JP4254093B2 - Method for producing 5-halogenoindole - Google Patents

Method for producing 5-halogenoindole Download PDF

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Publication number
JP4254093B2
JP4254093B2 JP2001319614A JP2001319614A JP4254093B2 JP 4254093 B2 JP4254093 B2 JP 4254093B2 JP 2001319614 A JP2001319614 A JP 2001319614A JP 2001319614 A JP2001319614 A JP 2001319614A JP 4254093 B2 JP4254093 B2 JP 4254093B2
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Japan
Prior art keywords
halogeno
reaction
halogenoindole
acid
fluoro
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JP2003128650A (en
Inventor
繁栄 西野
健二 弘津
修司 横山
毅 高橋
広行 小田
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Ube Corp
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Ube Industries Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/08Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Description

【0001】
【発明の属する技術分野】
本発明は、5-ハロゲノインドールの新規な製法に関する。5-ハロゲノインドールは、医薬、農薬等の中間原料として有用な化合物であり、特に、5-フルオロインドールは、抗生物質等の医薬品の合成中間体となり得る化合物である。
【0002】
【従来の技術】
従来、5-ハロゲノインドールの製法としては、以下の文献が開示されている。
▲1▼Heterocycles,22,195(1984);N,N-ジメチルホルムアミド中、5-ハロゲノ-2-ニトロトルエンにN,N-ジメチルホルムアミドジメチルアセタールを反応させて5-ハロゲノ-β-ジメチルアミノ-2-ニトロスチレンを生成させた後、次いで、水素雰囲気下、ラネーニッケルで還元・環化させて5-ハロゲノインドールを製造する方法が開示されている。しかしながら、この方法では、5-ハロゲノ-2-ニトロトルエンからの目的物の収率が低い(5-フルオロインドールで46.9%、5-クロロインドールで68.6%)という問題があった。
▲2▼J.Chem.Soc.,1959,1913;カリウムの存在下、ジエチルエーテルとエタノールの混合溶媒中で、5-フルオロ-2-ニトロトルエンにシュウ酸ジエチルを反応させて5-フルオロ-2-ニトロフェニルピルビン酸カリウムを生成させた後、次いで、これに、アンモニア水及び硫酸鉄を加えて反応させ、得られた固体を酸性条件下で加熱することによって、5-フルオロインドールを製造する方法が開示されている。しかしながら、この方法では、5-フルオロ-2-ニトロトルエン目的物の収率が15%と低いという問題があった。
▲3▼J.Heterocycl.Chem.,2,298(1965);テトラクロロメタン溶媒中で、m-フルオロトルエンにN-ブロモスクシンイミドを反応させてm-フルオロベンジルブロマイドとし、次いで、これに、水とエタノールの混合溶媒中で、シアン化カリウムを反応させてm-フルオロベンジルシアニドを生成させ、その後、これを硝酸等でニトロ化して2-ニトロ-5-フルオロベンジルシアニドとなし、更に、これを水素雰囲気下、パラジウム/炭素で還元・環化させて5-ハロゲノインドールを製造する方法が開示されている。しかしながら、この方法では、m-フルオロトルエンからの目的物の収率が21%と低いという問題があった。
いずれの製法も反応系が複雑であったり、収率が低い等の種々の問題点を含んでおり、工業的な製法としては不利であった。
【0003】
【発明が解決しようとする課題】
本発明の課題は、即ち、上記問題点を解決し、簡便な方法にて、入手が容易な2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルから5-ハロゲノインドールを高収率で得る、工業的に好適な5-ハロゲノインドールの製法を提供するものである。
【0004】
【課題を解決するための手段】
本発明の課題は、
(A)一般式(1)
【0005】
【化4】
【0006】
(式中、Rは、炭化水素基を示し、Xは、ハロゲン原子を示す。)
で示される2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルを脱炭酸させて、一般式(2)
【0007】
【化5】
【0008】
(式中、Xは、前記と同義である。)
で示される5-ハロゲノ-2-ニトロベンジルシアニドとする第一工程、
(B)次いで、5-ハロゲノ-2-ニトロベンジルシアニドを還元条件下で環化させる第二工程、
を含んでなることを特徴とする、一般式(3)
【0009】
【化6】
【0010】
(式中、Xは、前記と同義である。)
で示される5-ハロゲノインドールの製法。
【発明の実施の形態】
本発明は、
(A)一般式(1)で示される2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルを脱炭酸させて、一般式(2)で示される5-ハロゲノ-2-ニトロベンジルシアニドとする第一工程、
(B)次いで、5-ハロゲノ-2-ニトロベンジルシアニドを還元条件下で環化させる第二工程、
を含んでなる二つの工程によって5-ハロゲノインドールを反応生成物として得るものである。
【0011】
引き続き、前記の二つの工程を順次説明する。
(A)第一工程
本発明の第一工程は、一般式(1)で示される2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルを脱炭酸させて、一般式(2)で示される5-ハロゲノ-2-ニトロベンジルシアニドを得る工程である。
【0012】
本発明の第一工程で使用される2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルは、前記の一般式(1)で示される。その一般式(1)において、Rは、炭化水素基であり、具体的には、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等のアルキル基;シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等のシクロアルキル基;ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基等のアラルキル基;フェニル基、トリル基、ナフチル基、アントラニル基等のフェニル基が挙げられる。なお、これらの基は、各種異性体も含む。
【0013】
本発明の第一工程は、一般的に行われる脱炭酸方法であれば特に限定されないが、酸の存在下で行うのが好ましい。
【0014】
前記酸としては、例えば、塩酸、硫酸、硝酸、リン酸等の無機酸;メタンスルホン酸、酢酸等の有機酸が挙げられるが、好ましくは無機酸、更に好ましくは塩酸が使用される。なお、これらの酸は、単独又は二種以上を混合して使用しても良い。
【0015】
前記酸の使用量は、2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステル1molに対して、好ましくは1〜20mol、更に好ましくは5〜10molである。
【0016】
本発明の第一工程は、溶媒の存在下で反応させるのが好ましく、使用される溶媒としては、反応を阻害しないものならば特に限定されず、例えば、水;メタノール、エタノール、イソプロピルアルコール、n-ブチルアルコール、t-ブチルアルコール等のアルコール類;テトラヒドロフラン、ジオキサン等のエーテル類が挙げられるが、好ましくは水、アルコール類、更に好ましくは水、メタノール、エタノールが使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【0017】
前記溶媒の使用量は、溶液の均一性や攪拌性により適宜調節するが、2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステル1gに対して、好ましくは2〜100g、更に好ましくは4〜50gである。
【0018】
本発明の第一工程は、例えば、2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステル、酸及び溶媒を混合して攪拌させる等の方法によって行われる。その際の反応温度は、好ましくは5〜110℃、更に好ましくは20〜100℃であり、反応圧力は特に制限されない。
【0019】
本発明の第一工程によって5-ハロゲノ-2-ニトロベンジルシアニドが得られるが、これは、例えば、反応終了後、再結晶、蒸留、カラムクロマトグラフィー等による一般的な方法によって一旦単離・精製して第二工程に使用しても良いが、単離・精製を行わずに第二工程に使用しても構わない。
【0020】
(B)第二工程
本発明の第二工程は、第一工程で得られた5-ハロゲノ-2-ニトロベンジルシアニドを還元条件下で環化させて、5-ハロゲノインドールを得る工程である。
【0021】
本発明の第二工程は、一般的に行われる還元方法であれば特に限定されないが、触媒の存在下、水素雰囲気で行うのが好ましい。
【0022】
前記触媒としては、パラジウム、白金、ニッケルからなる群より選ばれる少なくとも一つの金属原子を含むものであり、具体的には、例えば、パラジウム/炭素、パラジウム/硫酸バリウム、水酸化パラジウム/炭素、白金/炭素、パラジウム-白金/炭素、酸化白金、ラネーニッケル等が挙げられるが、好ましくはパラジウム/炭素、ラネーニッケルが使用される。なお、これらの触媒は、単独又は二種以上を混合して使用しても良い。
【0023】
前記触媒の使用量は、5-ハロゲノ-2-ニトロベンジルシアニドに対して、金属原子換算で、好ましくは0.01〜10質量%、更に好ましくは0.05〜1質量%である。
【0024】
本発明の第二工程は、溶媒中で反応させるのが好ましく、使用される溶媒としては、反応を阻害しないものならば特に限定されず、例えば、水;メタノール、エタノール、イソプロピルアルコール、t-ブチルアルコール等のアルコール類;酢酸メチル、酢酸エチル等のカルボン酸エステル類;ベンゼン、トルエン等の芳香族炭化水素類;テトラヒドロフラン、ジオキサン等のエーテル類が挙げられるが、好ましくはアルコール類、カルボン酸エステル類、更に好ましくはメタノール、エタノール、酢酸エチルが使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【0025】
前記溶媒の使用量は、溶液の均一性や攪拌性により適宜調節するが、5-ハロゲノ-2-ニトロベンジルシアニド1gに対して、好ましくは1〜50g、更に好ましくは3〜30gである。
【0026】
本発明の第二工程は、例えば、水素雰囲気にて(不活性ガスで希釈されていても良い)、5-ハロゲノ-2-ニトロベンジルシアニド、触媒及び溶媒を混合して、攪拌させる等の方法によって行われる。その際の反応温度は、好ましくは0〜120℃、更に好ましくは20〜60℃であり、反応圧力は、好ましくは0.1〜5MPa、更に好ましくは0.1〜2MPaである。
【0027】
また、必要に応じて、反応性を高めるために酸や活性炭を加えても良く、酸としては、具体的には、例えば、塩酸、硝酸、硫酸、リン酸等の無機酸;ギ酸、酢酸、プロピオン酸等の有機酸が挙げられるが、好ましくは有機酸、更に好ましくは酢酸が使用される。なお、これらの酸は、単独又は二種以上を混合して使用しても良く、又、酸と活性炭を同時に使用しても構わない。
【0028】
前記酸の使用量は、5-ハロゲノ-2-ニトロベンジルシアニド1molに対して、好ましくは0.01〜20mol、更に好ましくは0.1〜5.0molである。
【0029】
前記活性炭の使用量は、5-ハロゲノ-2-ニトロベンジルシアニド1gに対して、好ましくは0.01〜10g、更に好ましくは0.1〜5.0gである。
【0030】
本発明の第二工程によって5-ハロゲノインドールが得られるが、これは、例えば、反応終了後、再結晶、蒸留、カラムクロマトグラフィー等による一般的な方法によって単離・精製される。
【0031】
【実施例】
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
【0032】
参考例1(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチルの合成)
攪拌装置、温度計及び滴下漏斗を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、ナトリウムメトキシド4.62g(83.8mmol)及びジメチルスルホキシド20mlを加え、次いで、室温で攪拌しながら、純度99%のシアノ酢酸メチル8.37g(83.8mmol)を10分間かけてゆるやかに滴下した。反応液の温度を20〜30℃に保ちながら、純度98%の2,4-ジフルオロニトロベンゼン6.76g(41.6mmol)を1時間かけてゆるやかに滴下した後、同温度で6時間反応させた。反応終了後、氷浴で反応液の温度を10℃以下に保ちながら、トルエン10mlを加え、1mol/l塩酸41.9ml(41.19mmol)をゆるやかに滴下した。次いで、有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄して、有機層を減圧下で濃縮した。得られた濃縮液をシリカゲルカラムクロマトグラフィー(充填剤:ワコーゲルC-200(和光純薬社製)、展開溶媒:トルエン)で精製し、白色結晶として、純度99.4%(高速液体クロマトグラフィーによる面積百分率)の2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル7.98gを得た(2,4-ジフルオロニトロベンゼン基準の単離収率:80.0%)。
2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチルの物性値は以下の通りであった。
【0033】
融点;43〜44℃
EI-MS(m/e);192(M-NO2)、CI-MS(m/e);239(M+1)
1H-NMR(CDCl3,δ(ppm));3.88(3H,s)、5.71(1H,s)、7.3〜7.4(1H,m)、7.45〜7.55(1H,m)、8.3〜8.4(1H,m)
【0034】
実施例1(5-フルオロ-2-ニトロベンジルシアニドの合成)
攪拌装置及び温度計を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、参考例1で合成した純度99.4%の2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル7.98g(33.3mmol)、6mol/l塩酸33ml及びメタノール33mlを加え、85℃まで昇温して9時間反応させた。反応終了後、反応液を氷浴で0〜10℃まで冷却して30分間攪拌して結晶を析出させた。析出して来た結晶を濾過した後、メタノール/水混合溶媒(=2/1(容量比))67ml中に加え、液温を70℃まで昇温させて結晶を完全に溶解させた後、再び反応液を氷浴で0〜10℃まで冷却して30分間攪拌して結晶を析出させた。析出して来た結晶を濾過した後に減圧下で乾燥させ、白色結晶として、純度99.0%(高速液体クロマトグラフィーによる定量値)の5-フルオロ-2-ニトロベンジルシアニド4.85gを得た(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の単離収率:80.1%)。
5-フルオロ-2-ニトロベンジルシアニドの物性値は以下の通りであった。
【0035】
融点;65〜66℃
EI-MS(m/e);180(M+)、CI-MS(m/e);181(M+1)
1H-NMR(CDCl3,δ(ppm));4.21(2H,s)、7.23〜7.28(1H,m)、7.46〜7.49(1H,m)、8.26〜8.31(1H,m)
【0036】
実施例2(5-フルオロインドールの合成)
攪拌装置、温度計、還流冷却器及びガス導入管を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、実施例1で合成した純度99.0%の5-フルオロ-2-ニトロベンジルシアニド4.85g(26.7mmol)及びメタノール60mlを加えた。次いで、反応液の温度を40〜45℃まで昇温して、攪拌しながら5質量%パラジウム/炭素(49%含水品)0.5gを加え、常圧にて水素を流速15.0ml/min.で吹き込みながら、同温度で3時間反応させた。その後、一旦、反応系内をアルゴン雰囲気にした後、再び5質量%パラジウム/炭素(49%含水品)0.5gを追加し、常圧にて水素を流速15.0ml/min.で吹き込みながら、同温度で更に3時間反応させた。反応終了後、反応液を濾過し、濾液を減圧下で濃縮した。得られた濃縮液をシリカゲルカラムクロマトグラフィー(充填剤:ワコーゲルC-200(和光純薬社製)、展開溶媒:トルエン)で精製し、白色結晶として、純度99.5%(高速液体クロマトグラフィーによる定量値)の5-フルオロインドール2.89gを得た(5-フルオロ-2-ニトロベンジルシアニド基準の単離収率:79.8%)。
5-フルオロインドールの物性値は以下の通りであった。
【0037】
融点;47〜48℃
EI-MS(m/e);135(M+)、CI-MS(m/e);136(M+1)
1H-NMR(CDCl3,δ(ppm));6.50(1H,s)、6.91〜6.98(1H,m)、7.23〜7.32(3H,m)、8.23(1H,brs)
【0038】
参考例2(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチルの合成)
攪拌装置、温度計及び滴下漏斗を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、ナトリウムメトキシド5.08g(92.2mmol)及びジメチルスルホキシド20mlを加え、次いで、室温で攪拌しながら、純度99%のシアノ酢酸メチル9.21g(92.2mmol)を10分間かけてゆるやかに滴下した。反応液の温度を-15〜-10℃に保ちながら、純度98%の2,4-ジフルオロニトロベンゼン6.80g(41.9mmol)を1時間かけてゆるやかに滴下した後、同温度で2時間反応させた。反応終了後、氷浴で反応液の温度を10℃以下に保ちながら、酢酸エチル50mlを加え、1mol/l塩酸50.3ml(50.3mmol)をゆるやかに滴下した。次いで、有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄して、有機層を減圧下で濃縮し、油状黄色液体として、純度69.8%の2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル13.55gを得た(2,4-ジフルオロニトロベンゼン基準の単離収率:94.7%)。
【0039】
実施例3(5-フルオロ-2-ニトロベンジルシアニドの合成)
攪拌装置及び温度計を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、参考例2で合成した純度69.8%の2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル13.55g(39.7mmol)、3mol/l塩酸79ml及びメタノール39mlを加え、85℃まで昇温して9時間反応させた。反応終了後、反応液を氷浴で0〜10℃まで冷却して30分間攪拌して結晶を析出させた。析出して来た結晶を濾過した後、メタノール/水混合溶媒(=2/1(容量比))27ml中に加え、液温を70℃まで昇温させて結晶を完全に溶解させた後、再び反応液を氷浴で0〜10℃まで冷却して30分間攪拌して結晶を析出させた。析出して来た結晶を濾過した後に減圧下で乾燥させ、白色結晶として、純度99.2%(高速液体クロマトグラフィーによる面積百分率)の5-フルオロ-2-ニトロベンジルシアニド6.27gを得た(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の単離収率:87.0%)。
【0040】
実施例4(5-フルオロインドールの合成)
攪拌装置、温度計、還流冷却器及びガス導入管を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、実施例3で合成した純度99.2%の5-フルオロ-2-ニトロベンジルシアニド6.27g(34.5mmol)及びメタノール40mlを加えた。次いで、反応液の温度を40〜45℃まで昇温して、攪拌しながら5質量%パラジウム/炭素(49%含水品)0.6gを加え、常圧にて水素を流速20.0ml/min.で吹き込みながら、同温度で3時間反応させた。その後、一旦、反応系内をアルゴン雰囲気にした後、再び5質量%パラジウム/炭素(49%含水品)0.6gを追加し、常圧にて水素を流速20.0ml/min.で吹き込みながら、同温度で更に3時間反応させた。反応終了後、反応液に活性炭0.5gを加え、70℃まで昇温し攪拌した。次いで、反応液を濾過し、濾液を減圧下で濃縮した。得られた濃縮液をメタノール6mlに溶解させ、0〜10℃の冷水33ml中にゆるやかに加えて結晶を析出させた。結晶を濾過後、減圧下で乾燥させ、白色結晶として、純度99.5%(高速液体クロマトグラフィーによる定量値)の5-フルオロインドール4.20gを得た(5-フルオロ-2-ニトロベンジルシアニド基準の単離収率:89.8%)。
【0041】
実施例5(5-フルオロインドールの合成)
攪拌装置、温度計、還流冷却器及びガス導入管を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、実施例1と同様な方法で合成した純度99.0%の5-フルオロ-2-ニトロベンジルシアニド4.85g(26.7mmol)、メタノール60ml及び酢酸0.45ml(26.6mmol)を加えた。次いで、反応液の温度を40〜45℃まで昇温して、攪拌しながら5質量%パラジウム/炭素(49%含水品)0.5gを加え、常圧にて水素を流速15.0ml/min.で吹き込みながら、同温度で10時間反応させた。反応終了後、反応液を濾過し、濾液を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、5-フルオロインドールが3.49g生成していた(5-フルオロ-2-ニトロベンジルシアニド基準の反応収率:95.0%)。
【0042】
実施例6(5-フルオロインドールの合成)
攪拌装置、温度計、還流冷却器及びガス導入管を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、実施例1と同様な方法で合成した純度99.0%の5-フルオロ-2-ニトロベンジルシアニド5.00g(27.5mmol)、メタノール30ml及び活性炭(武田薬品社製:白鷺A)3.0gを加えた。次いで、反応液の温度を40〜45℃まで昇温して、攪拌しながら5質量%パラジウム/炭素(49%含水品)0.5gを加え、常圧にて水素を流速15.0ml/min.で吹き込みながら、同温度で10時間反応させた。反応終了後、反応液を濾過し、濾液を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、5-フルオロインドールが3.49g生成していた(5-フルオロ-2-ニトロベンジルシアニド基準の反応収率:94.0%)。
【0043】
実施例7(5-フルオロインドールの合成)
攪拌装置、温度計及びガス導入管を備えた内容積100mlの耐圧容器に、アルゴン雰囲気下、実施例1と同様な方法で合成した純度99.0%の5-フルオロ-2-ニトロベンジルシアニド5.00g(27.5mmol)、メタノール30ml及び5質量%パラジウム/炭素(49%含水品)0.5gを加えた。次いで、反応系内を水素で置換した後、反応液の温度を55〜60℃まで昇温し、水素圧を0.9MPa(ゲージ圧)として、同温度で10時間反応させた。反応終了後、反応液を濾過し、濾液を高速液体クロマトグラフィーにより分析(絶対定量法)したところ、5-フルオロインドールが3.42g生成していた(5-フルオロ-2-ニトロベンジルシアニド基準の反応収率:92.0%)。
【0044】
【発明の効果】
本発明により、簡便な方法にて、入手が容易な2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルから5-ハロゲノインドールを高収率で得る、工業的に好適な5-ハロゲノインドールの製法を提供することが出来る。
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing 5-halogenoindoles. 5-halogenoindole is a compound useful as an intermediate raw material for pharmaceuticals, agricultural chemicals and the like, and in particular, 5-fluoroindole is a compound that can be a synthetic intermediate for pharmaceuticals such as antibiotics.
[0002]
[Prior art]
Conventionally, the following documents have been disclosed as a method for producing 5-halogenoindole.
(1) Heterocycles, 22 , 195 (1984); 5-halogeno-2-nitrotoluene in N, N-dimethylformamide was reacted with N, N-dimethylformamide dimethylacetal to give 5-halogeno-β-dimethylamino-2 A method for producing 5-halogenoindole by producing nitrostyrene and then reducing and cyclizing with Raney nickel in a hydrogen atmosphere is disclosed. However, this method has a problem that the yield of the desired product from 5-halogeno-2-nitrotoluene is low (46.9% for 5-fluoroindole and 68.6% for 5-chloroindole).
(2) J. Chem. Soc., 1959 , 1913; 5-fluoro-2-nitrotoluene is reacted with diethyl oxalate in a mixed solvent of diethyl ether and ethanol in the presence of potassium to give 5-fluoro-2- After producing potassium nitrophenylpyruvate, this was then reacted with aqueous ammonia and iron sulfate, and the resulting solid was heated under acidic conditions to produce 5-fluoroindole. It is disclosed. However, this method has a problem that the yield of the 5-fluoro-2-nitrotoluene target product is as low as 15%.
(3) J. Heterocycl. Chem., 2 , 298 (1965); In a tetrachloromethane solvent, m-fluorotoluene is reacted with N-bromosuccinimide to form m-fluorobenzyl bromide. In a mixed solvent of ethanol and ethanol, potassium cyanide is reacted to form m-fluorobenzyl cyanide, which is then nitrated with nitric acid or the like to form 2-nitro-5-fluorobenzyl cyanide. A method for producing 5-halogenoindole by reduction and cyclization with palladium / carbon in a hydrogen atmosphere is disclosed. However, this method has a problem that the yield of the target product from m-fluorotoluene is as low as 21%.
All of the production methods have various problems such as a complicated reaction system and a low yield, which is disadvantageous as an industrial production method.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems and to increase 5-halogenoindole from 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate which is easily available by a simple method. An industrially suitable process for producing 5-halogenoindole obtained in a yield is provided.
[0004]
[Means for Solving the Problems]
The subject of the present invention is
(A) General formula (1)
[0005]
[Formula 4]
[0006]
(In the formula, R represents a hydrocarbon group, and X represents a halogen atom.)
2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate represented by the general formula (2)
[0007]
[Chemical formula 5]
[0008]
(Wherein X is as defined above.)
A first step of 5-halogeno-2-nitrobenzyl cyanide represented by
(B) a second step of cyclizing 5-halogeno-2-nitrobenzyl cyanide under reducing conditions;
General formula (3), characterized by comprising
[0009]
[Chemical 6]
[0010]
(Wherein X is as defined above.)
A process for producing 5-halogenoindole represented by
DETAILED DESCRIPTION OF THE INVENTION
The present invention
(A) 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate represented by the general formula (1) is decarboxylated to give a 5-halogeno-2-nitro represented by the general formula (2) The first step of benzylcyanide,
(B) a second step of cyclizing 5-halogeno-2-nitrobenzyl cyanide under reducing conditions;
2-halogenoindole is obtained as a reaction product by two steps comprising:
[0011]
Subsequently, the two steps will be sequentially described.
(A) First Step In the first step of the present invention, 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate represented by the general formula (1) is decarboxylated to give a general formula (2 Is a step of obtaining 5-halogeno-2-nitrobenzyl cyanide represented by
[0012]
The 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester used in the first step of the present invention is represented by the above general formula (1). In the general formula (1), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. Alkyl groups such as decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group; aralkyl groups such as benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group; phenyl group , Phenyl groups such as tolyl group, naphthyl group and anthranyl group. These groups include various isomers.
[0013]
Although the 1st process of this invention will not be specifically limited if it is the decarboxylation method generally performed, It is preferable to carry out in presence of an acid.
[0014]
Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as methanesulfonic acid and acetic acid, but inorganic acids are preferable, and hydrochloric acid is more preferable. In addition, you may use these acids individually or in mixture of 2 or more types.
[0015]
The amount of the acid used is preferably 1 to 20 mol, more preferably 5 to 10 mol, relative to 1 mol of 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester.
[0016]
The first step of the present invention is preferably carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, n -Alcohols such as butyl alcohol and t-butyl alcohol; ethers such as tetrahydrofuran and dioxane may be mentioned, but water, alcohols, and more preferably water, methanol, and ethanol are used. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0017]
The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 2 to 100 g, based on 1 g of 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate, Preferably it is 4-50g.
[0018]
The first step of the present invention is performed, for example, by a method such as mixing 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester, acid and solvent and stirring. The reaction temperature at that time is preferably 5 to 110 ° C., more preferably 20 to 100 ° C., and the reaction pressure is not particularly limited.
[0019]
According to the first step of the present invention, 5-halogeno-2-nitrobenzylcyanide is obtained, which is once isolated by a general method such as recrystallization, distillation, column chromatography after the completion of the reaction. Although it may be purified and used in the second step, it may be used in the second step without isolation and purification.
[0020]
(B) Second step The second step of the present invention is a step in which 5-halogeno-2-nitrobenzyl cyanide obtained in the first step is cyclized under reducing conditions to obtain 5-halogenoindole. .
[0021]
The second step of the present invention is not particularly limited as long as it is a reduction method generally performed, but it is preferably performed in a hydrogen atmosphere in the presence of a catalyst.
[0022]
The catalyst contains at least one metal atom selected from the group consisting of palladium, platinum, and nickel. Specifically, for example, palladium / carbon, palladium / barium sulfate, palladium hydroxide / carbon, platinum / Carbon, palladium-platinum / carbon, platinum oxide, Raney nickel and the like are mentioned, and palladium / carbon and Raney nickel are preferably used. In addition, you may use these catalysts individually or in mixture of 2 or more types.
[0023]
The amount of the catalyst used is preferably 0.01 to 10% by mass, more preferably 0.05 to 1% by mass, in terms of metal atom, based on 5-halogeno-2-nitrobenzyl cyanide.
[0024]
The second step of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, t-butyl Alcohols such as alcohols; Carboxylic acid esters such as methyl acetate and ethyl acetate; Aromatic hydrocarbons such as benzene and toluene; Ethers such as tetrahydrofuran and dioxane are preferable, but alcohols and carboxylic acid esters are preferable. More preferably, methanol, ethanol or ethyl acetate is used. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0025]
The amount of the solvent used is appropriately adjusted depending on the homogeneity and agitation of the solution, but is preferably 1 to 50 g, more preferably 3 to 30 g, relative to 1 g of 5-halogeno-2-nitrobenzyl cyanide.
[0026]
In the second step of the present invention, for example, in a hydrogen atmosphere (which may be diluted with an inert gas), 5-halogeno-2-nitrobenzyl cyanide, a catalyst and a solvent are mixed and stirred. Done by the method. The reaction temperature at that time is preferably 0 to 120 ° C., more preferably 20 to 60 ° C., and the reaction pressure is preferably 0.1 to 5 MPa, more preferably 0.1 to 2 MPa.
[0027]
Further, if necessary, an acid or activated carbon may be added to increase the reactivity. Specific examples of the acid include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid; formic acid, acetic acid, Although organic acids, such as propionic acid, are mentioned, Preferably an organic acid is used, More preferably, an acetic acid is used. In addition, these acids may be used alone or in combination of two or more, or the acid and activated carbon may be used simultaneously.
[0028]
The amount of the acid used is preferably 0.01 to 20 mol, more preferably 0.1 to 5.0 mol, with respect to 1 mol of 5-halogeno-2-nitrobenzyl cyanide.
[0029]
The amount of the activated carbon used is preferably 0.01 to 10 g, more preferably 0.1 to 5.0 g, with respect to 1 g of 5-halogeno-2-nitrobenzyl cyanide.
[0030]
5-halogenoindole is obtained by the second step of the present invention, and this is isolated and purified by a general method such as recrystallization, distillation, column chromatography, etc. after the reaction is completed.
[0031]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0032]
Reference Example 1 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel, 4.62 g (83.8 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide and 20 ml of dimethyl sulfoxide were added under an argon atmosphere. % Methyl cyanoacetate 8.37 g (83.8 mmol) was slowly added dropwise over 10 minutes. While maintaining the temperature of the reaction solution at 20 to 30 ° C., 6.76 g (41.6 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 1 hour, followed by reaction at the same temperature for 6 hours. After completion of the reaction, 10 ml of toluene was added while keeping the temperature of the reaction solution at 10 ° C. or lower in an ice bath, and 41.9 ml (41.19 mmol) of 1 mol / l hydrochloric acid was slowly added dropwise. Then, the organic layer was separated, washed with 50 ml of water and 50 ml of saturated brine in this order, and the organic layer was concentrated under reduced pressure. The obtained concentrated liquid was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene) to obtain white crystals, purity 99.4% (area percentage by high performance liquid chromatography) Of 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate (isolated yield based on 2,4-difluoronitrobenzene: 80.0%).
The physical properties of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate were as follows.
[0033]
Melting point: 43-44 ° C
EI-MS (m / e); 192 (M-NO 2 ), CI-MS (m / e); 239 (M + 1)
1 H-NMR (CDCl 3 , δ (ppm)); 3.88 (3H, s), 5.71 (1H, s), 7.3 to 7.4 (1H, m), 7.45 to 7.55 (1H, m), 8.3 to 8.4 ( 1H, m)
[0034]
Example 1 (Synthesis of 5-fluoro-2-nitrobenzyl cyanide)
Methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate with a purity of 99.4% synthesized in Reference Example 1 under an argon atmosphere was placed in a 200-ml glass flask equipped with a stirrer and a thermometer. g (33.3 mmol), 33 ml of 6 mol / l hydrochloric acid and 33 ml of methanol were added, and the mixture was heated to 85 ° C. and reacted for 9 hours. After completion of the reaction, the reaction solution was cooled to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. After filtering the precipitated crystals, it was added to 67 ml of a methanol / water mixed solvent (= 2/1 (volume ratio)), and the liquid temperature was raised to 70 ° C. to completely dissolve the crystals. The reaction solution was cooled again to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 4.85 g of 5-fluoro-2-nitrobenzyl cyanide having a purity of 99.0% (quantitative value by high performance liquid chromatography) as white crystals (2 -(5-Fluoro-2-nitrophenyl) -2-cyanoacetic acid based on isolated yield: 80.1%).
The physical properties of 5-fluoro-2-nitrobenzyl cyanide were as follows.
[0035]
Melting point: 65-66 ° C
EI-MS (m / e); 180 (M +), CI-MS (m / e); 181 (M + 1)
1 H-NMR (CDCl 3 , δ (ppm)); 4.21 (2H, s), 7.23-7.28 (1H, m), 7.46-7.49 (1H, m), 8.26-8.31 (1H, m)
[0036]
Example 2 (Synthesis of 5-fluoroindole)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser, and a gas introduction tube, 98.5% purity of 5-fluoro-2-nitrobenzyl cyanide 4.85 synthesized in Example 1 was added under an argon atmosphere. g (26.7 mmol) and 60 ml of methanol were added. Next, the temperature of the reaction solution was raised to 40 to 45 ° C., 0.5 g of 5 mass% palladium / carbon (49% water-containing product) was added with stirring, and hydrogen was supplied at normal pressure with a flow rate of 15.0 ml / min. The reaction was carried out at the same temperature for 3 hours while blowing. Then, once the atmosphere in the reaction system was changed to an argon atmosphere, 0.5 g of 5% by mass palladium / carbon (49% water-containing product) was added again, and hydrogen was blown at a normal flow rate at a flow rate of 15.0 ml / min. The reaction was allowed to proceed for an additional 3 hours at temperature. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated solution was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene), and white crystals, purity 99.5% (quantitative value by high performance liquid chromatography) ) Was obtained (isolated yield based on 5-fluoro-2-nitrobenzyl cyanide: 79.8%).
The physical property values of 5-fluoroindole were as follows.
[0037]
Melting point: 47-48 ° C
EI-MS (m / e); 135 (M +), CI-MS (m / e); 136 (M + 1)
1 H-NMR (CDCl 3 , δ (ppm)); 6.50 (1H, s), 6.91 to 6.98 (1H, m), 7.23 to 7.32 (3H, m), 8.23 (1H, brs)
[0038]
Reference Example 2 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel, 5.08 g (92.2 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide were added under an argon atmosphere, followed by stirring at room temperature with a purity of 99. % 9.21 g (92.2 mmol) of methyl cyanoacetate was slowly added dropwise over 10 minutes. While maintaining the temperature of the reaction solution at -15 to -10 ° C, 6.80 g (41.9 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was dropped slowly over 1 hour, and then reacted at the same temperature for 2 hours. . After completion of the reaction, 50 ml of ethyl acetate was added while keeping the temperature of the reaction solution at 10 ° C. or lower in an ice bath, and 50.3 ml (50.3 mmol) of 1 mol / l hydrochloric acid was slowly added dropwise. Then, the organic layer was separated and washed with 50 ml of water and 50 ml of saturated brine in this order, and the organic layer was concentrated under reduced pressure to give 2- (5-fluoro-2-nitro with a purity of 69.8% as an oily yellow liquid. 13.55 g of methyl phenyl) -2-cyanoacetate was obtained (isolated yield based on 2,4-difluoronitrobenzene: 94.7%).
[0039]
Example 3 (Synthesis of 5-fluoro-2-nitrobenzyl cyanide)
Methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate with a purity of 69.8% synthesized in Reference Example 2 under an argon atmosphere was placed in a 200-ml glass flask equipped with a stirrer and a thermometer. g (39.7 mmol), 3 mol / l hydrochloric acid 79 ml and methanol 39 ml were added, and the mixture was heated to 85 ° C. and reacted for 9 hours. After completion of the reaction, the reaction solution was cooled to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. After filtering the precipitated crystals, it was added to 27 ml of a methanol / water mixed solvent (= 2/1 (volume ratio)), and the liquid temperature was raised to 70 ° C. to completely dissolve the crystals. The reaction solution was cooled again to 0 to 0 ° C. with an ice bath and stirred for 30 minutes to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 6.27 g of 5-fluoro-2-nitrobenzyl cyanide having a purity of 99.2% (area percentage by high performance liquid chromatography) as white crystals (2 -(5-Fluoro-2-nitrophenyl) -2-cyanoacetic acid based on isolated yield: 87.0%).
[0040]
Example 4 (Synthesis of 5-fluoroindole)
A 99.2% pure 5-fluoro-2-nitrobenzyl cyanide synthesized in Example 3 was placed in a 200 mL glass flask equipped with a stirrer, thermometer, reflux condenser and gas inlet tube under an argon atmosphere. g (34.5 mmol) and 40 ml of methanol were added. Next, the temperature of the reaction solution is raised to 40 to 45 ° C., 0.6 g of 5 mass% palladium / carbon (49% water-containing product) is added with stirring, and hydrogen is supplied at normal pressure with a flow rate of 20.0 ml / min. The reaction was carried out at the same temperature for 3 hours while blowing. Then, once the inside of the reaction system was put into an argon atmosphere, 0.6 g of 5% by mass palladium / carbon (49% water-containing product) was added again, and hydrogen was blown in at normal pressure at a flow rate of 20.0 ml / min. The reaction was allowed to proceed for an additional 3 hours at temperature. After completion of the reaction, 0.5 g of activated carbon was added to the reaction solution, and the mixture was heated to 70 ° C. and stirred. The reaction was then filtered and the filtrate was concentrated under reduced pressure. The obtained concentrated solution was dissolved in 6 ml of methanol and slowly added to 33 ml of cold water at 0 to 0 ° C. to precipitate crystals. The crystals were filtered and dried under reduced pressure to obtain 4.20 g of 5-fluoroindole having a purity of 99.5% (quantitative value by high performance liquid chromatography) as white crystals (based on 5-fluoro-2-nitrobenzyl cyanide standard). Isolated yield: 89.8%).
[0041]
Example 5 (Synthesis of 5-fluoroindole)
A 99.0% pure 5-fluoro-2-nitro synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser and a gas introduction tube. 4.85 g (26.7 mmol) of benzylcyanide, 60 ml of methanol and 0.45 ml (26.6 mmol) of acetic acid were added. Next, the temperature of the reaction solution was raised to 40 to 45 ° C., 0.5 g of 5 mass% palladium / carbon (49% water-containing product) was added with stirring, and hydrogen was supplied at normal pressure with a flow rate of 15.0 ml / min. The reaction was carried out at the same temperature for 10 hours while blowing. After completion of the reaction, the reaction solution was filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3.49 g of 5-fluoroindole was formed (based on 5-fluoro-2-nitrobenzyl cyanide standard). Reaction yield: 95.0%).
[0042]
Example 6 (Synthesis of 5-fluoroindole)
A 99.0% pure 5-fluoro-2-nitro synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser and a gas introduction tube. 5.00 g (27.5 mmol) of benzylcyanide, 30 ml of methanol and 3.0 g of activated carbon (manufactured by Takeda Pharmaceutical Co., Ltd .: Shirasagi A) were added. Next, the temperature of the reaction solution was raised to 40 to 45 ° C., 0.5 g of 5 mass% palladium / carbon (49% water-containing product) was added with stirring, and hydrogen was supplied at normal pressure with a flow rate of 15.0 ml / min. The reaction was carried out at the same temperature for 10 hours while blowing. After completion of the reaction, the reaction solution was filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3.49 g of 5-fluoroindole was formed (based on 5-fluoro-2-nitrobenzyl cyanide standard). Reaction yield: 94.0%).
[0043]
Example 7 (Synthesis of 5-fluoroindole)
In a pressure-resistant container having an internal volume of 100 ml equipped with a stirrer, a thermometer and a gas introduction tube, 5.00 g of 5-fluoro-2-nitrobenzyl cyanide having a purity of 99.0% synthesized in the same manner as in Example 1 under an argon atmosphere (27.5 mmol), 30 ml of methanol and 0.5 g of 5% by mass palladium / carbon (49% water-containing product) were added. Next, after the inside of the reaction system was replaced with hydrogen, the temperature of the reaction solution was raised to 55 to 60 ° C., and the hydrogen pressure was set to 0.9 MPa (gauge pressure), and the reaction was performed at the same temperature for 10 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3.42 g of 5-fluoroindole was formed (based on 5-fluoro-2-nitrobenzyl cyanide standard). Reaction yield: 92.0%).
[0044]
【The invention's effect】
According to the present invention, industrially suitable 5 is obtained in a simple manner by obtaining 5-halogenindole in a high yield from 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetate which is easily available. -We can provide a method for producing halogenoindole.

Claims (7)

(A)一般式(1)
(式中、Rは、炭化水素基を示し、Xは、ハロゲン原子を示す。)で示される2-(5-ハロゲノ-2-ニトロフェニル)-2-シアノ酢酸エステルを脱炭酸させて、一般式(2)
(式中、Xは、前記と同義である。)で示される5-ハロゲノ-2-ニトロベンジルシアニドとする第一工程、(B)次いで、5-ハロゲノ-2-ニトロベンジルシアニドを、パラジウム、白金及びニッケルからなる群より選ばれる少なくとも一つの金属原子を含む触媒 5- ハロゲノ -2- ニトロベンジルシアニドに対して、金属原子換算で0.01〜10質量%で存在させ5- ハロゲノ -2- ニトロベンジルシアニド1gに対して0.01〜10gの活性炭を加えて、水素を吹き込みながら環化させる第二工程、を含んでなることを特徴とする、一般式(3)
(式中、Xは、前記と同義である。)で示される5-ハロゲノインドールの製法。
(A) General formula (1)
(Wherein R represents a hydrocarbon group, and X represents a halogen atom) 2- (5-halogeno-2-nitrophenyl) -2-cyanoacetic acid ester represented by Formula (2)
(Wherein X has the same meaning as described above) 5-halogeno-2-nitrobenzyl cyanide shown in (B), then 5-halogeno-2-nitrobenzyl cyanide, palladium, a catalyst containing at least one metal atom selected from the group consisting of platinum and nickel with respect to 5-halogeno-2-nitrobenzyl cyanide is present in 0.01 to 10 mass% in terms of metal atom, 5 - adding 0.01~10g of activated carbon with respect halogeno-2-nitrobenzyl cyanide 1g, characterized in that it comprises a second step, the cyclization while introducing hydrogen, the formula (3)
(Wherein, X is as defined above), a method for producing 5-halogenoindole.
第二工程を、0.1〜5.0gの活性炭を加えて行う、請求項1記載のThe second step is performed by adding 0.1 to 5.0 g of activated carbon. 5-Five- ハロゲノインドールの製法。How to make halogenoindole. 第二工程を、常圧で行う、請求項1記載のThe second step is performed at normal pressure. 5-Five- ハロゲノインドールの製法。How to make halogenoindole. 第二工程を、酸を加えて行う、請求項1〜3のいずれか1項記載の5-ハロゲノインドールの製法。The method for producing 5-halogenoindole according to any one of claims 1 to 3 , wherein the second step is performed by adding an acid. 第一工程を、酸の存在下で行う請求項1〜4のいずれか1項記載の5-ハロゲノインドールの製法。The method for producing 5-halogenoindole according to any one of claims 1 to 4 , wherein the first step is performed in the presence of an acid. 触媒の使用量が、5-ハロゲノ-2-ニトロベンジルシアニドに対して、金属原子換算で、0.05〜1質量%である、請求項1〜5のいずれか1項記載の5-ハロゲノインドールの製法。The 5-halogeno of any one of Claims 1-5 whose usage-amount of a catalyst is 0.05-1 mass% in conversion of a metal atom with respect to 5-halogeno-2-nitrobenzyl cyanide. Indole manufacturing method. Xがフッ素原子である請求項1〜のいずれか1項記載の5-ハロゲノインドールの製法。X is a fluorine atom, The manufacturing method of 5-halogeno indole of any one of Claims 1-6 .
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