリン１３．９ｇ（収率４０．６％）を得た。
（^１Ｈ−ＮＭＲ値（ＣＤＣｌ_３／ＴＭＳ　δ（ｐｐｍ））：２．９１（２Ｈ，Ａｂｑ，Ｊ＝１７．０，Δν＝４６．１Ｈｚ），１．７３（２Ｈ，ｑ）、１．４２（３Ｈ，ｓ）、０．９６（３Ｈ，ｔ）
【０１０３】
本発明組成物は、広範囲の雑草を選択的に防除する上で、また、不耕起栽培のような新しい栽培方法への適用をする上で効果的な除草組成物を提供するものであり、特に、トウモロコシ畑における主要な雑草、例えばソバカズラ、サナエタデ、スベリヒユ、シロザ、アオゲイトウ、ノハラガラシ、アメリカツノクサネム、エビスグサ、イチビ、アメリカキンゴジカ、アメリカアサガオ、マルバアサガオ、ヨウシュチョウセンアサガオ、イヌホオズキ、オナモミ、ヒマワリ、セイヨウヒルガオ、トウダイグサ、アメリカセンダングサ、ブタクサ等の双子葉植物および、イヌビエ、エノコログサ、アキノエノコログサ、キンノエノコロ、メヒシバ、オヒシバ、セイバンモロコシ、シバムギ、シャッターケーン等の単子葉植物を有効に除草する一方、作物であるトウモロコシやトウモロコシの後作物であるダイズに対して問題となるような薬害を生じない。
【０１０４】
本発明除草性組成物を除草剤として使用するには他成分を加えず混合した形で使用してもよいが、製剤化に一般的に用いられる担体、界面活性剤、分散剤または補助剤等を配合して、水和剤、粒剤、微粒剤、粉剤、乳剤、水溶剤、懸濁剤、フロアブル等に製剤して使用することもできる。
【０１０５】
製剤化に際して用いられる担体としては、例えばタルク、ベントナイト、クレー、カオリン、珪藻土、ホワイトカーボン、バーミキュライト、炭酸カルシウム、消石灰、珪砂、硫安、尿素等の固体担体、イソプロピルアルコール、キシレン、シクロヘキサン、メチルナフタレン等の液体担体等があげられる。
【０１０６】
界面活性剤及び分散剤としては、例えばアルキルベンゼンスルホン酸金属塩、アルキルナフタレンスルホン酸ホルマリン縮合物金属塩、アルコール硫酸エステル塩、アルキルアリールスルホン酸塩、リグニンスルホン酸塩、ポリオキシエチレングリコールエーテル、ポリオキシエチレンアルキルアリールエーテル、ポリオキシエチレンソルビタンモノアルキレート等があげられる。補助剤としては、例えばカルボキシメチルセルロース、ポリエチレングリコール、アラビアゴム等があげられる。
【０１０７】
本発明組成物は、夫々の有効成分を上述の製剤手法により製剤した後、これらを混合することにより調製することもできる。このようにして製剤化された本発明組成物は、そのままでまたは水等で希釈して植物体に施用される。本発明組成物は、さらに、他の除草剤と混合して用いることにより除草効力の増強を期待でき、さらに殺虫剤、殺菌剤、植物生長調節剤、肥料、土壌改良剤等と併用することもできる。
【０１０８】
本発明組成物の施用量は、有効成分化合物である式［Ｉ］で表されるイソオキサゾリン誘導体より選ばれる一種と、次に示すＡ群から選ばれる少なくとも一種との合計量が一般に０．５〜９０重量％、好ましくは１〜８０重量％含有される。
Ａ群：アトラジン、シマジン、シアナジン、イソキサフルトール、フルメツラム、イマゼタピル、イマザピル、ジカンバ、クロピラリド、プロスルフロン、ハロスルフロン・メチル、リムスルフロン、ベンタゾン、カルフェントラゾン・エチル、メトリブジン、チフェンスルフロン・メチル、ニコスルフロン、プリミスルフロン、グルホシネート、グリホセート及びスルホセート
【０１０９】
【実施例】
次に、実施例を示す。以下の例では部は重量部を示す。
【０１１０】
〈製剤例１〉　水和剤
化合物１の５部、シアナジンの４０部にポリオキシエチレンオクチルフェニルエーテルの０．５部、アルキルナフタレンスルホン酸ホルマリン縮合物ナトリウム塩の０．５部、珪藻土の１２部、クレーの４２部を混合粉砕し、水和剤を得る。
【０１１１】
混合比、気象条件、製剤形態、施用時期、施用方法、施用場所、防除対象雑草、対象作物により変わり得るが、１ヘクタール当り有効成分化合物の合計量として、通常５０〜１５００ｇである。乳剤、水和剤、懸濁剤等は、その所定量を１ヘクタール当り通常１００〜１０００リットルの水で希釈して施用する。
【０１１２】
次に試験例をあげて本発明の除草剤組成物の奏する効果を説明する。
〈試験例〉　畑地土壌処理による雑草に対する除草効果試験
８０ｃｍ^２プラスチックポットに畑土壌を充填し、エノコログサ、シロザの種子を播種して覆土した。製剤例１に準じて調製した水和剤を有効成分が所定量になるよう秤り取り、水で希釈し、１０アール当り１００ｌの散布水量で小型噴霧器を用いて土壌表面に均一に散布した。その後、温室内で育成し、処理３０日目に表３の基準に従って、除草効果を調査した。結果を表４に示す。
【０１１３】
【表３】

【０１１４】
【表４】

【０１１５】
【発明の効果】
一般式［Ｉ］で表される化合物に次に示したＡ群から選ばれる少なくとも一種の除草剤を所定の割合で混合施用すると、各単剤で得られる活性の単純な合計に留まらず、相乗的に殺草効果が発揮され、畑地において問題となる種々の雑草、例えばイヌビエ、メヒシバ、エノコログサ、スズメノカタビラ、ジョンソングラス、ノスズメノテッポウ、野生エンバク等のイネ科雑草をはじめ、オオイヌタデ、アオビユ、シロザ、ハコベ、イチビ、アメリカキンゴジカ、アメリカツノクサネム、ブタクサ、アサガオの広葉雑草、ハマスゲ、キハマスゲ、ヒメクグ、カヤツリグサ、コゴメガヤツリ等の多年生および１年生カヤツリグサ科雑草の発芽前から生育期の広い範囲にわたって低薬量で優れた除草効果を発揮する。
Ａ群：アトラジン、シマジン、シアナジン、イソキサフルトール、フルメツラム、イマゼタピル、イマザピル、ジカンバ、クロピラリド、プロスルフロン、ハロスルフロン・メチル、リムスルフロン、ベンタゾン、カルフェントラゾン・エチル、メトリブジン、チフェンスルフロン・メチル、ニコスルフロン、プリミスルフロン、グルホシネート、グリホセート及びスルホセート
更に、水田に発生するタイヌビエ、タマガヤツリ、コナギ、アゼナ等の１年生雑草及びミズガヤツリ、クログワイ、ホタルイ等の多年生雑草についても発芽前から生育期の広い範囲にわたって低薬量で防除することができる。
【０１１６】
一方、本発明の除草剤組成物は、作物に対する安全性も高く、中でもイネ、コムギ、オオムギ、トウモロコシ、グレインソルガム、ダイズ、ワタ、テンサイ、芝、果樹等に対して高い安全性を示す。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a herbicidal composition which exhibits not only an additive effect but also a synergistic effect of each herbicide by mixing at least one member selected from the following group A with an isoxazoline derivative. .
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate
[0002]
[Prior art]
A wide variety of chemicals have been put into practical use from research and development of herbicides over many years, and these herbicides have contributed to labor saving in weed control work and improvement in productivity of agricultural and horticultural crops. However, there is still a need today to develop new drugs with better herbicidal properties.
[0003]
[Patent Document]
WO01 / 012613
[0004]
[Problems to be solved by the invention]
Herbicides used for useful crops are desired to be applied to soil or foliage, exhibit sufficient herbicidal effects at low doses, and exhibit high selectivity between crops and weeds.
[0005]
[Means for Solving the Problems]
The isoxazoline compound represented by the formula [I], which is one active ingredient of the herbicidal composition of the present invention, is described in WO 01/012613, and this compound is composed of rice, wheat, barley, corn, and grain. It is safe for sorghum, soybean, cotton, sugar beet, turf, fruit trees, etc. and has an excellent herbicidal effect by itself.
[0006]
The present inventors mixed one or two or more of the conventionally used herbicides shown in Group A with the isoxazoline derivative represented by the formula [I] at a predetermined ratio, whereby each of them was mixed. It has been found that not only the herbicidal effect is obtained additively, but also a synergistic herbicidal effect appears. In other words, the combined use of the two drugs broadens the herbicidal spectrum compared to the herbicidal application range of each single agent, and at the same time achieves the herbicidal effect earlier, maintains the effect, and achieves a lower dose than the single dose. As well as exhibiting sufficient effects, it is also safe for rice, wheat, barley, corn, grain sorghum, soybean, cotton, sugar beet, turf, fruit trees, etc. As a result, the present invention has been completed.
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate
That is, the present invention provides a compound represented by the general formula [I]:
[0007]
Embedded image

[0008]
Ｑwherein Q is a group —S (O)_n− (CR₅R₆)_mRepresents n, n represents an integer of 0 to 2, m represents an integer of 1 to 3, R₅And R₆Independently represent a hydrogen atom, a cyano group, an alkoxycarbonyl group or a C1-C6 alkyl group,
R₁And R₂Is a hydrogen atom, [C3-C8 cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylcarbonyl group, C1-C6 alkylthio group, C1-C6 alkylsulfinyl group, C1-C6 alkylsulfonyl group, C1-C6 alkylamino Group, di (C1-C6 alkyl) amino group, cyano group, C1-C6 alkoxycarbonyl group, C1-C6 alkylaminocarbonyl group, di (C1-C6 alkyl) aminocarbonyl group, (C1-C6 alkylthio) carbonyl group, A carboxyl group, a benzyloxy group (optionally substituted), a phenoxy group (optionally substituted) or a phenyl group (optionally substituted)] C1-C8 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxycarbonyl group, C1 C6 alkylaminocarbonyl group, di (C1 -C6 alkyl) aminocarbonyl group, C1 -C6 alkyl thio group, a carboxyl group, or (optionally substituted) phenyl group, or R₁And R₂May form a C3-C7 spiro ring together with these bonded carbon atoms,
R₃And R₄Represents a hydrogen atom, a C1-C8 alkyl group (which may be substituted with 1 to 3 identical or different halogen atoms, a C3-C8 cycloalkyl group or a C1-C6 alkoxy group) or a C3-C8 cycloalkyl group. Represents, R₃And R₄May form a C3-C7 spiro ring with these attached carbon atoms, or R₁, R₂, R₃And R₄May form a 5- to 8-membered ring with these bonded carbon atoms,
Y is a hydrogen atom, a C1-C6 alkoxycarbonyl group, a carboxyl group, a C2-C6 alkenyl group, [the same or different one to three halogen atoms, a C1-C6 alkoxy group, a C2-C6 alkenyloxy group, a C2-C6 An alkynyloxy group, a benzyloxy group (optionally substituted), a C1-C6 alkoxycarbonyl group, a carboxyl group, a hydroxyl group or a formyl group which may be substituted] a C1-C10 alkyl group or (1-5 Same or different R₇Represents a phenyl group,
R₇Is a hydrogen atom, [1 to 3 identical or different halogen atoms, a C1 to C6 alkoxy group, a hydroxyl group, a C1 to C6 alkylthio group, a C1 to C6 alkylsulfinyl group, a C1 to C6 alkylsulfonyl group, a C1 to C6 alkylamino A C1-C6 dialkylamino group, a cyano group or a (optionally substituted) phenoxy] C1-C6 alkyl group, (1-3 different or identical halogen atoms, C1 A C6-alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyl group or a C3-C8 cycloalkyl group which may be substituted) a C1-C6 alkoxy group; A C2-C6 alkenyl group, a C3-C8 cycloalkyloxy group, (identical or C1 to C6 alkylthio groups (which may be substituted by 1 to 3 halogen atoms or C1 to C6 alkoxy groups), (substituted by 1 to 3 identical or different halogen atoms or C1 to C6 alkoxy groups) C1 to C6 alkylsulfinyl group, C1 to C6 alkylsulfonyl group (which may be substituted with 1 to 3 identical or different halogen atoms or C1 to C6 alkoxy group), (optionally substituted) Good) substituted with a benzyloxy group, a (C1-C6 alkyl group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylcarbonyl (C1-C6 alkyl) group or a C1-C6 alkylsulfonyl (C1-C6 alkyl) group. An amino group, a halogen atom, a cyano group, a nitro group, a C1-C6 alkoxycarbonyl group, 3-C8 cycloalkyloxycarbonyl group, carboxyl group, C2-C6 alkenyloxycarbonyl group, C2-C6 alkynyloxycarbonyl group, (optionally substituted) benzyloxycarbonyl group, (optionally substituted) phenoxy Represents a carbonyl group or a C1-C6 alkylcarbonyloxy group. A herbicidal composition comprising an isoxazoline derivative represented by 又 は or a salt thereof and at least one selected from Group A shown below.
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate
In addition, the definition of the term used in this specification is shown below.
[0009]
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0010]
The alkyl group refers to a linear or branched alkyl group having 1 to 10 carbon atoms unless specifically limited, and includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. Group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, 3,3-dimethylbutyl group, heptyl group or octyl group. .
[0011]
The cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
[0012]
The alkoxy group indicates a (alkyl) -O- group in which the alkyl portion has the above-mentioned meaning, and examples thereof include a methoxy group and an ethoxy group.
[0013]
The alkylthio group, the alkylsulfinyl group, and the alkylsulfonyl group refer to the (alkyl) -S- group, the (alkyl) -SO- group, the (alkyl) -SO₂And represents, for example, a methylthio group, an ethylthio group, a methylsulfinyl group, a methylsulfonyl group or an ethylsulfonyl group.
[0014]
The alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, for example, an ethenyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group. , 3-butenyl group or 2-pentenyl group.
[0015]
The alkynyl group refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a 2-propynyl group, a 2-butynyl group, and a 3-butynyl group.
[0016]
The alkenyloxy group and the alkynyloxy group mean a (alkenyl) -O- group or an (alkynyl) -O- group in which the alkenyl or alkynyl moiety has the above-mentioned meaning, for example, a 2-propenyloxy group or a 2-propynyloxy group. And the like.
[0017]
The alkylamino group and the dialkylamino group mean that the alkyl portion has the above meaning (alkyl) -NH- group, (alkyl)₂It represents an N- group, and examples thereof include a methylamino group, an ethylamino group, and a dimethylamino group.
[0018]
The alkylcarbonyl group, the (alkylthio) carbonyl group, the alkoxycarbonyl group, the alkylaminocarbonyl group and the dialkylaminocarbonyl group mean that the alkyl, alkylthio, alkoxy, alkylamino or dialkylamino moiety has the above meaning (alkyl) -CO- A (alkylthio) -CO- group, an (alkoxy) -CO- group, a (alkylamino) -CO- group, a (dialkylamino) -CO- group, such as an acetyl group, a methylthiocarbonyl group, an ethoxycarbonyl group, Examples include a methoxycarbonyl group, a methylaminocarbonyl group, a dimethylaminocarbonyl group and the like.
[0019]
The alkylaminocarbonylamino group, the dialkylaminocarbonylamino group and the alkoxycarbonylamino group mean the above-mentioned meaning of an alkylaminocarbonyl, a dialkylaminocarbonyl or an alkoxycarbonyl moiety, a (alkylaminocarbonyl) -NH- group, a (dialkylaminocarbonyl) group. ) -NH- group and (alkoxycarbonyl) -NH- group, for example, methylaminocarbonylamino group, dimethylaminocarbonylamino group, methoxycarbonylamino group and the like.
[0020]
The optionally substituted phenyl group includes a phenyl group having 1 to 5 substituents such as a halogen atom, a C1 to C6 alkyl group or a C1 to C6 alkoxy group on the phenyl ring.
[0021]
Examples of the phenoxy group which may be substituted include a phenoxy group having 1 to 5 substituents such as a halogen atom, a C1 to C6 alkyl group or a C1 to C6 alkoxy group on a phenyl ring.
[0022]
The optionally substituted benzyloxy group includes a benzyloxy group having 1 to 7 substituents such as a halogen atom, a C1 to C6 alkyl group or a C1 to C6 alkoxy group on the phenyl ring and at the benzyl position. .
[0023]
The optionally substituted phenoxycarbonyl group includes a phenoxycarbonyl group having 1 to 5 substituents such as a halogen atom, a C1 to C6 alkyl group or a C1 to C6 alkoxy group on a phenyl ring.
[0024]
Salt is a compound represented by the general formula [I], when a hydroxyl group, a carboxyl group, an amino group or the like is present in the structure thereof, a salt of these with a metal or an organic base, or a mineral acid or an organic acid. As the metal, an alkali metal such as sodium or potassium or an alkaline earth metal such as magnesium or calcium can be mentioned. As the organic base, triethylamine or diisopropylamine can be mentioned. As the mineral acid, Hydrochloric acid or sulfuric acid can be used, and acetic acid, methanesulfonic acid or p-toluenesulfonic acid can be used as the organic acid.
[0025]
In the general formula [I], as a preferable compound group, Q is a group —S (O)_n− (CR₅R₆)_mRepresents n, n represents 2, m represents 1, R₅And R₆Represents a hydrogen atom; R₁And R₂Represents a C1-C4 alkyl group;₃And R₄Represents a hydrogen atom, and Y represents (1 to 5 identical or different R₇A phenyl group)₇Is a hydrogen atom, a C1-C6 alkyl group (optionally substituted with 1 to 3 different or different halogen atoms), (optionally substituted with 1 to 3 different or different halogen atoms) Examples include a compound group represented by a C1 to C6 alkoxy group, a C1 to C6 alkoxycarbonyl group, a C2 to C6 alkynyloxy group, a halogen atom, a nitro group, or a cyano group.
[0026]
BEST MODE FOR CARRYING OUT THE INVENTION
The composition of the present invention generally depends on the relative activity of each component, but is generally a compound represented by the above formula [I] per 1 part by weight of at least one compound selected from Group A shown below. Is contained in an amount of 0.001 to 50 parts by weight, preferably 0.001 to 10 parts by weight.
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate
One active ingredient of the composition of the present invention is a compound represented by the formula [I], which itself has excellent herbicidal activity.
[0027]
In particular, rice, wheat, barley, corn, grain sorghum, soybean, cotton, sugar beet, turf, fruit trees and the like are less phytotoxic and various weeds that are problematic in the field, such as dog millet, meshishiba, enokorogosa, sparrow caterpillar, johnsongrass, wild grass In addition to grass weeds such as sparrow lily, wild oat, and other species such as oenoptera, sylvestris, shiroza, chickweed, ibis, american sika deer, broadleaf weeds of tsunoxanem, ragweed, morning glory, mulberry, etc. It exerts an excellent herbicidal effect over a wide range of growing seasons from before the germination of annual Cyperaceae weeds.
[0028]
Furthermore, annual weeds such as red snapper, tamaya-tsuri, oak and azalea, and perennial weeds such as oats, kuroguwai and firefly which occur in paddy fields can be controlled at a low dose in a wide range from before germination to the growing season.
[0029]
Representative examples of the compound represented by the general formula [I], which is one active ingredient of the composition of the present invention, are compounds selected from isoxazoline derivatives or salts thereof described in WO 01/012613. Are shown in Tables 1 and 2.
[0030]
[Table 1]

[0031]
[Table 2]

[0032]
Production examples of the compound represented by the formula [I] which can be used in the composition of the present invention can be produced by the methods shown in the following production examples, but are not limited thereto.
[0033]
<Production Example 1>
Production of 3-benzylthio-5,5-dimethyl-2-isoxazoline (Compound No. 1)
Under a nitrogen stream, 3.2 g (23.2 mmol) of anhydrous potassium carbonate and 3-chloro-5,5-dimethyl-2 were added to a solution of 2.8 g (22.5 mmol) of benzyl mercaptan in 50 ml of N, N-dimethylformamide. 3.0 g (22.5 mmol) of isoxazoline was added, and the mixture was stirred at 100 ° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow oily substance (refractive index n_D ²⁰= 1.5521) to give 3.1 g (62.0% yield) of 3-benzylthio-5,5-dimethyl-2-isoxazoline.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.24-7.39 (5H, m), 4.26 (2H, s), 2.77 (2H, s), 1.40 (6H, s)
[0034]
<Production Example 2>
Production of 5-ethyl-3- (2,6-difluorobenzylsulfinyl) -5-methyl-2-isoxazoline (Compound No. 2)
M-Chloroperbenzoic acid 4 was added to a solution of 4.1 g (15.0 mmol) of 5-ethyl-3- (2,6-difluorobenzylthio) -5-methyl-2-isoxazoline in 50 ml of chloroform under ice-cooling. 6.6 g (purity 70%, 18.8 mmol) was added and stirred for 1 hour, and further stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic phase was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of potassium carbonate, water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent system: hexane-ethyl acetate) to give 5-ethyl-3- (2,6-difluorobenzylsulfinyl) as a white powder (melting point: 30 ° C. or lower). 1.5 g (yield 34.8%) of -5-methyl-2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.39-7.28 (1H, m), 7.03-6.94 (2H, m), 4.38 (2H, s), 3.04 (1H, ABq) , J = 17.2, Δν = 85.7 Hz) +3.12 (1H, s), 1.75 (2H, m), 1.44 (3H, s) +1.41 (3H, s), 0.1. 97 (3H, m)
[0035]
<Production Example 3>
Production of 5-ethyl-3- (2,6-difluorobenzylsulfonyl) -5-methyl-2-isoxazoline (Compound No. 3)
M-Chloroperbenzoic acid 1 was added to a solution of 0.8 g (2.8 mmol) of 5-ethyl-3- (2,6-difluorobenzylsulfinyl) -5-methyl-2-isoxazoline in 50 ml of chloroform under ice-cooling. 0.0 g (purity 70%, 4.1 mmol) was added and stirred for 1 hour, and further stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed successively with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of potassium carbonate, water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent system: hexane-ethyl acetate) to give 5-ethyl-3- (2,6-difluorobenzyl) as a white powder (melting point: 64 to 65 ° C). 0.6 g (yield 75%) of sulfonyl) -5-methyl-2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.36-7.46 (1H, m), 6.98-7.04 (2H, m), 4.73 (2H, s), 3.04 (2H, ABq) , J = 17.2, Δν = 51.1 Hz), 1.77 (2H, q), 1.46 (3H, s), 0.97 (3H, t)
[0036]
<Production Example 4>
Production of 3- (2,6-difluorobenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 4)
8.5 g of m-chloroperbenzoic acid was added to a solution of 3.9 g (15.2 mmol) of 3- (2,6-difluorobenzylthio) -5,5-dimethyl-2-isoxazoline in 50 ml of chloroform under ice-cooling. (Purity 70%, 34.5 mmol), and the mixture was stirred for 1 hour, and further stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed successively with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of potassium carbonate, water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was washed with diisopropyl ether, and 3- (2,6-difluorobenzylsulfonyl) -5,5-dimethyl-2-isoxazoline as a white powder (melting point: 110 to 111 ° C.) 4 g (77% yield) were obtained.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.35-7.45 (1H, m), 6.98-7.03 (2H, m), 4.72 (2H, s), 3.06 (2H, s) ), 1.51 (6H, s)
[0037]
<Production Example 5>
Production of 3- (2,6-difluorobenzylthio) -5,5-dimethyl-2-isoxazoline (Compound No. 5)
To a solution of 5.0 g (28.2 mmol) of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline in 50 ml of N, N-dimethylformamide was added 4.5 g (purity) of sodium hydrosulfide hydrate under ice-cooling. 70%, 56.1 mmol), 7.8 g (56.4 mmol) of anhydrous potassium carbonate and 8.7 g (56.5 mmol) of Rongalite were added and stirred for 2 hours. Thereafter, 5.8 g (28.0 mmol) of 2,6-difluorobenzylbenzyl bromide was added, and the mixture was further stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with a saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3- (2,6-difluorobenzylthio) -5,5-dimethyl-2-isoxazoline as a white powder (melting point: 77 to 80 ° C.). 5.8 g (80% yield) was obtained.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.20-7.28 (1H, m), 6.86-6.93 (2H, m), 4.35 (2H, s), 2.81 (2H, s) ), 1.43 (6H, s)
[0038]
<Production Example 6>
Production of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline (Compound No. 6)
To a solution of 143.0 g (1.07 mol) of 3-chloro-5,5-dimethyl-2-isoxazoline in 500 ml of N, N-dimethylformamide was added 1000 g of an aqueous solution of sodium methylmercaptan (content 15%, 2. 14 mol), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with a saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 115.0 g (yield: 74%) of a crude product of 3-methylthio-5,5-dimethyl-2-isoxazoline. Then, 115.0 g (corresponding to 741.2 mmol) of a crude product of 3-methylthio-5,5-dimethyl-2-isoxazoline was dissolved in 11 of chloroform, and m-chloroperbenzoic acid (purity 70%) was cooled under ice-cooling. ) 392.0 g (1.59 mol) was added and stirred for 1 hour. Thereafter, the mixture was further stirred at room temperature for 12 hours. After completion of the reaction, the precipitated m-chlorobenzoic acid was filtered off, and the filtrate was washed with an aqueous solution of sodium hydrogen sulfite, water, an aqueous solution of sodium hydrogen carbonate and brine in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was washed with diisopropyl ether, and 77.6 g of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 82 to 84 ° C) (yield: 59.1). %).
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 3.26 (3H, s), 3.12 (2H, s), 1.51 (6H, s)
[0039]
<Production Example 7>
Production of 3- (5-chloro-2-difluoromethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 12)
[0040]
(1) Production of 5-chloro-2-difluoromethoxytoluene
In a solution of 7.1 g (50.0 mmol) of 4-chloro-2-methylphenol in 100 ml of N, N-dimethylformamide, 10.4 g (75.0 mmol) of anhydrous potassium carbonate was added. While stirring the reaction solution, chlorodifluoromethane was introduced at 50 ° C. After confirming the disappearance of the raw materials, the introduction of chlorodifluoromethane was stopped, and the reaction solution was cooled to room temperature. Thereafter, the reaction solution was poured into water and extracted with diisopropyl ether. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5.4 g (yield: 56.6%) of colorless and transparent crystals of 5-chloro-2-difluoromethoxytoluene.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.21 (1H, Δd)}, {7.15 (1H, Δq)}, {7.01 (1H, Δd)}, {6.47 (1H, Δt, ΔJ = 73.8 Hz)}, 2.26 (3H, Δs)
[0041]
(2) Production of 5-chloro-2-difluoromethoxybenzyl bromide
In a solution of 2.4 g (12.5 mmol) of 5-chloro-2-difluoromethoxytoluene in 30 ml of carbon tetrachloride, 2.2 g (12.5 mmol) of N-bromosuccinimide and 2,2′-azobis ( Isobutyronitrile) (0.2 g, 1.3 mmol) was added, and the mixture was heated under reflux for 2 hours under light irradiation. After the completion of the reaction, the mixture was cooled to room temperature and insolubles were separated by filtration. The solvent was distilled off under reduced pressure to obtain a crude product of 5-chloro-2-difluoromethoxybenzyl bromide.
[0042]
(3) Production of 3- (5-chloro-2-difluoromethoxybenzylthio) -5,5-dimethyl-2-isoxazoline
In a solution of 1.9 g (10.0 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide, 1.6 g of sodium hydrosulfide hydrate (purity 70%, 20 (0.0 mmol) and stirred for 1 hour. Thereafter, 1.4 g (10.0 mmol) of anhydrous potassium carbonate, 1.6 g (10.0 mmol) of Rongalite and the crude product of 5-chloro-2-difluoromethoxybenzylbromide obtained in (2) (12. (Equivalent to 5 mmol) and further stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 2.4 g of 3- (5-chloro-2-difluoromethoxybenzylthio) -5,5-dimethyl-2-isoxazoline (yield 74). 0.5%).
[0043]
(4) Production of 3- (5-chloro-2-difluoromethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 12)
M-chloroperbenzoic acid was added to a solution of 2.4 g (7.5 mmol) of 3- (5-chloro-2-difluoromethoxybenzylthio) -5,5-dimethyl-2-isoxazoline in 15 ml of chloroform under ice-cooling. 4.6 g (purity 70%, 18.6 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with n-hexane to give 3- (5-chloro-2-difluoromethoxybenzylsulfonyl) -5,5-dimethyl-white crystals (melting point: 53 to 54 ° C). 1.9 g (72.2% yield) of 2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.51 (1H, Δd)}, {7.39 (1H, Δq)}, {7.19 (1H, Δd)}, {6.52 (1H, Δt, ΔJ = 73.2 Hz)}, 4.69 (2H, {s)}, {3.02 (2H, {s)}, 1.49 (6H, {s)
[0044]
<Production Example 8>
Production of 3- (2-difluoromethoxy-5-methylbenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 16)
[0045]
(1) Production of 2-hydroxy-5-methylbenzoic acid methyl ester
To a solution of 25.0 g (164.3 mmol) of 5-methylsalicylic acid in 200 ml of N, N-dimethylformamide at room temperature was added 11.9 g (86.3 mmol) of anhydrous potassium carbonate and 24.5 g (172.5 mmol) of methyl iodide. ) And stirred overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic layer was washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 27.3 g of 2-hydroxy-5-methylbenzoic acid methyl ester (100% yield).
[0046]
(2) Production of methyl 2-difluoromethoxy-5-methylbenzoate
To a solution of 27.3 g (164.3 mmol) of 2-hydroxy-5-methylbenzoic acid methyl ester in 200 ml of N, N-dimethylformamide, 34.0 g (246.5 mmol) of anhydrous potassium carbonate was added at room temperature. While stirring the reaction solution, chlorodifluoromethane was introduced at 100 ° C. After confirming the disappearance of the raw materials (after about 4 hours), the introduction of chlorodifluoromethane was stopped, and the reaction solution was cooled to room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 25.3 g (yield: 71.3%) of 2-difluoromethoxy-5-methylbenzoic acid methyl ester as a yellow liquid.
[0047]
(3) Production of 2-difluoromethoxy-5-methylphenylmethanol
To a solution of 0.6 g (15 mmol) of lithium aluminum hydride in 30 ml of tetrahydrofuran was added dropwise a solution of 3.2 g (15 mmol) of 2-difluoromethoxy-5-methylbenzoic acid methyl ester in 10 ml of tetrahydrofuran at room temperature. After confirming the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 2-difluoromethoxy-5-methylphenylmethanol.
[0048]
(4) Production of 2-difluoromethoxy-5-methylbenzyl chloride
To a 30 ml solution of the crude product of 2-difluoromethoxy-5-methylphenylmethanol (corresponding to 15 mmol) obtained in (3) in 30 ml of chloroform was added 5.4 g (45 mmol) of thionyl chloride at room temperature, followed by stirring for 3 hours. Thereafter, the solvent was distilled off under reduced pressure to obtain a crude product of 2-difluoromethoxy-5-methylbenzyl chloride.
[0049]
(5) Production of 3- (2-difluoromethoxy-5-methylbenzylthio) -5,5-dimethyl-2-isoxazoline
To a solution of 1.0 g (5 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 20 ml of N, N-dimethylformamide, 0.8 g (purity 70%, 10 mmol) of sodium hydrosulfide hydrate Was added and stirred for 1 hour. Thereafter, 0.7 g (5 mmol) of anhydrous potassium carbonate, 0.7 g (5 mmol) of Rongalit and a crude product of 2-difluoromethoxy-5-methylbenzyl chloride obtained in (4) (equivalent to 15 mmol) were added. And further stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 1.5 g of 3- (2-difluoromethoxy-5-methylbenzylthio) -5,5-dimethyl-2-isoxazoline (yield: Quantitative).
[0050]
(6) Production of 3- (2-difluoromethoxy-5-methylbenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 16)
M-chloroperbenzoic acid was added to a solution of 1.5 g (5.0 mmol) of 3- (2-difluoromethoxy-5-methylbenzylthio) -5,5-dimethyl-2-isoxazoline in 30 ml of chloroform under ice-cooling. 3.1 g (purity 70%, 12.5 mmol) was added and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3- (2-difluoromethoxy-5-methylbenzylsulfonyl) -5,5-dimethyl- as pale yellow crystals (melting point: 71 to 73 ° C). 1.1 g (yield: 66.0%) of 2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.31 (1H, Δd)}, {7.21 (1H, Δq)}, {7.11 (1H, Δd)}, {6.50 (1H, Δt, ΔJ = 73.9 Hz)}, 4.67 (2H, s), 2.99 (2H, s), 2.36 (3H, s), 1.47 (6H, s)
[0051]
<Production Example 9>
Production of 3- (2-difluoromethoxy-5-methoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 17)
[0052]
(1) Production of methyl 2-hydroxy-5-methoxybenzoate
In a solution of 25.0 g (148.7 mmol) of 5-methoxysalicylic acid in 200 ml of N, N-dimethylformamide, at room temperature, 10.8 g (78.1 mmol) of anhydrous potassium carbonate and 21.1 g (148.7 mmol) of methyl iodide were added. ) And stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 14.6 g (yield 53.9%) of methyl 2-hydroxy-5-methoxybenzoate.
[0053]
(2) Preparation of 2-difluoromethoxy-5-methoxybenzoic acid methyl ester A solution of 14.6 g (80.1 mmol) of 2-hydroxy-5-methoxybenzoic acid methyl ester in 100 ml of N, N-dimethylformamide at room temperature. 13.3 g (96.2 mmol) of anhydrous potassium carbonate were added. While stirring the reaction solution, chlorodifluoromethane was introduced at 100 ° C. After confirming the disappearance of the raw materials (after about 6 hours), the introduction of chlorodifluoromethane was stopped, and the reaction solution was cooled to room temperature. Thereafter, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.5 g (yield 18.8%) of 2-difluoromethoxy-5-methoxybenzoic acid methyl ester as a yellow liquid.
[0054]
(3) Production of 2-difluoromethoxy-5-methoxyphenylmethanol
To a solution of 0.6 g (15.1 mmol) of lithium aluminum hydride in 30 ml of tetrahydrofuran was added dropwise a solution of 3.5 g (15.1 mmol) of 2-difluoromethoxy-5-methoxybenzoic acid methyl ester in 10 ml of tetrahydrofuran at room temperature. . After confirming the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 2-difluoromethoxy-5-methoxyphenylmethanol.
[0055]
(4) Production of 2-difluoromethoxy-5-methoxybenzyl chloride
To a solution of the crude product of 2-difluoromethoxy-5-methoxyphenylmethanol (equivalent to 15.1 mmol) obtained in (3) in 30 ml of chloroform, 5.4 g (45.3 mmol) of thionyl chloride was added at room temperature to obtain a solution. Stirred for hours. Thereafter, the solvent was distilled off under reduced pressure to obtain a crude product of 2-difluoromethoxy-5-methoxybenzyl chloride.
[0056]
(5) Production of 3- (2-difluoromethoxy-5-methoxybenzylthio) -5,5-dimethyl-2-isoxazoline
In a solution of 2.9 g (15.1 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide, 2.4 g of sodium hydrosulfide hydrate (purity 70%, 30%). .2 mmol) and stirred for 1 hour. Thereafter, 2.08 g (15.1 mmol) of anhydrous potassium carbonate and a crude product of 2-difluoromethoxy-5-methoxybenzyl chloride (corresponding to 15.1 mmol) obtained in (4) were added, and further added at room temperature. Stirred for hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, and 2.3 g of 3- (2-difluoromethoxy-5-methoxybenzylthio) -5,5-dimethyl-2-isoxazoline (yield 48). 0.0%).
[0057]
(6) Production of 3- (2-difluoromethoxy-5-methoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 17)
M-Chloroperbenzoic acid was added to a solution of 0.5 g (1.6 mmol) of 3- (2-difluoromethoxy-5-methoxybenzylthio) -5,5-dimethyl-2-isoxazoline in 10 ml of chloroform under ice-cooling. 1.0 g (purity 70%, 3.8 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed successively with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to give 3- (2-difluoromethoxy-5-methoxybenzylsulfonyl) -5,5-dimethyl-2- white crystal (melting point 70 to 71 ° C). 0.4 g (63.4% yield) of isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.17 (1H, d)}, {7.04 (1H, d)}, {6.93 (1H, q)}, 6.47 (1H, t, J = 74.1 Hz)}, 4.68 (2H, s), {3.81 (3H, s)}, 2.99 (2H, s), 1.47 (6H, s)
[0058]
<Production Example 10>
Production of 3- [2,3-bis (difluoromethoxy) benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (Compound No. 18)
[0059]
(1) Production of 2,3-bis (difluoromethoxy) toluene
In a solution of 5.0 g (40.3 mmol) of 3-methylcatechol in 100 ml of N, N-dimethylformamide, 12.3 g (89.0 mmol) of anhydrous potassium carbonate was added. While stirring the reaction solution, chlorodifluoromethane was introduced at room temperature. Stirred at 70 ° C. for 2 hours. After confirming the disappearance of the raw materials, the introduction of chlorodifluoromethane was stopped, and the reaction solution was cooled to room temperature. Thereafter, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.82 g (9.1% yield) of 2,3-bis (difluoromethoxy) toluene.
(¹H-NMR value (CDCl₃/ TMS) δ (ppm)): {7.17-7.09 (3H, m)}, 6.52 (1H, t, J = 75.0 Hz), 6.50 (1H, t, J = 73.6 Hz) ), 2.35 (3H, s)
[0060]
(2) Production of 2,3-bis (difluoromethoxy) benzyl bromide
In a solution of 0.82 g (3.66 mmol) of 2,3-bis (difluoromethoxy) toluene in 20 ml of carbon tetrachloride, 0.68 g (3.82 mmol) of N-bromosuccinimide and 2,2′-azobis 0.06 g (0.37 mmol) of (isobutyronitrile) was added, and the reaction solution was refluxed by light irradiation for 3 hours. After the completion of the reaction, the mixture was cooled to room temperature and insolubles were separated by filtration. The solvent was distilled off under reduced pressure to obtain a crude product of 2,3-bis (difluoromethoxy) benzyl bromide.
[0061]
(3) Production of 3- [2,3-bis (difluoromethoxy) benzylthio] -5,5-dimethyl-2-isoxazoline
To a solution of 0.73 g (3.82 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide was added 0.60 g of sodium hydrosulfide hydrate (purity 70%, 7%). .49 mmol) and stirred for 2 hours. Thereafter, 0.53 g (3.82 mmol) of anhydrous potassium carbonate, 0.59 g (3.82 mmol) of Rongalite and the crude product of 2,3-bisdifluoromethoxybenzylbromide obtained in 2) (3.66 mmol) E) was added to a solution of N, N-dimethylformamide in 20 ml, and the mixture was further stirred at room temperature for 11 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, and 0.87 g of 3- [2,3-bis (difluoromethoxy) benzylthio] -5,5-dimethyl-2-isoxazoline (yield 67). .3%).
(¹H-NMR value (CDCl₃/ TMS) δ (ppm)): {7.46 (1H, dd)}, {7.24-7.16 (2H, m)}, 6.60 (1H, t, J = 74.3 Hz), 6.52 ( 1H, {t, J = 73.2 Hz)}, {4.35 (2H, s)}, 2.78 (2H, s), 1.41 (6H, s)
[0062]
(4) Production of 3- [2,3-bis (difluoromethoxy) benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (Compound No. 18)
M-chloroperbenzoic acid was added to a solution of 0.87 g (2.46 mmol) of 3- (2,3-bis (difluoromethoxy) benzylthio) -5,5-dimethyl-2-isoxazoline in 30 ml of chloroform under ice-cooling. 1.52 g (purity 70%, 6.17 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with n-hexane to give 3- [2,3-bis (difluoromethoxy) benzylsulfonyl] -5,5-dimethyl white crystals (melting point: 84 to 86 ° C). 0.84 g of 2-isoxazoline (88.5% yield) was obtained.
(¹H-NMR value (CDCl₃/ TMS) δ (ppm)): {7.50-7.46 (1H, Δm)}, {7.34-7.32 (2H, Δm)}, {6.60 (1H, Δt, J = 73.6 Hz), 6.52 (1H, {t, J = 72.8 Hz)}, {4.74 (2H, s)}, {3.06 (2H, s)}, 1.49 (6H, s)
[0063]
<Production Example 11>
Production of 3- (4-chloro-2-difluoromethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 19)
[0064]
(1) Production of methyl 4-chlorosalicylate
1 ml of sulfuric acid was added to a solution of 5.0 g (29.0 mmol) of 4-chlorosalicylic acid in 50 ml of ethanol. The reaction solution was refluxed for 8 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, the residue was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed sequentially with water, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.05 g (yield: 52%) of methyl 4-chlorosalicylate.
[0065]
(2) Production of methyl 4-chloro-2-difluoromethoxybenzoate
1.71 g (30.0 mmol) of powdered potassium hydroxide and 0.10 g (0.31 mmol) of potassium hydroxide in a solution of 3.05 g (15.0 mmol) of 4-chlorosalicylic acid methyl ester in 30 ml of tetrahydrofuran Was added. Chlorodifluoromethane was introduced at room temperature while stirring the reaction solution. After confirming the disappearance of the raw materials, the introduction was stopped. The reaction solution was kept stirring at room temperature overnight. The insoluble material was separated by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 1.33 g (yield 35%) of methyl 4-chloro-2-difluoromethoxybenzoate.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.86 (1H, Δd)}, {7.29 (2H, Δm)}, {6.57 (1H, t, J = 74.2 Hz)}, {4.38 (2H, Δq), 1.38 (3H, t)
[0066]
(3) Production of 4-chloro-2-difluoromethoxyphenylmethanol
A solution of 1.33 g (5.3 mmol) of 4-chloro-2-difluoromethoxybenzoic acid methyl ester in 5 ml of tetrahydrofuran was added dropwise to a solution of 0.2 g (5.3 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran at room temperature. . After confirming the completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution. The solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-chloro-2-difluoromethoxyphenylmethanol.
[0067]
(4) Production of 4-chloro-2-difluoromethoxybenzyl chloride
To a dichloromethane solution of the crude product of 4-chloro-2-difluoromethoxyphenylmethanol (equivalent to 5.3 mmol) obtained in (3), 0.63 g (5.3 mmol) of thionyl chloride was added at room temperature for 2 hours. Stirred. Thereafter, the solvent was distilled off under reduced pressure to obtain a crude product of 4-chloro-2-difluoromethoxybenzyl chloride.
[0068]
(5) Production of 3- (4-chloro-2-difluoromethoxybenzyldithio) -5,5-dimethyl-2-isoxazoline
To a solution of 0.89 g (4.7 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 15 ml of N, N-dimethylformamide was added 0.75 g of sodium hydrosulfide hydrate (purity 70%, 9%). 0.3 mmol) and stirred for 1 hour. Thereafter, 0.65 g (4.7 mmol) of anhydrous potassium carbonate, 0.72 g (4.7 mmol) of Rongalite and the crude product of 4-chloro-2-difluoromethoxybenzyl chloride obtained in 4) (5.3). (Equivalent to 1 mmol) and further stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and 0.85 g of 3- (4-chloro-2-difluoromethoxybenzyldithio) -5,5-dimethyl-2-isoxazoline was obtained (yield 57%). ) Got.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.47 (1H, Δd)}, {7.16 (2H, Δm)}, {6.55 (1H, t, {J = 73.1 Hz)}, {4.25 (2H, Δs), 2.75 (2H, {s)}, 1.40 (6H, {s)
[0069]
(6) Production of 3- (4-chloro-2-difluoromethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 19)
M-chloroperbenzoic acid was added to a solution of 3- (4-chloro-2-difluoromethoxybenzylthio) -5,5-dimethyl-2-isoxazoline 0.85 g (2.6 mmol) in 20 ml of chloroform under ice-cooling. 1.63 g (purity 70%, 6.6 mmol) was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 0.80 g of 3- (4-chloro-2-difluoromethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline as white crystals (melting point: 80 to 82 ° C.) (86 yield) %).
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.47 (1H, Δd)}, {7.28 (2H, Δm)}, {6.54 (1H, t, {J = 73.1 Hz)}, {4.70 (2H, Δs), 3.02 (2H, {s)}, 1.48 (6H, {s)
[0070]
<Production Example 12>
Production of 2- (5,5-dimethylisoxazolin-3-ylsulfonylmethyl) -3-fluorobenzonitrile (Compound No. 22)
[0071]
(1) Production of methyl 3-fluoro-2-methylbenzoate
In a solution of 4.8 g (31.1 mmol) of 3-fluoro-2-methylbenzoic acid in 50 ml of N, N-dimethylformamide, at room temperature, 4.3 g (31.1 mmol) of anhydrous potassium carbonate and 4.4 g of methyl iodide. (31.1 mmol) was added and stirred overnight. After confirming the completion of the reaction, the reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5.2 g (yield 99.4%) of 3-fluoro-2-methylbenzoic acid methyl ester.
[0072]
(2) Production of methyl 2-bromomethyl-3-fluorobenzoate
To a solution of 8.5 g (50.5 mmol) of 3-fluoro-2-methylbenzoic acid methyl ester in 100 ml of carbon tetrachloride was added 9.5 g (53.1 mmol) of N-bromosuccinimide and 2,2 ′ at room temperature. 0.9 g (5.3 mmol) of azobis (isobutyronitrile) were added. The reaction solution was refluxed for 2.5 hours. After the completion of the reaction, the mixture was cooled to room temperature and insolubles were separated by filtration. The solvent was distilled off under reduced pressure to obtain a crude product of 2-bromomethyl-3-fluorobenzoic acid methyl ester.
[0073]
(3) Production of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) 3-fluorobenzoic acid methyl ester
To a solution of 9.6 g (50 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 100 ml of N, N-dimethylformamide, 8.0 g (purity 70%, 100 mmol) of sodium hydrosulfide hydrate was added. Was added and stirred for 1 hour. Thereafter, 6.9 g (50 mmol) of anhydrous potassium carbonate, 7.9 g (50 mmol) of Rongalite and a crude product of methyl 2-bromomethyl-3-fluorobenzoate obtained in (4) (50. (Equivalent to 5 mmol), and the mixture was further stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography, and 7.3 g of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzoic acid methyl ester was obtained (yield 49.9%). ) Got.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.72 (1H, Δd)}, {7.37 to 7.21 (2H, Δm)}, {4.69 (2H, Δs)}, {3.94 (3H, Δs), 2. 78 (2H, {s)}, 1.40 (6H, {s)
[0074]
(4) Production of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzoic acid
In a solution of 14.3 g (48.1 mmol) of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzoic acid methyl ester in 100 ml of tetrahydrofuran, 2.3 g of sodium hydroxide (57. (7 mmol) was added, and the mixture was stirred overnight. After confirming the completion of the reaction, the reaction solution was poured into water, the pH was adjusted to 4, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 10.6 g of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzoic acid (yield 77.9%).
[0075]
(5) Production of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzamide
0.73 g of N, N'-carbonyldiimidazole in a solution of 0.85 g (3.0 mmol) of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzoic acid in 10 ml of tetrahydrofuran at room temperature (4.5 mmol) and stirred for 1 hour. Further, 10 ml of 28% aqueous ammonia was added to the reaction solution, followed by stirring overnight. After confirming the completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. After the obtained organic layer was washed with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.84 g (yield 99.3%) of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzamide.
[0076]
(6) Production of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzonitrile
0.47 g (5.95 mmol) of pyridine was added at room temperature to a solution of 0.84 g (2.98 mmol) of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzamide in 10 ml of 1,4-dioxane. ), And 0.75 g (3.57 mmol) of trifluoroacetic anhydride was added under ice-cooling, followed by stirring at room temperature for 4 hours. After confirming the completion of the reaction, the reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography, and 0.64 g of white powder of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzonitrile (yield: 81. 0%).
[0077]
(7) Production of 2- (5,5-dimethylisoxazolin-3-ylsulfonylmethyl) -3-fluorobenzonitrile (Compound No. 22)
To a solution of 0.64 g (2.42 mmol) of 2- (5,5-dimethylisoxazolin-3-ylthiomethyl) -3-fluorobenzonitrile in 20 ml of chloroform was added 1.49 g of m-chloroperbenzoic acid under ice-cooling. (Purity 70%, 6.05 mmol) and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 0.51 g of 2- (5,5-dimethylisoxazolin-3-ylsulfonylmethyl) -3-fluorobenzonitrile as white crystals (melting point: 112 to 114 ° C) (yield: 71.1) %).
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.61-7.41} (3H, Δm), 4.89 (2H, Δs), 3.16 (2H, Δs), 1.54 (6H, Δs)
[0078]
<Production Example 13>
Production of 3- [2,3-dichloro-6- (2,2,2-trifluoroethoxy) benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (Compound No. 30)
[0079]
(1) Production of 3,4-dichloro-2-hydroxymethylphenol
10.0 g (61.0 mmol) of 3,4-dichlorophenol and 18.4 g (610.0 mmol) of paraformaldehyde are suspended in 50 ml of water, and 49 g (310.0 mmol) of a 25% aqueous solution of sodium hydroxide are added thereto. Was added. The reaction solution was stirred at 60 ° C. for 12 hours. The reaction solution was cooled to room temperature, and then poured into water, made acidic with an aqueous citric acid solution, and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.5 g of white crystals of 3,4-dichloro-2-hydroxymethylphenol (yield 21%).
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {8.42 (1H, Δs)}, {7.25 (1H, Δd)}, {6.75 (1H, Δd)}, {5.15 (2H, s)}, {2.58 (1H, s)
[0080]
(2) Production of [2,3-dichloro-6- (2,2,2-trifluoroethoxy) phenyl] methanol
In a solution of 1.0 g (5.2 mmol) of 3,4-dichloro-2-hydroxymethylphenol in 20 ml of N, N-dimethylformamide, 0.72 g (5.2 mmol) of anhydrous potassium carbonate and trifluoromethanesulfonic acid 2 , 2,2-trifluoroethyl 1.21 g (5.2 mmol) were added. The reaction solution was stirred overnight at room temperature. After confirming the disappearance of the raw materials, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain [2,3-dichloro-6- (2,2,2-trifluoroethoxy) phenyl] methanol.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): {7.41 (1H, d)}, 6.78 (1H, d), 4.92 (2H, s), 4.41 (2H, q).
[0081]
(3) Production of 2,3-dichloro-6- (2,2,2-trifluoroethoxy) benzyl bromide
To a solution of 1.43 g (equivalent to 5.2 mmol) of [2,3-dichloro-6- (2,2,2-trifluoroethoxy) phenyl] methanol in 20 ml of diethyl ether, 0.71 g of phosphorus tribromide (2. 6 mmol) and stirred for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with diethyl ether. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 2,3-dichloro-6- (2,2,2-trifluoroethoxy) benzyl bromide.
[0082]
(4) Production of 3- [2,3-dichloro-6- (2,2,2-trifluoroethoxy) benzylthio] -5,5-dimethyl-2-isoxazoline
To a solution of 1.00 g (5.2 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide was added 0.84 g of sodium hydrosulfide hydrate (purity 70%, 10%). (0.0 mmol) and stirred for 2 hours. Then, 0.72 g (5.2 mmol) of anhydrous potassium carbonate, Rongalit (CH₂(OH) SO₂Na ・ 2H₂O) 0.80 g (5.2 mmol) and the crude product of 2,3-dichloro-6- (2,2,2-trifluoroethoxy) benzyl bromide obtained in (3) (equivalent to 5.2 mmol) ) In N, N-dimethylformamide (20 ml) was added, and the mixture was further stirred at room temperature for 11 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3- [2,3-dichloro-6- (2,2,2-trifluoroethoxy)] benzylthio] -5,5-dimethyl- 0.70 g (yield 34%) of 2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS) δ (ppm)): {7.38 (1H, dd)}, 6.76 (1H, d), 4.55 (2H, s), 4.40 (2H, q), 2.82 (2H) , {S)}, {1.43 (6H, {s)
[0083]
(5) Production of 3- [2,3-dichloro-6- (2,2,2-trifluoroethoxy) benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (Compound No. 30)
To a solution of 0.70 g (1.8 mmol) of 3- [2,3-dichloro-6- (2,2,2-trifluoroethoxy)] benzylthio] -5,5-dimethyl-2-isoxazoline in 15 ml of chloroform. Under ice-cooling, 1.11 g (purity 70%, 4.5 mmol) of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with n-hexane to give 3- [2,3-dichloro-6- (2,2,2-trifluoroethoxy) as white crystals (melting point: 135 to 137 ° C). ) Benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (0.62 g, yield 82%).
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.51 (1H, Δd)}, {6.87 (1H, Δd)}, {5.06 (2H, Δs)}, {4.45 (2H, Δq)}, {3.08 (2H, 2H, s), 1.52 (6H, s)
[0084]
<Production Example 14>
Production of 3- [2,3-dichloro-6- (2-propynyloxy) benzylthio] -5,5-dimethyl-2-isoxazoline (Compound No. 32)
[0085]
(1) Production of [2,3-dichloro-6- (2-propynyloxy) phenyl] methanol
In a solution of 1.0 g (5.2 mmol) of 3,4-dichloro-2-hydroxymethylphenol in 20 ml of N, N-dimethylformamide, 0.72 g (5.2 mmol) of anhydrous potassium carbonate and 0.3 g of 3-bromopropyne were added. 62 g (5.2 mmol) were added. The reaction solution was stirred overnight at room temperature. After confirming the disappearance of the raw materials, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain [2,3-dichloro-6- (2-propynyloxy) phenyl] methanol.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.38 (1H, Δd)}, {6.92 (1H, Δd)}, 4.90 (2H, Δs), 4.76 (2H, d), 2.55 (1H, t), 2.27 (1H, s)
[0086]
(2) Production of 2,3-dichloro-6- (2-propynyloxy) benzyl bromide
To a solution of 1.20 g (equivalent to 5.2 mmol) of [2,3-dichloro-6- (2-propynyloxy) phenyl] methanol in 20 ml of diethyl ether, 0.71 g (2.6 mmol) of phosphorus tribromide was added. Stir for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with diethyl ether. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 2,3-dichloro-6- (2-propynyloxy) benzyl bromide.
[0087]
(3) Production of 3- [2,3-dichloro-6- (2-propynyloxy) benzylthio] -5,5-dimethyl-2-isoxazoline
To a solution of 1.00 g (5.2 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide was added 0.84 g of sodium hydrosulfide hydrate (purity 70%, 10%). (0.0 mmol) and stirred for 2 hours. Then, 0.72 g (5.2 mmol) of anhydrous potassium carbonate, Rongalit (CH₂(OH) SO₂Na ・ 2H₂O) N, N of 0.80 g (5.2 mmol) and the crude product of 2,3-dichloro-6- (2-propynyloxy) benzyl bromide (equivalent to 5.2 mmol) obtained in (2) -A solution of 20 ml of dimethylformamide was added, and the mixture was further stirred at room temperature for 11 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3- [2,3-dichloro-6- (2-propynyloxy) benzylthio] -5,5-dimethyl-2-isoxazoline. 81 g (46% yield) were obtained.
(¹H-NMR value (CDCl₃/ TMS) δ (ppm)): {7.38 (1H, d)}, 6.93 (1H, d), 4.76 (2H, d), 4.54 (2H, s), 2.83 (2H) , {S)}, {1.43 (6H, {s)
[0088]
(4) Production of 3- [2,3-dichloro-6- (2-propynyloxy) benzylthio] -5,5-dimethyl-2-isoxazoline (Compound No. 32)
A solution of 0.81 g (2.4 mmol) of 3- [2,3-dichloro-6- (2-propynyloxy) benzylthio] -5,5-dimethyl-2-isoxazoline in 15 ml of chloroform was added with m. 1.45 g (purity 70%, 5.9 mmol) of -chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with n-hexane to give 3- [2,3-dichloro-6- (2-propynyloxy) benzylthio] -5 as white crystals (melting point: 113 to 115 ° C). 0.67 g (yield 75%) of 1,5-dimethyl-2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.47 (1H, Δd)}, 7.02 (1H, Δd), {5.03 (2H, Δs), {4.77 (2H, Δd)}, {3.05 (2H, s), 2.56 (1H, s), 1.50 (6H, s)
[0089]
<Production Example 15>
Production of 3- [2,3-dichloro-6- (2,2-difluoroethoxy) benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (Compound No. 33)
[0090]
(1) Production of 2,2-difluoroethyl methanesulfonate
To a solution of 0.5 g (6.1 mmol) of 2,2-difluoroethanol and 0.68 g (6.7 mmol) of triethylamine in 15 ml of dichloromethane was added 0.77 g (6.7 mmol) of methanesulfonyl chloride in dichloromethane under ice-cooling. 5 ml of the solution was added dropwise. After completion of the dropwise addition, the reaction solution was stirred at 10 ° C. or lower for 1 hour. The reaction solution was poured into water and extracted with dichloromethane. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 2,2-difluoroethyl methanesulfonate.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 6.01 (1H, tt, J = 3.68, J = 54.59), 4.38 (2H, tt, J = 3.92, J = 13.19), 3.12 (2H, s)
[0091]
(2) Production of [2,3-dichloro-6- (2,2-difluoroethoxy) phenyl] methanol
In a solution of 1.0 g (5.2 mmol) of 3,4-dichloro-2-hydroxymethylphenol in 20 ml of N, N-dimethylformamide, 0.72 g (5.2 mmol) of anhydrous potassium carbonate and (1) were obtained. 0.92 g (corresponding to 6.1 mmol) of the obtained 2,2-difluoroethyl methanesulfonate was added. The reaction solution was stirred at 70 ° C. for 18 hours. After confirming the disappearance of the raw materials, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of [2,3-dichloro-6- (2,2-difluoroethoxy) phenyl] methanol.
[0092]
(3) Production of 2,3-dichloro-6- (2,2-difluoroethoxy) benzyl bromide
0.83 g (3.1 mmol) of phosphorus tribromide was added to a solution of 1.57 g (equivalent to 6.1 mmol) of [2,3-dichloro-6- (2,2-difluoroethoxy) phenyl] methanol in 20 ml of diethyl ether. Was added and stirred for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with diethyl ether. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 2,3-dichloro-6- (2,2-difluoroethoxy) benzyl bromide.
[0093]
(4) Production of 3- [2,3-dichloro-6- (2,2-difluoroethoxy) benzylthio] -5,5-dimethyl-2-isoxazoline
To a solution of 1.17 g (6.1 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide was added 0.98 g of sodium hydrosulfide hydrate (purity 70%, 12%). (0.0 mmol) and stirred for 2 hours. Thereafter, 0.84 g (6.1 mmol) of anhydrous potassium carbonate, 0.94 g (6.1 mmol) of Rongalite and 2,3-dichloro-6- (2,2-difluoroethoxy) benzyl obtained in (3) A solution of a crude bromide product (equivalent to 6.1 mmol) in N, N-dimethylformamide (20 ml) was added, and the mixture was further stirred at room temperature for 11 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3- [2,3-dichloro-6- (2,2-difluoroethoxy)] benzylthio] -5,5-dimethyl-2-iso- 0.40 g of oxazoline (18% yield) was obtained.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.38 (1H, d), 6.76 (1H, d), 6.15 (1H, tt, J = 4.02, J = 54.88), 4.55 (1H, s), 4.22 (2H, tt, J = 4.02, J = 12.62), 2.81 (1H, s), 1.43 (6H, s)
[0094]
(5) Production of 3- [2,3-dichloro-6- (2,2-difluoroethoxy) benzylsulfonyl] -5,5-dimethyl-2-isoxazoline (Compound No. 33)
A solution of 0.40 g (1.1 mmol) of 3- [2,3-dichloro-6- (2,2-difluoroethoxy)] benzylthio] -5,5-dimethyl-2-isoxazoline in 15 ml of chloroform was ice-cooled. Below, 0.67 g (purity 70%, 2.7 mmol) of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with n-hexane to give 3- [2,3-dichloro-6- (2,2-difluoroethoxy) benzylsulfonyl as white crystals (melting point: 118 to 120 ° C.). 0.45 g (yield 95%) of -5,5-dimethyl-2-isoxazoline was obtained.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 7.48 (1H, s), 6.85 (1H, d), 6.16 (1H, tt, J = 4.21, J = 55.06), 5.05 (1H, s), 4.25 (2H, tt, J = 4.20, J = 12.83), 2.81 (1H, s), 1.43 (6H, s)
[0095]
<Production Example 16>
Production of 3- (2,5-dichloro-4-ethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 47)
[0096]
(1) Production of 2,5-dichloro-4-hydroxymethylphenol
5.0 g (31.0 mmol) of 2,5-dichlorophenol and 9.21 g (310,0 mmol) of paraformaldehyde were suspended in 30 ml of water, and 25 g (150.0 mmol) of a 25% aqueous solution of sodium hydroxide was added thereto. added. The reaction solution was stirred at 70 ° C. for 12 hours. The reaction solution was cooled to room temperature, and then poured into water, made acidic with an aqueous citric acid solution, and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.45 g (41% yield) of white crystals of 2,5-dichloro-4-hydroxymethylphenol.
(¹H-NMR value (DMSO-d₆Δ (ppm)): 10.51 (1H, s), 7.41 (1H, s), 6.96 (1H, s), 5.30 (1H, s), 4.41 (2H, s)
[0097]
(2) Production of (2,5-dichloro-4-ethoxyphenyl) methanol
In a solution of 1.23 g (6.3 mmol) of 2,5-dichloro-4-hydroxymethylphenol in 25 ml of N, N-dimethylformamide, 0.88 g (6.3 mmol) of anhydrous potassium carbonate and 0.99 g of iodoethane ( 6.3 mmol). The reaction solution was stirred overnight at room temperature. After confirming the disappearance of the raw materials, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (2,5-dichloro-4-ethoxyphenyl) methanol.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.47 (1H, Δs)}, {6.92 (1H, Δs)}, {4.68 (2H, s)}, {4.08 (2H, Δq), 1.47 (3H, t)
[0098]
(3) Production of (2,5-dichloro-4-ethoxy) benzyl bromide
0.85 g (3.2 mmol) of phosphorus tribromide was added to a solution of 1.40 g (equivalent to 6.3 mmol) of (2,5-dichloro-4-ethoxyphenyl) methanol in 20 ml of diethyl ether, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with diethyl ether. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of (2,5-dichloro-4-ethoxy) benzyl bromide.
[0099]
(4) Production of 3- (2,5-dichloro-4-ethoxybenzylthio) -5,5-dimethyl-2-isoxazoline
To a solution of 1.20 g (6.3 mmol) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline in 30 ml of N, N-dimethylformamide was added 1.01 g of sodium hydrosulfide hydrate (purity 70%, 13%). (0.0 mmol) and stirred for 2 hours. Thereafter, 0.87 g (6.3 mmol) of anhydrous potassium carbonate and Rongalit (CH₂(OH) SO₂Na ・ 2H₂O) N, N-dimethylformamide of 0.97 g (6.3 mmol) and a crude product of (2,5-dichloro-4-ethoxy) benzyl bromide (corresponding to 6.3 mmol) obtained in (3) A 20 ml solution was added, and the mixture was further stirred at room temperature for 11 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 1.53 g of 3- (2,5-dichloro-4-ethoxybenzylthio) -5,5-dimethyl-2-isoxazoline (yield). 73%).
(¹H-NMR value (CDCl₃/ TMS) δ (ppm)): {7.51 (1H, s)}, 6.92 (1H, s), 4.29 (2H, s), 4.08 (2H, Ｈq), 2.77 (2H) , {S)}, 1.46 (3H, t), 1.41 (6H, s)
[0100]
(5) Production of 3- (2,5-dichloro-4-ethoxybenzylsulfonyl) -5,5-dimethyl-2-isoxazoline (Compound No. 47)
M-chloroperbenzoic acid was added to a solution of 1.53 g (4.6 mmol) of 3- (2,5-dichloro-4-ethoxybenzylthio) -5,5-dimethyl-2-isoxazoline in 15 ml of chloroform under ice-cooling. 2.82 g (purity 70%, 11.0 mmol) of acid was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed sequentially with an aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with n-hexane to give 3- (2,5-dichloro-4-ethoxybenzylsulfonyl) -5,5-dimethyl white crystals (melting point: 155 to 156 ° C). 1.39 g of 2-isoxazoline (83% yield) was obtained.
(¹H-NMR value (CDCl₃/ TMS {δ (ppm)): {7.51 (1H, s)}, {6.92 (1H, s)}, {4.29 (2H, s)}, {4.07 (2H, sq)}, 2.77 (2H, s). s), 1.47 (3H, t), 1.41 (6H, s)
[0101]
(Example of production of intermediate)
<Reference Example 1>
Production of 3-chloro-5,5-dimethyl-2-isoxazoline
To a solution of 182.7 g (2.05 mol) of glyoxylic acid aldoxime in 2 l of dimethoxyethane was added slowly 534.0 g (4.0 mol) of N-chlorosuccinimide at 65 to 70 ° C, and then heated for 1 hour. Refluxed. After adding 1440.0 g (14.4 mol) of potassium hydrogen carbonate and 10 ml of water under ice cooling, 360.0 g (6.4 mol) of 2-methylpropene was added to the reaction solution, followed by stirring at room temperature for 24 hours. The reaction solution was poured into water and extracted with isopropyl ether. The obtained organic layer was washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 107.7 g (yield: 40.0%) of 3-chloro-5,5-dimethyl-2-isoxazoline as a yellow viscous liquid.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 2.93 (2H, s), 1.47 (6H, s)
[0102]
<Reference Example 2>
Production of 3-chloro-5-ethyl-5-methyl-2-isoxazoline
To a solution of 20.6 g (231.7 mmol) of glyoxylic acid aldoxime in 500 ml of dimethoxyethane, 61.9 g (463.4 mmol) of N-chlorosuccinimide was gradually added at 60 ° C. After the addition was completed, the mixture was heated under reflux for 10 minutes. Next, 50 ml (463.4 mmol) of 2-methyl-1-butene, 98.9 g (1622 mmol) of potassium hydrogen carbonate and 10 ml of water were added under ice cooling, and the mixture was stirred for 12 hours. The reaction solution was poured into water and extracted with n-hexane. The obtained organic layer was washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 13.9 g (yield: 40.6%) of 3-chloro-5-ethyl-5-methyl-2-isoxazoline as a pale yellow viscous liquid.
(¹H-NMR value (CDCl₃/ TMS δ (ppm)): 2.91 (2H, Abq, J = 17.0, Δν = 46.1 Hz), 1.73 (2H, q), 1.42 (3H, s), 0.96 (3H, t)
[0103]
The composition of the present invention is to provide an effective herbicidal composition for selectively controlling a wide range of weeds and for applying to new cultivation methods such as no-tillage cultivation, In particular, the main weeds in the corn field, such as buckwheat, sanaetade, suberhideum, shiroza, aogetou, haragarashi, tsunoxanem, ibisgusa, ibis, american godzica, american morning glory, malva sagao, swordfish, swordfish And dicots such as convolvulus biloba, euphorbia, american rosemary, ragweed, and monocotyledonous plants such as dog millet, enokorogosa, achinohokorogosa, kinenookoro, meshishiba, ohishiba, seiban sorghum, shibamugi, and shatter cane. No phytotoxicity, such as a problem with respect to soybean crop after corn and corn are crops.
[0104]
In order to use the herbicidal composition of the present invention as a herbicide, the herbicidal composition may be used in the form of a mixture without adding other components. Can be formulated into wettable powders, granules, fine granules, powders, emulsions, aqueous solvents, suspensions, flowables and the like.
[0105]
Carriers used in the formulation include, for example, talc, bentonite, clay, kaolin, diatomaceous earth, white carbon, vermiculite, calcium carbonate, slaked lime, silica sand, ammonium sulfate, urea and other solid carriers, isopropyl alcohol, xylene, cyclohexane, methylnaphthalene, etc. And the like.
[0106]
Examples of the surfactant and dispersant include metal salts of alkylbenzene sulfonic acid, metal salts of alkyl naphthalene sulfonic acid formalin condensate, alcohol sulfates, alkyl aryl sulfonates, lignin sulfonates, polyoxyethylene glycol ethers, and polyoxyethylene glycols. Ethylene alkyl aryl ether, polyoxyethylene sorbitan monoalkylate and the like can be mentioned. Examples of the auxiliary include carboxymethylcellulose, polyethylene glycol, gum arabic and the like.
[0107]
The composition of the present invention can also be prepared by formulating each active ingredient by the above-mentioned formulation technique and then mixing them. The composition of the present invention thus formulated is applied to a plant body as it is or diluted with water or the like. The composition of the present invention can further be expected to enhance herbicidal efficacy by being used in combination with other herbicides, and can also be used in combination with insecticides, fungicides, plant growth regulators, fertilizers, soil improvers, and the like. it can.
[0108]
The application amount of the composition of the present invention is such that the total amount of one selected from isoxazoline derivatives represented by the formula [I], which is an active ingredient compound, and at least one selected from the following group A is generally 0.5. -90% by weight, preferably 1-80% by weight.
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate
[0109]
【Example】
Next, examples will be described. In the following examples, parts are parts by weight.
[0110]
<Formulation example 1> wettable powder
5 parts of compound 1, 40 parts of cyanazine, 0.5 part of polyoxyethylene octyl phenyl ether, 0.5 part of sodium salt of alkylnaphthalenesulfonic acid formalin condensate, 12 parts of diatomaceous earth, and 42 parts of clay are mixed and ground. To obtain a wettable powder.
[0111]
Although it may vary depending on the mixing ratio, weather conditions, formulation, application time, application method, location of application, weeds to be controlled and target crops, the total amount of the active ingredient compound per hectare is usually 50 to 1500 g. Emulsions, wettable powders, suspending agents and the like are applied by diluting a predetermined amount thereof with water of usually 100 to 1000 liters per hectare.
[0112]
Next, the effects of the herbicidal composition of the present invention will be described with reference to test examples.
<Test example> (1) Test for weeding effect on weeds by upland soil treatment
80cm²A plastic pot was filled with field soil, and seeds of Enocologha and Shiroza were sown and covered. The wettable powder prepared according to Formulation Example 1 was weighed so that the active ingredient became a predetermined amount, diluted with water, and uniformly sprayed on the soil surface with a small sprayer at a spraying water amount of 100 l per 10 ares. Thereafter, the plants were grown in a greenhouse, and on the 30th day of the treatment, the herbicidal effect was investigated according to the criteria in Table 3. Table 4 shows the results.
[0113]
[Table 3]

[0114]
[Table 4]

[0115]
【The invention's effect】
When at least one herbicide selected from the group A shown below is mixed and applied to the compound represented by the general formula [I] at a predetermined ratio, not only the sum of the activities obtained by each single agent but also the synergistic effect is obtained. Various weeds that are effectively herbicidally effective and are problematic in the field, such as grasses such as barnyardgrass, meadowgrass, enokorogusa, sparrowgrass, johnsongrass, nosymenotepou, wild oat, etc. Perennial and annual perennial and perennial cyperaceous weeds, such as, butterflies, stingrays, stag beetles, sedge horns, ragweed, morning glory, broadleaf weeds, astragalus, yellow croaker, cyperaceae, and cyperaceous weeds. Exhibits an excellent weeding effect.
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate
Furthermore, annual weeds such as red snapper, tamaya-tsuri, oak and azalea, and perennial weeds such as oats, kuroguwai and firefly which occur in paddy fields can be controlled at a low dose in a wide range from before germination to the growing season.
[0116]
On the other hand, the herbicidal composition of the present invention has high safety against crops, and particularly shows high safety against rice, wheat, barley, corn, grain sorghum, soybean, cotton, sugar beet, turf, fruit trees and the like.

Claims (4)

General formula [I]

In the formula, Q represents a group —S (O) _n — (CR ₅ R ₆ ) _m —, n represents an integer of 0 to 2, m represents an integer of 1 to 3, R ₅ and R ₆ Independently represent a hydrogen atom, a cyano group, an alkoxycarbonyl group or a C1-C6 alkyl group,
R ₁ and R ₂ represent a hydrogen atom, [C3-C8 cycloalkyl group, C1-C6 alkoxy group, C1-C6 alkylcarbonyl group, C1-C6 alkylthio group, C1-C6 alkylsulfinyl group, C1-C6 alkylsulfonyl group, C1-C6 alkylamino group, di (C1-C6 alkyl) amino group, cyano group, C1-C6 alkoxycarbonyl group, C1-C6 alkylaminocarbonyl group, di (C1-C6 alkyl) aminocarbonyl group, (C1-C6 Alkylthio) carbonyl, carboxyl, benzyloxy (optionally substituted), phenoxy (optionally substituted) or phenyl (optionally substituted) phenyl] -C8 alkyl group, C3-C8 cycloalkyl group, C1-C6 alkoxycar Alkenyl groups, C1 -C6 alkylaminocarbonyl group, di (C1 -C6 alkyl) aminocarbonyl group, C1 -C6 alkyl thio group, a carboxyl group, or (optionally substituted) phenyl group, or _{R 1} and R ₂ may form a C3-C7 spiro ring together with these bonded carbon atoms,
R ₃ and R ₄ are a hydrogen atom, a C1 to C8 alkyl group (which may be substituted with 1 to 3 identical or different halogen atoms, a C3 to C8 cycloalkyl group or a C1 to C6 alkoxy group) or a C3 to C4 C8 cycloalkyl group, _{R 3} and _{R 4} may form a spiro ring of C3~C7 with these bonded carbon atoms, or _{R 1,} R 2, _{R 3} and _{R 4} have these binding It may form a 5- to 8-membered ring together with the carbon atom,
Y is a hydrogen atom, a C1-C6 alkoxycarbonyl group, a carboxyl group, a C2-C6 alkenyl group, [the same or different one to three halogen atoms, a C1-C6 alkoxy group, a C2-C6 alkenyloxy group, a C2-C6 An alkynyloxy group, a benzyloxy group (optionally substituted), a C1-C6 alkoxycarbonyl group, a carboxyl group, a hydroxyl group or a formyl group which may be substituted] a C1-C10 alkyl group or (1-5 A phenyl group (substituted with the same or different R ₇ )
R ₇ is a hydrogen atom, [1 to 3 identical or different halogen atoms, C1 to C6 alkoxy group, hydroxyl group, C1 to C6 alkylthio group, C1 to C6 alkylsulfinyl group, C1 to C6 alkylsulfonyl group, C1 to C6 Alkylamino group, C1-C6 dialkylamino group, cyano group or (optionally substituted), which may be substituted with phenoxy] C1-C6 alkyl group, (1 to 3 identical or different halogen atoms, A C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyl group or a C3-C8 cycloalkyl group which may be substituted) Groups, C2-C6 alkenyl groups, C3-C8 cycloalkyloxy groups, (identical or May be substituted with different 1 to 3 halogen atoms or C1 to C6 alkoxy groups) C1 to C6 alkylthio group, (substituted with the same or different 1 to 3 halogen atoms or C1 to C6 alkoxy groups) C1 to C6 alkylsulfinyl group (optionally substituted), C1 to C6 alkylsulfonyl group (which may be substituted with 1 to 3 identical or different halogen atoms or C1 to C6 alkoxy group), (substituted Substituted with a benzyloxy group, a (C1-C6 alkyl group, a C1-C6 alkylsulfonyl group, a C1-C6 alkylcarbonyl (C1-C6 alkyl) group or a C1-C6 alkylsulfonyl (C1-C6 alkyl) group) Amino group, halogen atom, cyano group, nitro group, C1-C6 alkoxycarbonyl , A C3-C8 cycloalkyloxycarbonyl group, a carboxyl group, a C2-C6 alkenyloxycarbonyl group, a C2-C6 alkynyloxycarbonyl group, a (optionally substituted) benzyloxycarbonyl group, (optionally substituted) Represents a phenoxycarbonyl group or a C1 to C6 alkylcarbonyloxy group. A herbicidal composition comprising an isoxazoline derivative represented by｝ or a salt thereof, and at least one member selected from the group A shown below.
Group A: atrazine, simazine, cyanazine, isoxaflutol, flumeturam, imazethapyr, imazapyr, dicamba, clopyralid, prosulfuron, halosulfuron-methyl, rimsulfuron, bentazon, carfentrazone-ethyl, metribuzin, thifensulfuron-ethyl Methyl, nicosulfuron, primisulfuron, glufosinate, glyphosate and sulfosate In the general formula [I],
Q is a group _{-S (O) n - (CR} 5 R 6) m - represents, n represents an integer of 0 to 2, m represents 1, _{R 5} and _{R 6} represent a hydrogen atom,
R ₁ and R ₂ represent a hydrogen atom, a C ₁ -C 8 alkyl group (optionally substituted with a C 3 -C 8 cycloalkyl group or a C ₁ -C 6 alkoxy group) or a C 3 -C 8 cycloalkyl group, or R and R ₂ May form a C3-C7 spiro ring together with these bonded carbon atoms,
R ₃ and _{R 4} represents a hydrogen atom or a (same or different 1 to 3 halogen atoms may be substituted by C3C8 Roarukiru group or C1~C6 alkoxy) C1 to C8 alkyl group, _{R 3} and R ₄ may form a spiro ring of C3~C7 with these bonded carbon atoms, or _{R 1,} R 2, _{R 3} and _{R 4} form a 5- to 8-membered ring together with these carbon atom attached May be
Y represents a phenyl group (substituted with 1 to 5 identical or different R ₇ ),
R ₇ represents a hydrogen atom, [1 to 3 identical or different halogen atoms, a C1 to C6 alkoxy group, a hydroxyl group, a C1 to C6 alkylthio group, a C1 to C6 alkylsulfinyl group, a C1 to C6 alkylsulfonyl group, a C1 to C6 An alkylamino group, a C1-C6 dialkylamino group, a cyano group or a (optionally substituted) phenoxy] C1-C6 alkyl group, (1-3 different or different halogen atoms, A C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyl group or a C3-C8 cycloalkyl group which may be substituted) Group, C3-C8 cycloalkyloxy group, halogen atom, nitro group or cyano group The herbicidal composition according to claim 1, which is an isoxazoline derivative or a salt thereof. In the general formula [I],
Q is a group _{-S (O) n - (CR} 5 R 6) m - represents, n represents an integer of 0 to 2, m represents 1, _{R 5} and _{R 6} represent a hydrogen atom,
R ₁ and R ₂ represent a C1-C8 alkyl group,
R ₃ and R ₄ represent a hydrogen atom,
Y represents a phenyl group (substituted with 1 to 5 identical or different R ₇ ),
R ₇ is a hydrogen atom, a C1 to C6 alkyl group (which may be substituted with 1 to 3 identical or different halogen atoms or a C1 to C6 alkoxy group), or a 1 to 3 identical or different halogen atom Or a C1-C6 alkoxy group, a C1-C6 alkoxy group, a C1-C6 alkoxycarbonyl group, a C2-C6 alkenyloxy group, a C2-C6 alkynyloxy group, a halogen atom, a nitro group or a cyano group. The herbicidal composition according to claim 1, which is an isoxazoline derivative or a salt thereof. In the general formula [I],
Q represents a group —S (O) _n — (CR ₅ R ₆ ) _m —, n represents 2, m represents 1, R ₅ and R ₆ represent a hydrogen atom,
R ₁ and R ₂ represent a C1-C4 alkyl group,
R ₃ and R ₄ represent a hydrogen atom,
Y represents a phenyl group (substituted with 1 to 5 identical or different R ₇ ),
R ₇ is a hydrogen atom, a C1 to C6 alkyl group (which may be substituted with the same or different 1 to 3 halogen atoms), or a C1 to C6 alkyl group (which may be substituted with 1 to 3 different or different halogen atoms) The herbicidal composition according to claim 1, which is an isoxazoline derivative representing a C1-C6 alkoxy group, a C1-C6 alkoxycarbonyl group, a C2-C6 alkynyloxy group, a halogen atom, a nitro group or a cyano group, or a salt thereof. .