JP4956760B2 - Method for producing 3-bromobenzoic acid or alkyl ester thereof - Google Patents

Description

〔２〕臭素酸塩が臭素酸のアルカリ金属塩またはアルカリ土類金属塩である上記[１]に記載する製造方法。
【０００７】
また、本発明は上記[１]〜上記[２]の製造方法に基づく以下の製造方法に関する。
〔３〕上記[１]または上記[２]の何れかの方法によって製造した３-ブロモ-２,４-ジハロゲノ-５-ニトロ安息香酸またはそのアルキルエステル（２位および４位のハロゲンはフッ素または塩素）を還元して上記ニトロ基がアミノ基に置換された３-ブロモ-２,４-ジハロゲノ-５-アミノ安息香酸またはそのアルキルエステルとし、さらにこれをジアゾ化した後に脱ジアゾフッ素化することによって、３-ブロモ-２,４-ジハロゲノ-５-フルオロ安息香酸またはそのアルキルエステル（２位および４位のハロゲンはフッ素または塩素）を製造する方法。
【０００８】
【発明の実施の形態】
以下、本発明を実施の形態に基づいて具体的に説明する。
３-ブロモ-２,４-ジハロゲノ-５-フルオロ安息香酸誘導体は２,４-ジハロゲノ５-フルオロ安息香酸誘導体を臭素化すれば得られるが、従来技術から理解されるように、２,４-ジハロゲノ-５-フルオロ安息香酸誘導体の臭素化は容易ではなく、本発明者等もこれまで種々検討したが工業的に十分な結果を得ることはできなかった。３-ブロモ-２,４-ジハロゲノ-５-フルオロ安息香酸誘導体を製造するには、どのような構造の化合物を出発物質に用いるか、また、どのような段階で臭素化およびフッ素化を行うかが重要である。
【０００９】
本発明は、図１に示すように、２,４-ジハロゲノ-５-ニトロ安息香酸誘導体を出発物質とし、(1)臭素化、(2)還元、(3)フッ素化の各工程を経て３-ブロモ-２,４-ジハロゲノ-５-フルオロ安息香酸誘導体を製造する方法である。出発物質の２,４-ジハロゲノ-５-ニトロ安息香酸誘導体は、例えば、２,４-ジハロゲノ安息香酸誘導体のニトロ化などによって容易に得ることができる。以下、各工程を詳細に説明する。
【００１０】
（１）臭素化
本発明の方法は、第一段階として、２,４-ジハロゲノ-５-ニトロ安息香酸誘導体を臭素化して次式(I)で示される３-ブロモ-２,４-ジハロゲノ-５-ニトロ安息香酸誘導体を製造する。

（式中、Ｘ1，Ｘ2 はハロゲン、Ｒは水素またはＣ1〜Ｃ6の直鎖または分岐のアルキル基）
ここで、出発物質の２,４-ジハロゲノ-５-ニトロ安息香酸誘導体の芳香環はニトロ基、カルボキシル基、ハロゲンによって著しく不活性化されているため、分子状臭素を臭素源とする一般的な臭素化反応の方法では目的物を得るのは困難である。このような不活性化された芳香環を臭素化する方法としては、鉄粉や各種ルイス酸を触媒として使用し、あるいは発煙硫酸中で反応を行う例が知られているが、本化合物の場合、いずれも反応が殆ど進行しないか、分解物のみが生成して極めて低収率となり、満足な結果が得られない。
【００１１】
また、このような不活性な芳香族化合物を臭素化する他の方法として、臭素源に臭素酸塩を使用し、硫酸中で反応を行う例が報告されている（J.Org.Chem,1981,46,2169）。この報告によれば、４０〜７０重量％の希硫酸中で臭素酸カリウムを臭素源として反応を行うことにより、電子吸引基によって芳香環が不活性化されているニトロベンゼンや安息香酸の臭素化がそれぞれ８８％、６２％の収率で可能であるとしている。ただし、硫酸の濃度が収率に大きな影響を与え、濃度が７０重量％を越えると臭素酸カリウムが制御不能な速度で分解し、この時に発生する分子状臭素はもはや臭素化剤として作用しないため収率が急激に低下することが知られている。事実、ニトロベンゼンの臭素化の例では、硫酸濃度６８％において最大収率８８％で目的物が得られるが、硫酸濃度が７０％になると収率は１５％まで低下することが指摘されており、これは硫酸濃度が７０％の時には反応が進行する前に臭素酸カリウムが分解してしまうためであることが示唆されている。
【００１２】
このような従来例に対して、本発明は、あえて濃度７０〜９０重量％の高濃度硫酸を用いたものであり、本発明の方法によれば、３-ブロモ-２,４-ジハロゲノ-５-ニトロ安息香酸誘導体が高収率で得られる。
出発物質の２,４-ジハロゲノ-５-ニトロ安息香酸誘導体は、ニトロ基以外にもカルボキシル基やハロゲンで置換されているため、ニトロベンゼンよりも反応性はさらに低いと考えられ、臭素化反応の進行は困難であることが予想されたが、硫酸濃度７０％のとき収率は１０％程度であるのに対して、硫酸濃度をさらに高めたところ、予想に反して収率は向上し、硫酸濃度９０％のときに収率７１％となり最も良好な結果を得た。
このように、本発明は、従来の知識からは予測し得なかった事実として、本件のような極度に芳香環が不活性化された化合物については、硫酸濃度は高い方が好ましく、７０〜１００％という高濃度が好適であることを見い出した。
【００１３】
反応操作としては、(イ)原料の芳香族化合物と臭素酸塩および水を混合撹拌下に硫酸を徐々に添加する方法と、臭素酸塩と硫酸の順序を入れ替え、(ロ)原料の芳香族化合物と硫酸および水を混合撹拌下に臭素酸塩を徐々に添加する方法とがある。硫酸濃度が上記のように高濃度の場合には、臭素酸塩の分解を抑制するため後者の方法が好ましい。
【００１４】
臭素化剤である臭素酸塩は、カリウム、ナトリウムなどのアルカリ金属塩の他にアルカリ土類金属塩を使用することができる。臭素酸塩の添加割合は、原料の芳香族化合物に対して１.０〜５倍当量、好ましくは１.０〜３倍当量が適当である。これによって原料の芳香族化合物がほぼ全量消費されるまで十分転化率を上げることが可能であり、精製分離の手間が省けるので都合が良い。
反応温度は−５０〜１５０℃が良く、−２０〜１００℃が好ましい。反応時間は反応温度にもよるが、０.０１〜２０時間、通常は０.１〜１０時間が適当である。
【００１５】
なお、上記臭素化工程において、２,４-ジハロゲノ-５-ニトロ安息香酸誘導体に代えて２,４-ジハロゲノ-５-アミノ安息香酸誘導体を出発物質として用い、これを臭素化して３-ブロム-２,４-ジハロゲノ-５-アミノ安息香酸誘導体を得ようとすると、６-ブロム体が高選択的に生成し、目的の３-ブロム体は殆ど得られない。
【００１６】
（２）還元
本発明の方法は、第二段階として、式(I)の３-ブロモ-２,４-ジハロゲノ-５-ニトロ安息香酸誘導体を還元して次式(II)で示される３-ブロモ-２,４-ジハロゲノ-５-アミノ安息香酸誘導体とする。

（式中のＸ1,Ｘ2およびＲは式Iと同じ）
式(I)のニトロ化合物から式(II)のアミノ化合物を得るには、通常の還元反応を支障なく利用することができる。一例を挙げれば、接触水素化によって良好な収率で還元を行うことができる。触媒としては白金、パラジウム、ロジウム、ルテニウム、イリジウム、ラネ-ニッケルなどが使用でき、これらの金属は活性炭やアルミナ、硫酸バリウムなどの不活性担体に保持されていても艮い。
触媒の使用量は原料芳香族化合物に対して０.１〜１０重量％が適当である。溶媒としては、水、アルコール、酢酸エチルなどのエステル類、エーテル類、ベンゼンやへキサンなどの芳香族または脂肪族炭化水棄類などが使用できる。反応温度は０〜５０℃が好ましい。反応時間は反応温度にもよるが、通常は０.５〜２０時間が適当である。反応圧力は０〜１０気圧が好ましい。
接触水素化以外の方法として、例えば、塩酸中で鉄や亜鉛、塩化錫を使用する反応でも高収率で目的物を得ることが可能である。
【００１７】
なお、式(I)で示される３-ブロモ-２,４-ジハロゲノ-５-ニトロ安息香酸誘導体、および式(II)で示される３-ブロモ-２,４-ジハロゲノ-５-アミノ安息香酸誘導体はいずれもケミカルアブストラクト(Chemical Abstract)などに記載されておらず、新規化合物と考えられる。
【００１８】
（３）フッ素化
本発明の方法は、第三段階として、式(II)の３-ブロモ-２,４-ジハロゲノ-５-アミノ安息香酸誘導体を還元して次式(III)で示される３-ブロモ-２,４-ジハロゲノ-５-フルオロ安息香酸誘導体を得る。

（式中のＸ1,Ｘ2およびＲは式Iと同じ）
上記化合物のフッ素化は通常のジアゾ化反応と脱ジアゾフッ素化反応を組み合わせることにより可能である。例えば、式(II)のアミノ化合物に亜硝酸付与剤とフッ化水素を加えてジアゾ化し、生成したジアゾニウム塩を熱または光によって分解してフッ素化を行うことができる。また、亜硝酸付与剤とフッ化水素と共に塩基を併用しても良い。
【００１９】
亜硝酸付与剤としては通常のジアゾ化剤が使用可能であり、具体的には無水亜硝酸、亜硝酸ソーダ、亜硝酸カリウムなどが好適である。亜硝酸付与剤の添加量は少なくとも式(II)のアミノ化合物に対して当量以上必要である。
塩基としてはフッ化水素と錯体を形成する塩基、すなわち酸素、窒素、リン、イオウなどを含む化合物を使用することができる。具体的にはエチルエーテルなどのエーテル類、トリエチルアミンやピリジンなどのアミン類、ケトン類、アルデヒド類、エステル類などが好適である。
フッ化水素と塩基の割合は、塩基がフッ化水素と塩基の合計量に対して５〜９０重量％、好ましくは５〜４５重量％であり、この範囲を外れると収率が低下する。ジアゾ化反応の温度は−１００〜１００℃、好ましくは−５０〜５０℃である。
【００２０】
上記ジアゾニウム塩を脱ジアゾフッ素化して目的の３-ブロモ-５-フルオロ安息香酸誘導体を得る。
ジアゾニウム塩を含む反応液は、ジアゾニウム塩を単離することなく引き続いて熱または光によって脱ジアゾフッ素化反応を行うことも可能である。熱分解によって行う場合には反応温度は２０〜２５０℃が適当であり、４０〜２００℃が好ましい。光分解によって行う場合には光源として高圧水銀灯、低圧水銀灯などが好適に用いられ、照射時間は０.５〜２０時間が好ましい。反応温度は−５０〜１５０℃、好ましくは−２０〜１００℃である。なお、この反応において熱分解と光分解を比較した場合、収率面では光分解の方が有利である。
【００２１】
【実施例および比較例】
本発明の実施例を比較例と共に以下に示す。なお、％は特に示さない限り重量％である。
【００２２】
実施例１（F₂NMAの臭素化によるBF₂NAMの製造：図２）
マグネット回転子、温度計および排気口を備えた５０mlの三口フラスコに、２,４-ジフルオロ-５-ニトロ安息香酸メチル(F₂NMA)４.３４g（純度約99.3wt％,約20mmol）と８５重量％硫酸１６mlを仕込み、室温で撹拌して溶解させた。フラスコを外部から内温が４.５℃になるまで冷却し、これにロートを使用して臭素酸カリウム３.３４g(20mmol)を２６分かけて投入し、反応させた（最高温度32℃）。この投入直後に反応液を採取し、ガスクロマトグラフィー(ＧＣ)にて反応の進行を見たところ、原料のＦ₂ＮＡＭと目的反応生成物の３-ブロモ-２,４-ジフルオロ-５-ニトロ安息香酸メチル(BF₂NAM)の量は各々約５０％であった。
引き続き、この反応液に臭素酸カリウム２.３４g(14mmol)を１３分かけて投入した(温度19〜23℃)。再度、反応液を採取し、ＧＣにて測定したところＦ₂ＮＡＭの残存量は約１.５％であった。反応液を氷４０gに移し、塩化メチレン５０mlを用いて２回(計100ml)抽出を行い、抽出液を併せて蒸留水１００mlで洗浄し、次いで、２％濃度チオ硫酸ソーダ水溶液１５０mlで処理し、抽出液層を分液後、硫酸ナトリウムで乾燥し、ロータリーエバポレーターで濃縮して、重量４.１９ｇの粗収物（目的物BF₂NAMのGC純度97.4％,略収率68％）を得た。
【００２３】
実施例２
容量２００mlの三口フラスコ、機械式撹拌装置の他は実施例１と同様の装置を用い、Ｆ₂ＮＡＭ４３.４g(約0.2mol)および９０重量％硫酸１４０mlを仕込み、実施例１と同様にして溶解させ、冷却後、臭素酸カリウム５６.８g(0.34mol)を２３０分かけて投入し、反応させた(最高温度24℃)。反応途中の分析は行わず、臭素酸カリウムの投入終了後１０分間冷却および撹拌を続けた。反応液を氷５００gに移し、塩化メチレン２００mlで１回、１００mlで２回(計400ml)の抽出を行い、抽出液を併せて蒸留水５００mlで洗浄し、次いで２％チオ硫酸ソーダ水溶液５００mlで処理し、抽出液層を分液後硫酸ナ卜リウムで乾燥し、ロータリーエバポレーターで濃縮して、重量４２.３５ｇの粗収物（目的物BF₂NAMのGC純度98.9％、略収率71％）を得た。
粗収物の全量をメタノール／水（５:１）２４０mlに溶解して再結晶精製し、更に濾液を再結晶した２番晶と合わせて、減圧乾燥して目的生成物ＢＦ₂ＮＡＭ ４１.３７g(純度99.1重量％,収率約69％)を得た。このＢＦ₂ＮＡＭの物性は以下のとおりである。
融点：３６〜３７℃
質量スペクトル(EI)：ｍ／ｚ＝２９５
¹Ｈ-ＮＨＲ(270MHz,CDCl₃)
δ値(ppm)：４.００(3H,S)、８.７４(1H,dd,J=8.3Hz,7.3Hz)
【００２４】
実施例３（BF₂NAMの還元によるBF₂AAMの製造：図３）
機械式撹拌機、圧力計および温度計を備えたモネル製の３００mlオートクレーブにＢＦ₂ＮＡＭ ４４.４g(純度99.1重量％,約0.15mol)、酢酸エチル１００ml、５％パラジウムカーボン触媒(含水50％)５gを仕込み、窒素置換、水素置換後、水素にて５kg/cm²に加圧し保持して接触水素還元を行った。この反応は室温で行ったが、内温が３０℃を越えない様に適宜外部から冷却した。３０分毎に反応器での水素の吸収を確認し、水素の吸収が止み、発熱が収まった時点を終了とした（反応時間５時間）。
反応終了後、系内を室素置換し、反応液をビーカーに移し、酢酸エチル９００mlを加えて結晶を溶解させた後、触媒を濾別した。濾液をロータリーエバボレーターで濃縮し、乾固させ、メタノール２００mlを加えて再結晶を行った。濾液を濃縮し、再度再結晶を行った２番晶と合わせて滅圧乾燥し、重量２９.５gの粗収物（3-ブロモ-2,4-ジフルオロ-5-アミノ安息香酸メチル(BF₂AAM)、純度98.1％,略収率72％）を得た。
粗収物全量を塩化メチレン６００mlに溶解させ、３５％塩酸１４gを滴下してＢＦ₂ＡＡＭ塩酸塩として結晶を析出させ、外部から氷冷後濾過し、結晶を塩化メチレン１００mlで洗浄した後、吸引乾燥した。結晶をビーカーに移し、塩化メチレン６００mlおよび水２００ml加え分散させ、１０％炭酸カリウム水溶液を滴下して中和した（ｐＨ８）。
塩化メチレン層を分液し、硫酸ナトリウムで乾燥後、ロータリーエバポレーターで濃縮し、更に減圧乾燥を行い、ＢＦ₂ＡＡＭ ２８.６g(純度99重量％,収率約70％)を得た。このＢＦ₂ＡＡＭの物性は以下のとおりである。
融点：１６１〜１６３℃
質量スペクトル(EI)：ｍ/ｚ＝２６５
¹Ｈ-ＮＭＲ(270MHz,CDCl₃)
δ値(ppm）：３.８０(2H,brs,NH₂)、３.９２(3H,S)、７.３３(1H,dd,J=9.3Hz,6.4Hz)
【００２５】
実施例４（BF₂AAMのフッ素化によるBF₃AMの製造：図４）
マグネット回転子を備えた１００mlの透明フッ素樹脂容器に、７０重量％フッ化水素／３０重量％ピリジン１００gを入れ、ＢＦ₂ＡＡＭ ５.３５g(純度99重量％,約19mmol)を加え、室温で溶解させた。
この反応液を外部から冷却し、−２２〜−３℃の温度で亜硝酸ソーダ１.５２g(22mmol)を加え(４分)、室温で撹拌(60分,〜12℃)してジアゾ化反応を行った。次いで、室温で１kw高圧水銀灯(理工科学産業製UVL-1000HC)で紫外線を２０時間照射し、光脱ジアゾフッ素化反応を行わせた。反応液を氷１００g中に移し、塩化メチレン５０mlで１回、２０mlで２回(計90ml)の抽出を行い、抽出液を併せて蒸留水１００mlで洗浄し、１０％炭酸カリウム水溶液で中和した（ｐＨ７）。
再度蒸留水１００mlで洗浄し、抽出液層を分液して硫酸ナトリウムで乾燥後、ロータリーエバポレーターで濃縮し、５.３gの反応粗収物(3-ブロモ-2,4,5-トリフルオロ安息香酸メチル(BF₃AM)のＧＣ純度96.5％,反応略収率98％)を得た。この反応粗収物を約０.５３kpaの減圧下に分留して、４.６gの目的生成物ＢＦ₃ＡＭ（純度99.6重量％,BF３AAMからの収率約90％）を得た。このＢＦ₃ＡＭの物性は以下のとおりである。
沸点：８８〜９０℃(0.53kpa)
質量スペクトル(EI)：Ｍ／Ｚ＝２６８
¹Ｈ-ＮＭＲ(270MHz,CDCl₃)
δ値(ppm）：３.９５(3H,s)、７.８０(1H,ddd,J=10.0Hz,8.5Hz,6.4Hz)
【００２６】
実施例５（C₂NAMの臭素化によるBC₂NAMの製造：図５）
実施例２において、反応器を５００mlのセパラブルフラスコおよび４口カバーに代えた他は同様の装置を用い、２,４-ジクロロ-５-ニトロ安息香酸メチル(C₂NAM)７５.０g(純度約99重量％,約0.3mol)、および９０重量％硫酸３００mlを仕込み、臭素酸カリウム４０.１g(0.24mol)を８４分かけて投入し、反応させ（投入温度12〜14℃)、ＧＣで反応の進行を観察した（原料C₂NAM14.6％,目的反応生成物3-ブロモ-2,4-ジクロロ-5-ニトロ安息香酸メチル(BC₂NAM)81.4％)。
更に、臭素酸カリウム１０g(0.06mol)を２０分かけて投入し、反応させた（投入温度12〜14℃）。２０分間撹拌を継続後、反応液を氷１kgに移し、塩化メチレン１lで３回に分けて抽出し、水１lで洗浄し、２％チオ硫酸ナトリウム水溶液１lで処理し、抽出液を分液後硫酸ナトリウムで乾燥し、濃縮して、６５.８ｇの粗収物(目的物BC₂NAMのGC純度95.2％,略収率63％)を得た。
粗収物の全量をメタノール／水（５:１）５００mlに溶解して再結晶精製し、更に濾液を再結晶した２番晶と合わせて、減圧乾燥して目的生成物ＢＣ₂ＮＡＭ ５７.５g(純度98.4重量％,収率約57％)を得た。このＢＣ₂ＮＡＭの物性は以下のとおりである。
融点：７１〜７３℃
質量スペクトル(EI)：Ｍ／Ｚ＝３２７
¹Ｈ-ＮＭＲ(270MHz,CDCl₃)
δ値(ppm）：３.９９(3H,s)、８.２１(1H,s)
【００２７】
実施例６（BC₂NAMの還元によるBC₂AAMの製造：図６）
実施例３と同様の装置を用い、ＢＣ₂ＮＡＭ４９.３g(純度約98.4重量％,約0.147mol)、酢酸エチル１５０mlおよび５％-パラジウムカーボン触媒(含水50％)５gを仕込み、室温で２.５時間接触水素還元反応を行った(内温26〜28℃)。反応終了後、結晶を溶解するための酢酸エチルの追加量を６００mlとした他は実施例３と同様の操作を行い、４３.８ｇの粗収物(目的物BC₂AAMのGC純度96％,略収率95％)を得た。この粗収物の全量をメタノール４００mlに溶解して実施例３と同様の再結晶操作をし、３５重量％塩酸を３０g使用した以外は実施例３と同様の精製操作を行い、３６.７７gの目的生成物（３-ブロモ-２,４-ジクロロ-５-アミノ安息香酸メチル(BC₂AAM)、純度98重量％,収率約81％）を得た。このＢＣ₂ＡＡＭの物性値は以下のとおりである。
融点：１６４〜１６７℃
質量スペクトル(EI)：ｍ／ｚ＝２９７
¹Ｈ-ＮＭＲ(270MHz,CDCl₃)
δ値(ppm）：３.９２(3H,s)、４.３２(2H,brs,NH₂)、７.１３(1H,S)
【００２８】
実施例７（BC₂AAMのフッ素化によるBC₂FAMの製造：図７）
実施例４と同様の装置に、７０重量％フッ化水素／３０重量％ピリジン３３.４ｇを取り、ＢＣ₂ＡＡＭ６.０１ｇ(純度重量９８％,約19.7mmol)を加えて攪拌した、このスラリー状の反応液を外部から冷却し、−２〜−８℃の温度範囲で亜硝酸ソーダ１.５２ｇ(約22mmol)を加え(４分)、室温で撹拌し(60分,〜25℃)、ジアゾ化反応を行った。この反応液を−４０℃に冷却し、攪拌しながら、−２０℃に冷却された無水フッ化水素酸６６.６ｇを５分かけて滴下し、約９０wt％フッ化水素／１０wt％ピリジン１００ｇの反応液とした。
次いで、室温で１Kw高圧水銀灯(理工科学産業製UVL-1000HC)で紫外線を８時間照射し、光脱ジアゾフッ素化反応を行わせた。反応液を氷１５０ｇに移し、塩化メチレン２０mlで３回(計60ml)の抽出を行い、抽出液を併せて実施例４と同様の後処理をし、６.０ｇの反応粗収物（3-ブロモ-2,4-ジクロロ-5-フルオロ安息香酸メチル(BC₂FAM)のＧＣ純度94.3％,反応略収率95％）を得た。このＢＣ₂ＦＡＭの物性は以下のとおりである。
融点：８５〜８７℃
質量スペクトル(EI)：ｍ／ｚ＝３００
¹Ｈ-ＮＭＲ(270MHz,CDCl₃)
δ値(ppm）：３.９５(3H,s)、７.５９(1H,d,J=8.3Hz)
【００２９】
比較例１（F₃AMの臭素化）
容量２５mlである他は実施例１と同様な装置に、２,４,５-トリフルオロ安息香酸メチル(F₃AM)１.９g(純度99.6重量％,約10mmol)および９０重量％硫酸７.５mlを仕込み、加えた臭素酸カリウム量２.８g(17mmol)、臭素酸カリウムの投入に要した時間３５分(温度15〜26℃)以外は実施例１とほぼ同様の操作をした。得られた反応粗収物は０.６９gであり、目的物ＢＦ₃ＡＭ約４５％の他、原料Ｆ₃ＡＭ約３０％およびジブロモ体約４％、その他を含んでおり、仕込みＦ₃ＡＭからのＢＦ₃ＡＭ略収率約１１％、原料転化率約８０％であった。
【００３０】
比較例２（F₃AMの臭素化）
実施例１の装置に還流冷却器を追加し、Ｆ₃ＡＭ １.９g(純度99.6重量％,約10mmol)および鉄粉０.０７gを仕込み、８０℃に加熱した。臭素１.０g(6mmol)を５分かけて滴下した後８０℃で１時間反応させた。更に、鉄粉０.０７gを追加し臭素１.０g(6mmol)を５分かけて滴下し、１００℃に昇温して２時間反応させ、冷却した。反応内容物に塩化メチレン１０mlを入れ溶解し、濾過により固形物を除き、水５０mlで洗浄し、３％チオ硫酸ナトリウム水溶液２００mlで処理し、更に水５０mlで洗浄し、有機層を分液し、硫酸ナトリウムで乾燥し、ロータリーエバポレーターで濃縮した。反応粗収物量は０.３gであり、ＧＣ分析結果によれば、目的物ＢＦ₃ＡＭは２.１％、原料Ｆ₃ＡＭは９７.２％であった。
【００３１】
比較例３（F₂NAMの臭素化）
マグネット回転子および還流冷却器を備えた１０mlナスフラスコにＦ₂ＮＡＭ ２.１７g(純度約99.3重量％,約10mmol)、２５％発煙硫酸(オリウム)５ml、無水塩化アルミニウム０.１gおよび臭素３.２g(20mmol)を仕込み、７０℃で４時間反応させ、比較例２と同様の後処理を行った。反応粗収物量は０.４gであり、ＧＣ分析結果によれば、目的物ＢＦ₂ＮＡＭは僅か０.７％であり、原料Ｆ₃ＮＡＭは９５.３％であった。
【００３２】
比較例４（F₂NAMの臭素化）
比較例１と同様の装置に水８mlおよび９８％濃硫酸８mlを仕込み氷で冷却し、Ｆ₂ＮＡＭ２.１７g(純度約99.3重量％,約10mmol)および臭素酸カリウム１.６７g(10mmol)を仕込み、１０〜２０℃で９０分間反応させた。反応内容物を氷３０gに移した後は実施例１と同様の操作をした。反応粗収物量は２.１gであり、ＧＣ分析結果によれば、目的物ＢＦ₂ＮＡＭは１３.４％、原料Ｆ₂ＮＡＭは８３.７％であり、原料Ｆ₂ＮＡＭの転化率は１４％、原料Ｆ₂ＮＡＭからの目的物ＢＦ₂ＮＡＭの略収率は９％、原料転化率からの略収率は６９％であった。
【００３３】
比較例５（F₂AAMの臭素化：図８）
比較例１と同様な装置に、１５％塩酸１２.２g(塩酸として約50mmol)仕込み、外部から氷冷し、これに２,４-ジフルオロ-５-アミノ安息香酸メチル（F₃AAM）１.８７g(純度約100重量％,約10mmol)を投入した。内温を５℃以下に保ち、臭素１.６g(10mmol)を滴下し(3分)、１〜４℃で７０分反応させた。反応液を氷水５０gに移し、１０％炭酸カリウム水溶液で中和し(ｐＨ８)、塩化メチレン３０mlで１回、２０mlで２回(計70ml)の抽出を行い、抽出液を３％チオ硫酸ナトリウム水溶液２００mlで洗浄し、硫酸ナトリウムで乾燥し、ロータリーエバボレーターで濃縮し、反応粗収物２.５８gを得た。ガスクロ質量分析(GC-MS)により、これはブロモ-２,４-ジフルオロ-５-アミノ安息香酸メチル(BF₂AAM)であることを確認した（BF₂AAMのGC純度98.0％,反応略収率95％）。
この反応粗収物を塩化メチレン５mlに溶解し、３５重量％ 塩酸１.２gを滴下しＢＦ₂ＡＡＭ塩酸塩として結晶を析出させ、外部から氷冷後に濾過し、結晶を塩化メチレン２mlで洗浄した後、吸引乾燥した。結晶をビーカーに移し、塩化メチレン１０mlおよび水５ml加え分散させ、１０％炭酸カリウム水溶液を滴下して中和した(ｐＨ８)。塩化メチレン層を分液し、硫酸ナトリウムで乾燥後、ロータリーエバポレーターで濃縮し、更に減圧乾燥を行い、ＢＦ₂ＡＡＭ２.４７g(純度98.6重量％,収率約91％)を得た。このＢＦ₂ＡＡＭを詳細に分析した結果、目的物の３-ブロム体ではなく、６-ブロモ-２,４-ジフルオロ-５-ニトロ安息香酸メチル(6i-BF₂AAM)であることが確認された。この物性は以下のとおりである。
融点：７７〜７９℃
質量スペクトル(EI)：ｍ／ｚ＝２６５
¹Ｈ-ＮＭＲ(270MHz,CDCl₃)

【００３４】
比較例６（C₂NAMの臭素化）
還流冷却管を追加した以外は実施例１と同様の装置を用い、Ｃ₂ＮＡＭ５.０g（純度約99重量％,約20mmol）、水１４mlおよび臭素酸カリウム３.３g(20mmol)を仕込み６５℃に加熱し、濃硫酸１６mlを８２分かけて滴下し(60〜69℃)、７０℃で更に１時間反応させた。反応液を採取し、ＧＣで反応の進行を観察したところ、原料のＣ₂ＮＡＭは９５％であり、目的物のＢＣ₂ＮＡＭは僅か３.４％であった。
【００３５】
【発明の効果】
本発明の製造方法によれば医薬、農薬等の中間体として有用な３-ブロモ-５-フルオロ-２,４-ジハロゲノ安息香酸誘導体を入手容易な原材料を使用して安価に工業的に効率よく製造することが可能である。
【図面の簡単な説明】
【図１】 本発明の製造工程を示す説明図。
【図２】 実施例１の合成方法を示す説明図。
【図３】 実施例３の合成方法を示す説明図。
【図４】 実施例４の合成方法を示す説明図。
【図５】 実施例５の合成方法を示す説明図。
【図６】 実施例６の合成方法を示す説明図。
【図７】 実施例７の合成方法を示す説明図。
【図８】 比較例５の合成方法を示す説明図。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a 3-bromo-5-fluorobenzoic acid derivative, and a novel intermediate thereof. 3-Bromobenzoic acid derivatives are used as intermediates for pharmaceuticals, agricultural chemicals and the like, and are particularly important as intermediates for fluoroquinoline-based synthetic antibacterial agents.
[0002]
[Prior art]
3-Bromo-2,4-dihalogeno-5-fluorobenzoic acid derivative is a fluoroquinolone synthetic antibacterial agent for producing 8-bromo-6-fluoro-4-oxo-3-quinolinecarboxylic acid derivative It is an important intermediate.
As a method for producing this 3-bromo-2,4-dihalogeno-5-fluorobenzoic acid derivative, for example, 3-bromo-2,4,5-trifluoro is obtained from 3-chloro-4-fluoroaniline through a number of steps. A method of synthesizing benzoic acid (EP216-245) or substituting one fluorine of tetrafluorophthalonitrile with bromine to form 4-bromo-3,5,6-trifluorophthalic acid. A method for synthesizing 3-bromo-2,4,5-trifluorobenzoic acid (JP-A-3-284649) is known.
[0003]
However, since the former method has many manufacturing steps, the final yield is extremely low. In the latter method, when bromination of tetrafluorophthalonitrile, expensive lithium bromide is used, and the reaction rate of tetrafluorophthalonitrile needs to be suppressed to 20 to 50%. Therefore, productivity is extremely low. There is a problem.
[0004]
In addition, 2- (2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline is brominated and hydrolyzed to synthesize 3-bromo-2,4,5-trifluorobenzoic acid. Method (J. Heterocyc1ic Chem., 33, 1407, 1996) or a method of synthesizing 3-bromo-2,4,5-trifluorobenzoic acid by bromination of 2,4,5-trifluorobenzoic acid ( No. 9-67303) is known, but none of them is suitable for industrial implementation because it requires expensive organolithium compounds or requires reaction at low temperatures.
[0005]
[Problems to be solved by the invention]
Thus, 5-fluoro-3-bromo-2,4There is no prior known method suitable for industrial production of dihalogenobenzoic acid derivatives. The present invention solves the above-mentioned conventional problems, and includes 5-fluoro-3-bromo-2,4Provided is a method for easily producing a dihalogenobenzoic acid derivative with good yield. In the description of the present invention, 3-bromobenzoic acid or its alkyl ester is referred to as a 3-bromobenzoic acid derivative for convenience.
[0006]
[Means for solving problems]
That is, this invention relates to the following manufacturing methods.
[1]2,4-dihalogeno-5-nitrobenzoic acid or an alkyl ester thereof (halogens at positions 2 and 4 are fluorine or chlorine) and bromate in a mixture of 70 to 100% by weight sulfuric acid to By brominating 4-dihalogeno-5-nitrobenzoic acid or its alkyl ester, the following formula (I) (wherein X ¹ , X ² Is fluorine or chlorine,R is hydrogen or a C1-C6 linear or branched alkyl group)A process for producing 3-bromo-2,4-dihalogeno-5-nitrobenzoic acid represented by the formula (1) or an alkyl ester thereof (halogens at the 2nd and 4th positions are fluorine or chlorine).

[2] The production method according to the above [1], wherein the bromate is an alkali metal salt or alkaline earth metal salt of bromic acid.
[0007]
  Moreover, this invention relates to the following manufacturing methods based on the manufacturing method of said [1]-said [2].
[3] 3-Bromo-2,4-dihalogeno-5-nitrobenzoic acid or an alkyl ester thereof produced by the method according to [1] or [2] above (the halogens at the 2- and 4-positions are fluorine or Chlorine) to form 3-bromo-2,4-dihalogeno-5-aminobenzoic acid or an alkyl ester thereof in which the above nitro group is substituted with an amino group, which is further diazotized and then dediazofluorinated. To produce 3-bromo-2,4-dihalogeno-5-fluorobenzoic acid or an alkyl ester thereof (halogens at the 2- and 4-positions are fluorine or chlorine).
[0008]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be specifically described based on embodiments.
The 3-bromo-2,4-dihalogeno-5-fluorobenzoic acid derivative can be obtained by brominating the 2,4-dihalogeno-5-fluorobenzoic acid derivative. As understood from the prior art, 2,4- Bromination of dihalogeno-5-fluorobenzoic acid derivatives is not easy, and the present inventors have made various studies so far, but industrially sufficient results could not be obtained. To prepare 3-bromo-2,4-dihalogeno-5-fluorobenzoic acid derivatives, what structure of the compound is used as a starting material, and at what stage bromination and fluorination are carried out is important.
[0009]
As shown in FIG. 1, the present invention uses a 2,4-dihalogeno-5-nitrobenzoic acid derivative as a starting material, and passes through the steps of (1) bromination, (2) reduction, and (3) fluorination. This is a method for producing a bromo-2,4-dihalogeno-5-fluorobenzoic acid derivative. The starting 2,4-dihalogeno-5-nitrobenzoic acid derivative can be easily obtained, for example, by nitration of a 2,4-dihalogenobenzoic acid derivative. Hereinafter, each process will be described in detail.
[0010]
(1) Bromination
In the method of the present invention, as a first step, a 2,4-dihalogeno-5-nitrobenzoic acid derivative is brominated to give 3-bromo-2,4-dihalogeno-5-nitrobenzoic acid represented by the following formula (I): A derivative is produced.

(Wherein X1 and X2 are halogen, R is hydrogen or a C1-C6 linear or branched alkyl group)
Here, since the aromatic ring of the 2,4-dihalogeno-5-nitrobenzoic acid derivative, which is a starting material, is remarkably inactivated by a nitro group, a carboxyl group, and a halogen, a general bromine source is used. It is difficult to obtain the target product by the bromination reaction method. Examples of methods for brominating such deactivated aromatic rings are known to use iron powder and various Lewis acids as catalysts, or to react in fuming sulfuric acid. In either case, the reaction hardly proceeds, or only a decomposed product is produced, resulting in a very low yield, and satisfactory results cannot be obtained.
[0011]
In addition, as another method for brominating such an inert aromatic compound, an example of using bromate as a bromine source and reacting in sulfuric acid has been reported (J. Org. Chem, 1981). , 46,2169). According to this report, bromination of nitrobenzene and benzoic acid, in which the aromatic ring is inactivated by an electron withdrawing group, is performed by using potassium bromate as a bromine source in 40 to 70% by weight of dilute sulfuric acid. It is said that it is possible with a yield of 88% and 62%, respectively. However, the concentration of sulfuric acid has a large effect on the yield, and when the concentration exceeds 70% by weight, potassium bromate decomposes at an uncontrollable rate, and the molecular bromine generated at this time no longer acts as a brominating agent. It is known that the yield decreases rapidly. In fact, in the example of bromination of nitrobenzene, the target product is obtained with a maximum yield of 88% at a sulfuric acid concentration of 68%, but it has been pointed out that when the sulfuric acid concentration reaches 70%, the yield decreases to 15%. It is suggested that this is because potassium bromate is decomposed before the reaction proceeds when the sulfuric acid concentration is 70%.
[0012]
In contrast to such a conventional example, the present invention dares to use high-concentration sulfuric acid having a concentration of 70 to 90% by weight. According to the method of the present invention, 3-bromo-2,4-dihalogeno-5 is used. -Nitrobenzoic acid derivatives are obtained in high yield.
The starting 2,4-dihalogeno-5-nitrobenzoic acid derivative is substituted with a carboxyl group or halogen in addition to the nitro group, so it is considered to be less reactive than nitrobenzene, and the bromination reaction proceeds However, when the sulfuric acid concentration was 70%, the yield was about 10%, but when the sulfuric acid concentration was further increased, the yield improved unexpectedly and the sulfuric acid concentration The yield was 71% when 90% and the best result was obtained.
Thus, as a fact that the present invention could not be predicted from conventional knowledge, a compound having an extremely inactivated aromatic ring as in the present case preferably has a higher sulfuric acid concentration, and is preferably 70 to 100. It has been found that a high concentration of% is suitable.
[0013]
As the reaction operation, (i) the raw material aromatic compound, bromate and water are mixed and stirred, and sulfuric acid is gradually added, and the order of bromate and sulfuric acid is changed. There is a method in which a bromate is gradually added with mixing and stirring a compound, sulfuric acid and water. When the sulfuric acid concentration is high as described above, the latter method is preferred in order to suppress decomposition of bromate.
[0014]
As the bromate which is a brominating agent, alkaline earth metal salts can be used in addition to alkali metal salts such as potassium and sodium. The addition ratio of bromate is 1.0 to 5 times equivalent, preferably 1.0 to 3 times equivalent to the starting aromatic compound. This makes it possible to sufficiently increase the conversion rate until almost all of the starting aromatic compound is consumed, which is convenient because it eliminates the need for purification and separation.
The reaction temperature is preferably −50 to 150 ° C., and preferably −20 to 100 ° C. Although the reaction time depends on the reaction temperature, 0.01 to 20 hours, usually 0.1 to 10 hours is appropriate.
[0015]
In the above bromination step, a 2,4-dihalogeno-5-aminobenzoic acid derivative was used as a starting material instead of the 2,4-dihalogeno-5-nitrobenzoic acid derivative, which was brominated to give 3-bromo- When an attempt is made to obtain a 2,4-dihalogeno-5-aminobenzoic acid derivative, the 6-bromo compound is produced with high selectivity, and the desired 3-bromo compound is hardly obtained.
[0016]
(2) Reduction
In the method of the present invention, as a second step, 3-bromo-2,4-dihalogeno-5-nitrobenzoic acid derivative of formula (I) is reduced to produce 3-bromo-2, which is represented by the following formula (II): 4-Dihalogeno-5-aminobenzoic acid derivative.

(Where X1, X2 and R are the same as in formula I)
In order to obtain the amino compound of the formula (II) from the nitro compound of the formula (I), a usual reduction reaction can be used without any trouble. As an example, reduction can be performed in good yield by catalytic hydrogenation. As the catalyst, platinum, palladium, rhodium, ruthenium, iridium, rane-nickel and the like can be used, and these metals may be supported on an inert carrier such as activated carbon, alumina, barium sulfate or the like.
The amount of the catalyst used is suitably 0.1 to 10% by weight based on the starting aromatic compound. As the solvent, water, esters such as alcohol and ethyl acetate, ethers, aromatic or aliphatic carbonized water such as benzene and hexane, and the like can be used. The reaction temperature is preferably 0 to 50 ° C. The reaction time depends on the reaction temperature, but usually 0.5 to 20 hours is appropriate. The reaction pressure is preferably 0 to 10 atmospheres.
As a method other than catalytic hydrogenation, for example, a target product can be obtained in a high yield even in a reaction using iron, zinc, or tin chloride in hydrochloric acid.
[0017]
A 3-bromo-2,4-dihalogeno-5-nitrobenzoic acid derivative represented by the formula (I) and a 3-bromo-2,4-dihalogeno-5-aminobenzoic acid derivative represented by the formula (II) Are not described in chemical abstracts, etc., and are considered to be novel compounds.
[0018]
(3) Fluorination
In the method of the present invention, as a third step, 3-bromo-2,4-dihalogeno-5-aminobenzoic acid derivative of the formula (II) is reduced to give 3-bromo-2, A 4-dihalogeno-5-fluorobenzoic acid derivative is obtained.

(Where X1, X2 and R are the same as in formula I)
Fluorination of the above compound is possible by combining a normal diazotization reaction and a dediazofluorination reaction. For example, diazotization can be performed by adding a nitrous acid imparting agent and hydrogen fluoride to an amino compound of formula (II), and the resulting diazonium salt can be decomposed by heat or light to perform fluorination. Moreover, you may use a base together with a nitrous acid providing agent and hydrogen fluoride.
[0019]
As the nitrous acid imparting agent, a normal diazotizing agent can be used, and specifically, anhydrous nitrous acid, sodium nitrite, potassium nitrite and the like are suitable. The amount of nitrous acid imparting agent added is at least equivalent to the amino compound of formula (II).
As the base, a base that forms a complex with hydrogen fluoride, that is, a compound containing oxygen, nitrogen, phosphorus, sulfur and the like can be used. Specifically, ethers such as ethyl ether, amines such as triethylamine and pyridine, ketones, aldehydes and esters are preferred.
The ratio of hydrogen fluoride to base is 5 to 90% by weight, preferably 5 to 45% by weight, based on the total amount of hydrogen fluoride and base. If the ratio is outside this range, the yield decreases. The temperature of the diazotization reaction is −100 to 100 ° C., preferably −50 to 50 ° C.
[0020]
The diazonium salt is dediazofluorinated to obtain the desired 3-bromo-5-fluorobenzoic acid derivative.
The reaction solution containing a diazonium salt can be subsequently subjected to a dediazofluorination reaction by heat or light without isolating the diazonium salt. When it is carried out by thermal decomposition, the reaction temperature is suitably 20 to 250 ° C, preferably 40 to 200 ° C. When carrying out by photolysis, a high pressure mercury lamp, a low pressure mercury lamp or the like is suitably used as the light source, and the irradiation time is preferably 0.5 to 20 hours. The reaction temperature is −50 to 150 ° C., preferably −20 to 100 ° C. In this reaction, when thermal decomposition and photolysis are compared, photolysis is more advantageous in terms of yield.
[0021]
Examples and Comparative Examples
Examples of the present invention are shown below together with comparative examples. % Is% by weight unless otherwise specified.
[0022]
Example 1(F₂BF by bromination of NMA₂Production of NAM: Fig. 2)
A 50 ml three-necked flask equipped with a magnet rotor, thermometer and exhaust vent was added to methyl 2,4-difluoro-5-nitrobenzoate (F₂NMA) 4.34 g (purity about 99.3 wt%, about 20 mmol) and 85 wt% sulfuric acid 16 ml were charged and dissolved by stirring at room temperature. The flask was cooled from the outside to an internal temperature of 4.5 ° C., and potassium bromate (3.34 g, 20 mmol) was added to the flask using a funnel over 26 minutes to allow reaction (maximum temperature 32 ° C.). . Immediately after this addition, the reaction solution was collected and the progress of the reaction was observed by gas chromatography (GC).₂NAM and the desired reaction product methyl 3-bromo-2,4-difluoro-5-nitrobenzoate (BF₂The amount of NAM) was about 50% each.
Subsequently, 2.34 g (14 mmol) of potassium bromate was added to the reaction solution over 13 minutes (temperature 19 to 23 ° C.). When the reaction solution was collected again and measured by GC, F₂The residual amount of NAM was about 1.5%. The reaction solution is transferred to 40 g of ice, extracted twice with 50 ml of methylene chloride (100 ml in total), the extracts are combined and washed with 100 ml of distilled water, and then treated with 150 ml of 2% strength aqueous sodium thiosulfate solution. The extract layer was separated, dried over sodium sulfate, and concentrated on a rotary evaporator to obtain a crude product (target BF) weighing 4.19 g.₂The NAM GC purity was 97.4%, and the yield was about 68%.
[0023]
Example 2
Other than the 200 ml three-necked flask and the mechanical stirring device, the same apparatus as in Example 1 was used.₂Charge 43.4 g (about 0.2 mol) of NAM and 140 ml of 90% by weight sulfuric acid, dissolve in the same manner as in Example 1, and after cooling, add 56.8 g (0.34 mol) of potassium bromate over 230 minutes to react. (Maximum temperature 24 ° C). Analysis during the reaction was not performed, and cooling and stirring were continued for 10 minutes after the addition of potassium bromate. The reaction solution is transferred to 500 g of ice, extracted once with 200 ml of methylene chloride and twice with 100 ml (400 ml in total). The extracts are combined and washed with 500 ml of distilled water, and then treated with 500 ml of 2% aqueous sodium thiosulfate solution. The extract layer was separated, dried with sodium sulfate, and concentrated with a rotary evaporator to obtain a crude product (target product BF) weighing 42.35 g.₂GC purity of NAM 98.9%, approximately 71% yield) was obtained.
The total amount of the crude product was dissolved in 240 ml of methanol / water (5: 1) and purified by recrystallization. The filtrate was combined with the recrystallized second crystal and dried under reduced pressure to obtain the desired product BF.₂41.37 g of NAM (purity 99.1% by weight, yield about 69%) was obtained. This BF₂The physical properties of NAM are as follows.
Melting point: 36-37 ° C
Mass spectrum (EI): m / z = 295
¹H-NHR (270MHz, CDCl_Three)
δ value (ppm): 4.00 (3H, S), 8.74 (1H, dd, J = 8.3Hz, 7.3Hz)
[0024]
Example 3(BF₂BF by reduction of NAM₂Production of AAM: Fig. 3)
BF to Monel 300ml autoclave equipped with mechanical stirrer, pressure gauge and thermometer₂Charge 44.4 g of NAM (purity 99.1% by weight, approx. 0.15 mol), 100 ml of ethyl acetate, 5 g of 5% palladium on carbon catalyst (water content 50%), nitrogen substitution, hydrogen substitution, 5 kg / cm with hydrogen²The mixture was pressurized and held to perform catalytic hydrogen reduction. This reaction was performed at room temperature, but was appropriately cooled from the outside so that the internal temperature did not exceed 30 ° C. The absorption of hydrogen in the reactor was confirmed every 30 minutes, and the time when the absorption of hydrogen ceased and the exotherm ceased was terminated (reaction time 5 hours).
After completion of the reaction, the inside of the system was replaced with nitrogen, the reaction solution was transferred to a beaker, 900 ml of ethyl acetate was added to dissolve the crystals, and the catalyst was filtered off. The filtrate was concentrated on a rotary evaporator, dried to dryness, and recrystallized by adding 200 ml of methanol. The filtrate was concentrated, combined with the recrystallized second crystal, and vacuum-dried to give a crude product (methyl 2-bromo-2,4-difluoro-5-aminobenzoate (BF) weighing 29.5 g.₂AAM), 98.1% purity, approximately 72% yield).
The total amount of the coarse product is dissolved in 600 ml of methylene chloride, and 14 g of 35% hydrochloric acid is added dropwise to BF.₂Crystals were precipitated as AAM hydrochloride, filtered from the outside with ice cooling, washed with 100 ml of methylene chloride, and then suction dried. The crystals were transferred to a beaker, dispersed by adding 600 ml of methylene chloride and 200 ml of water, and neutralized by adding dropwise a 10% aqueous potassium carbonate solution (pH 8).
The methylene chloride layer was separated, dried over sodium sulfate, concentrated with a rotary evaporator, and dried under reduced pressure.₂28.6 g of AAM (purity 99% by weight, yield about 70%) was obtained. This BF₂The physical properties of AAM are as follows.
Melting point: 161-163 ° C
Mass spectrum (EI): m / z = 265
¹H-NMR (270 MHz, CDCl_Three)
δ value (ppm): 3.80 (2H, brs, NH₂), 3.92 (3H, S), 7.33 (1H, dd, J = 9.3Hz, 6.4Hz)
[0025]
Example 4(BF₂BF by fluorination of AAM_ThreeManufacturing of AM: Fig. 4)
A 100 ml transparent fluororesin container equipped with a magnet rotor is charged with 100 g of 70 wt% hydrogen fluoride / 30 wt% pyridine, and BF₂5.35 g of AAM (purity 99% by weight, about 19 mmol) was added and dissolved at room temperature.
This reaction liquid is cooled from the outside, 1.52 g (22 mmol) of sodium nitrite is added at a temperature of −22 to −3 ° C. (4 minutes), and stirred at room temperature (60 minutes, to 12 ° C.) for diazotization reaction. Went. Next, ultraviolet light was irradiated for 20 hours at room temperature with a 1 kw high-pressure mercury lamp (UVL-1000HC, manufactured by Riko Kagaku Sangyo) to carry out a photo-dediazofluorination reaction. The reaction solution was transferred into 100 g of ice and extracted once with 50 ml of methylene chloride and twice with 20 ml (total of 90 ml). The extracts were combined and washed with 100 ml of distilled water and neutralized with 10% aqueous potassium carbonate solution. (PH 7).
The extract was washed again with 100 ml of distilled water, and the extract layer was separated, dried over sodium sulfate, concentrated on a rotary evaporator, and 5.3 g of crude reaction product (3-bromo-2,4,5-trifluorobenzoate). Methyl acid (BF_ThreeAM) with a GC purity of 96.5% and a reaction yield of approximately 98%. The crude reaction product was fractionally distilled at a reduced pressure of about 0.53 kpa to give 4.6 g of the desired product BF._ThreeAM (purity 99.6% by weight, about 90% yield from BF3AAM) was obtained. This BF_ThreeThe physical properties of AM are as follows.
Boiling point: 88-90 ° C (0.53 kpa)
Mass spectrum (EI): M / Z = 268
¹H-NMR (270 MHz, CDCl_Three)
δ value (ppm): 3.95 (3H, s), 7.80 (1H, ddd, J = 10.0Hz, 8.5Hz, 6.4Hz)
[0026]
Example 5(C₂BC by bromination of NAM₂Production of NAM: Fig. 5)
In Example 2, a similar apparatus was used except that the reactor was replaced with a 500 ml separable flask and a 4-neck cover, and methyl 2,4-dichloro-5-nitrobenzoate (C₂NAM) 75.0 g (purity about 99% by weight, about 0.3 mol) and 90% by weight sulfuric acid 300 ml were charged, and potassium bromate 40.1 g (0.24 mol) was added over 84 minutes and reacted (input temperature 12). The progress of the reaction was observed with GC (raw material C)₂NAM 14.6%, target reaction product methyl 3-bromo-2,4-dichloro-5-nitrobenzoate (BC₂NAM) 81.4%).
Furthermore, 10 g (0.06 mol) of potassium bromate was added over 20 minutes to cause the reaction (input temperature: 12 to 14 ° C.). After stirring for 20 minutes, the reaction mixture is transferred to 1 kg of ice, extracted with 1 l of methylene chloride in three portions, washed with 1 l of water, treated with 1 l of 2% aqueous sodium thiosulfate, and the extract is separated. Dry over sodium sulfate and concentrate to 65.8 g of crude product (target BC₂A GC purity of NAM of 95.2% and an approximate yield of 63%) was obtained.
The total amount of the crude product was dissolved in 500 ml of methanol / water (5: 1) and purified by recrystallization. The filtrate was combined with the recrystallized second crystal and dried under reduced pressure to obtain the desired product BC.₂57.5 g of NAM (purity 98.4% by weight, yield about 57%) was obtained. This BC₂The physical properties of NAM are as follows.
Melting point: 71-73 ° C
Mass spectrum (EI): M / Z = 327
¹H-NMR (270 MHz, CDCl_Three)
δ value (ppm): 3.99 (3H, s), 8.21 (1H, s)
[0027]
Example 6(BC₂BC by reduction of NAM₂Production of AAM: Fig. 6)
Using the same device as in Example 3, BC₂49.3 g of NAM (purity: about 98.4% by weight, about 0.147 mol), 150 ml of ethyl acetate and 5 g of 5% -palladium carbon catalyst (water content: 50%) were charged, and catalytic hydrogen reduction reaction was carried out at room temperature for 2.5 hours (internal temperature) 26-28 ° C). After completion of the reaction, the same operation as in Example 3 was carried out except that the additional amount of ethyl acetate for dissolving the crystals was 600 ml, and 43.8 g of a crude product (target product BC₂AAM GC purity of 96% was obtained (approximately 95% yield). The total amount of this crude product was dissolved in 400 ml of methanol and recrystallized in the same manner as in Example 3. The same purification procedure as in Example 3 was carried out except that 30 g of 35% by weight hydrochloric acid was used. The desired product (methyl 3-bromo-2,4-dichloro-5-aminobenzoate (BC₂AAM), a purity of 98% by weight, and a yield of about 81%. This BC₂The physical property values of AAM are as follows.
Melting point: 164-167 ° C
Mass spectrum (EI): m / z = 297
¹H-NMR (270 MHz, CDCl_Three)
δ value (ppm): 3.92 (3H, s), 4.32 (2H, brs, NH)₂), 7.13 (1H, S)
[0028]
Example 7(BC₂BC by fluorination of AAM₂Production of FAM: Fig. 7)
In the same apparatus as in Example 4, 33.4 g of 70 wt% hydrogen fluoride / 30 wt% pyridine was taken and BC₂6.01 g of AAM (purity weight 98%, about 19.7 mmol) was added and stirred. The slurry-like reaction liquid was cooled from the outside, and 1.52 g (about 22 mmol) of sodium nitrite at a temperature range of −2 to −8 ° C. ) Was added (4 minutes), and the mixture was stirred at room temperature (60 minutes, ˜25 ° C.) to conduct a diazotization reaction. The reaction solution was cooled to −40 ° C., and 66.6 g of anhydrous hydrofluoric acid cooled to −20 ° C. was added dropwise over 5 minutes while stirring, and about 90 wt% hydrogen fluoride / 10 wt% pyridine 100 g was added. It was set as the reaction liquid.
Next, ultraviolet light was irradiated for 8 hours at room temperature with a 1 Kw high-pressure mercury lamp (UVL-1000HC, manufactured by Riko Kagaku Sangyo) to carry out a photodeazo difluorination reaction. The reaction solution was transferred to 150 g of ice, extracted three times with 20 ml of methylene chloride (total 60 ml), and the extract was combined and subjected to the same post-treatment as in Example 4 to obtain 6.0 g of a crude reaction product (3- Methyl bromo-2,4-dichloro-5-fluorobenzoate (BC₂FAM) was obtained with a GC purity of 94.3% and a reaction yield of approximately 95%. This BC₂The physical properties of FAM are as follows.
Melting point: 85-87 ° C
Mass spectrum (EI): m / z = 300
¹H-NMR (270 MHz, CDCl_Three)
δ value (ppm): 3.95 (3H, s), 7.59 (1H, d, J = 8.3 Hz)
[0029]
Comparative Example 1(F_ThreeAM bromination)
Except for the volume of 25 ml, an apparatus similar to that of Example 1 was used to add methyl 2,4,5-trifluorobenzoate (F_ThreeAM) 1.9 g (purity 99.6 wt%, about 10 mmol) and 90 wt% sulfuric acid 7.5 ml were charged, the amount of potassium bromate added 2.8 g (17 mmol), and the time required for charging the potassium bromate 35 minutes ( The operation was almost the same as in Example 1 except that the temperature was 15 to 26 ° C. The obtained crude reaction product was 0.69 g, and the desired product BF._ThreeAbout 45% AM, raw material F_ThreeContains about 30% AM, about 4% dibromo, and others._ThreeBF from AM_ThreeThe AM yield was about 11%, and the raw material conversion rate was about 80%.
[0030]
Comparative Example 2(F_ThreeAM bromination)
A reflux condenser is added to the apparatus of Example 1, and F_Three1.9 g of AM (purity 99.6% by weight, about 10 mmol) and 0.07 g of iron powder were charged and heated to 80 ° C. Bromine (1.0 g, 6 mmol) was added dropwise over 5 minutes, followed by reaction at 80 ° C. for 1 hour. Further, 0.07 g of iron powder was added, and 1.0 g (6 mmol) of bromine was added dropwise over 5 minutes, the temperature was raised to 100 ° C., the mixture was reacted for 2 hours, and cooled. 10 ml of methylene chloride was dissolved in the reaction contents, the solid was removed by filtration, washed with 50 ml of water, treated with 200 ml of 3% aqueous sodium thiosulfate solution, and further washed with 50 ml of water, and the organic layer was separated. The extract was dried over sodium sulfate and concentrated on a rotary evaporator. The reaction crude yield is 0.3 g. According to the GC analysis result, the target product BF_ThreeAM is 2.1%, raw material F_ThreeAM was 97.2%.
[0031]
Comparative Example 3(F₂Bromination of NAM)
F was added to a 10 ml eggplant flask equipped with a magnet rotor and reflux condenser.₂2.17 g of NAM (purity of about 99.3 wt%, about 10 mmol), 5 ml of 25% fuming sulfuric acid (orium), 0.1 g of anhydrous aluminum chloride and 3.2 g (20 mmol) of bromine were reacted and reacted at 70 ° C. for 4 hours. The post-treatment as in Example 2 was performed. The reaction crude yield is 0.4 g. According to the GC analysis result, the target product BF₂NAM is only 0.7% and raw material F_ThreeThe NAM was 95.3%.
[0032]
Comparative Example 4(F₂Bromination of NAM)
In the same apparatus as in Comparative Example 1, 8 ml of water and 8 ml of 98% concentrated sulfuric acid were charged and cooled with ice.₂2.17 g of NAM (purity about 99.3% by weight, about 10 mmol) and 1.67 g (10 mmol) of potassium bromate were charged and reacted at 10 to 20 ° C. for 90 minutes. After the reaction contents were transferred to 30 g of ice, the same operation as in Example 1 was performed. The reaction gross yield is 2.1 g. According to the GC analysis result, the target product BF₂NAM is 13.4%, raw material F₂NAM is 83.7%, raw material F₂NAM conversion is 14%, raw material F₂Target BF from NAM₂The approximate yield of NAM was 9%, and the approximate yield from the raw material conversion was 69%.
[0033]
Comparative Example 5(F₂Bromination of AAM: Fig. 8)
The same apparatus as in Comparative Example 1 was charged with 12.2 g of 15% hydrochloric acid (about 50 mmol as hydrochloric acid), cooled with ice from the outside, and added with methyl 2,4-difluoro-5-aminobenzoate (F_ThreeAAM) 1.87 g (purity about 100% by weight, about 10 mmol) was added. While maintaining the internal temperature at 5 ° C. or less, 1.6 g (10 mmol) of bromine was added dropwise (3 minutes), and the reaction was carried out at 1-4 ° C. for 70 minutes. The reaction solution was transferred to 50 g of ice water, neutralized with 10% aqueous potassium carbonate solution (pH 8), extracted once with 30 ml of methylene chloride and twice with 20 ml (total 70 ml), and the extracted solution was 3% aqueous sodium thiosulfate solution. Washing with 200 ml, drying with sodium sulfate, and concentration with a rotary evaporator gave 2.58 g of crude reaction product. According to gas chromatography mass spectrometry (GC-MS), this is methyl bromo-2,4-difluoro-5-aminobenzoate (BF₂AAM) (BF₂GC purity of AAM 98.0%, reaction yield 95%).
This reaction crude product was dissolved in 5 ml of methylene chloride, and 1.2 g of 35% by weight hydrochloric acid was added dropwise to add BF.₂Crystals were precipitated as AAM hydrochloride, filtered after cooling with ice from the outside, and the crystals were washed with 2 ml of methylene chloride and dried by suction. The crystals were transferred to a beaker, dispersed by adding 10 ml of methylene chloride and 5 ml of water, and neutralized by adding dropwise a 10% aqueous potassium carbonate solution (pH 8). The methylene chloride layer was separated, dried over sodium sulfate, concentrated with a rotary evaporator, and dried under reduced pressure.₂2.47 g of AAM (purity 98.6% by weight, yield about 91%) was obtained. This BF₂As a result of detailed analysis of AAM, methyl 6-bromo-2,4-difluoro-5-nitrobenzoate (6i-BF₂AAM). The physical properties are as follows.
Melting point: 77-79 ° C
Mass spectrum (EI): m / z = 265
¹H-NMR (270 MHz, CDCl_Three)

[0034]
Comparative Example 6(C₂Bromination of NAM)
Except for the addition of the reflux condenser, the same apparatus as in Example 1 was used.₂NAM 5.0 g (purity about 99% by weight, about 20 mmol), water 14 ml and potassium bromate 3.3 g (20 mmol) were charged and heated to 65 ° C., and concentrated sulfuric acid 16 ml was added dropwise over a period of 82 minutes (60-69 ° C.). The mixture was further reacted at 70 ° C. for 1 hour. The reaction solution was collected and the progress of the reaction was observed by GC.₂NAM is 95%, the target BC₂NAM was only 3.4%.
[0035]
【The invention's effect】
According to the production method of the present invention, a 3-bromo-5-fluoro-2,4-dihalogenobenzoic acid derivative useful as an intermediate for pharmaceuticals, agricultural chemicals and the like can be industrially efficiently produced at low cost using readily available raw materials. It is possible to manufacture.
[Brief description of the drawings]
FIG. 1 is an explanatory view showing a manufacturing process of the present invention.
2 is an explanatory diagram showing a synthesis method of Example 1. FIG.
3 is an explanatory diagram showing a synthesis method of Example 3. FIG.
4 is an explanatory diagram showing a synthesis method of Example 4. FIG.
5 is an explanatory diagram showing a synthesis method of Example 5. FIG.
6 is an explanatory diagram showing a synthesis method of Example 6. FIG.
7 is an explanatory diagram showing a synthesis method of Example 7. FIG.
8 is an explanatory diagram showing a synthesis method of Comparative Example 5. FIG.

Claims (3)

2,4-dihalogeno-5-nitrobenzoic acid or an alkyl ester thereof (halogens at positions 2 and 4 are fluorine or chlorine) and bromate in a mixture of 70 to 100% by weight sulfuric acid to By brominating 4-dihalogeno-5-nitrobenzoic acid or its alkyl ester, the following formula (I) (wherein X ¹ and X ² are fluorine or chlorine, R is hydrogen or C ¹ -C 6 linear or Production of 3-bromo-2,4-dihalogeno-5-nitrobenzoic acid represented by a branched alkyl group) or an alkyl ester thereof (halogens at 2 and 4 positions are fluorine or chlorine) Method.

The process according to claim 1, wherein the bromate is an alkali metal salt or alkaline earth metal salt of bromic acid. Reduction of 3-bromo-2,4-dihalogeno-5-nitrobenzoic acid or an alkyl ester thereof produced by the method of claim 1 or claim 2 (halogens at the 2- and 4-positions are fluorine or chlorine). 3-bromo-2,4-dihalogeno-5-aminobenzoic acid or an alkyl ester thereof in which the above nitro group is substituted with an amino group, and diazotized and then dediazofluorinated to give 3-bromo A method for producing -2,4-dihalogeno-5-fluorobenzoic acid or an alkyl ester thereof (halogens at the 2-position and 4-position are fluorine or chlorine) .

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