JP4922534B2 - Method for preparing 2-aminoethylpyridine - Google Patents
Method for preparing 2-aminoethylpyridine Download PDFInfo
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- JP4922534B2 JP4922534B2 JP2002521198A JP2002521198A JP4922534B2 JP 4922534 B2 JP4922534 B2 JP 4922534B2 JP 2002521198 A JP2002521198 A JP 2002521198A JP 2002521198 A JP2002521198 A JP 2002521198A JP 4922534 B2 JP4922534 B2 JP 4922534B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【0001】
本発明は、農薬の製造のための中間体として有用である、2−アミノメチルピリジン類(特に2−アミノメチル−3−クロロ−5−トリフルオロメチルピリジン)の新しい調製のための、および、その調製において使用する2−シアノピリジン類の調製のための新しい方法に関する。
【0002】
シアノピリジンの接触水素化によりアミノメチルピリジンが得られることは知られている。しかしながら、シアノピリジン化合物が追加のハロゲン原子を含んでいる場合、この還元は、競合する脱ハロゲン化反応により複雑化する場合がある。P.N.ライランダー(P.N.Rylander)の「水素化方法(Hydrogenation Methods, Best Synthetic Series, Academic Press, 1985)」の148頁によれば、パラジウムは通常脱ハロゲン化反応を行いたい場合に選択される触媒であり、そして白金およびロジウムは、比較的非効果的であり、それ故、ハロゲンを温存したい場合に、水素化にたびたび用いられる。
【0003】
上記した従来技術の教示とは反対に、我々はパラジウム触媒の使用により追加のハロゲン化原子を含むシアノピリジンの還元において特に良好な結果が得られることを発見した。我々は最小限の脱ハロゲン化しか起こらず、工業的規模の工程に適用できる、別のハロゲン原子を有する2−アミノメチルピリジンの調製のための新しい方法を開発した。
【0004】
ピリジン部分の2位にシアノ基を導入するための多くの方法が報告されている。これらは典型的には、極性溶媒中、例えばジメチルスルホキシドまたはジメチルホルムアミド中の、ハロゲン、特に臭素またはフッ素の置換を含んでいる。更にまた、活性化ピリジンN−オキシドまたはN−アルキルピリジンを原料とする多くの方法がある。これらのシアン化経路の多くは銅またはニッケルを含む重金属試薬を使用する。例えば、欧州特許0034917号は120℃でのジメチルホルムアミド中のシアン化銅との反応による2−ブロモ類縁体から2−シアノ−3−クロロ−5−トリフルオロメチルピリジンの調製を開示している。
【0005】
しかしながら、これらの従来技術の方法の多くは、低収率、毒性流出物をもたらす重金属の使用または回収が困難な極性溶媒の使用を含む複数の難点を含んでいる。更にまた、ピリジンN−オキシドまたはN−アルキルピリジンの形成を含む方法は数工程を含む。これらの難点は工業的規模にまでスケールアップする際に更に重大なものとなる。
【0006】
独国特許公開117970号は極性溶媒中での活性化剤およびシアン化物源を用いた2−ハロピリジン化合物のシアン化を記載しており、これにより上記した不都合な点の多くを回避している。しかしながら、この操作法においてもなお、工業的規模の工程のための費用を最小限とするためには活性化剤および非プロトン性溶媒の再使用を必要とする。
【0007】
我々は今、工業的規模の工程に適用できる2−シアノピリジン類の調製のための代替となる進歩した方法を開発した。
【0008】
本発明の第1の態様によれば、下記式(I):
【0009】
【化8】
で示される化合物またはその塩の調製方法(A)であって、下記式(II):
【0010】
【化9】
[式中、Xはハロゲンであり、各Yは同じかまたは異なっていて、ハロゲン、ハロアルキル、アルコキシカルボニルまたはアルキルスルホニルであり、そしてnは0から3である]の化合物またはその塩の接触水素化を包含する上記調製方法が提供される。
【0011】
本発明においてはハロゲンとはフッ素、塩素または臭素原子を意味する、好ましいハロゲン原子は塩素である。
【0012】
ハロアルキルとは典型的にはハロゲン原子1個以上で置換されたC1からC6アルキル部分を意味する。例えばC1からC6アルキル部分はメチル、エチル、n−プロピルまたはi−プロピルであって良く、好ましくはメチルである。C1からC6アルキル部分は好ましくは塩素またはフッ素原子1個以上で置換されている。より好ましいハロアルキル基はトリフルオロメチルである。
【0013】
アルコキシカルボニル基は典型的にはC1からC6アルコキシカルボニル、例えばメトキシカルボニル、エトキシカルボニル、n−プロポキシカルボニルまたはi−プロポキシカルボニルである。
【0014】
アルキルスルホニル基は典型的にはC1からC6部分が上述の通り定義されるC1からC6アルキルスルホニルである。
【0015】
好ましくはXは塩素である。
【0016】
好ましくはYハロゲンまたはハロアルキル(より好ましくはトリフルオロメチル)である。
【0017】
化合物(II)は好ましくは3−クロロ−2−シアノ−5−トリフルオロメチルピリジンである。
【0018】
触媒は、一般にパラジウム、白金、ルテニウム、ニッケルおよびコバルトから選択される金属を含有する。使用する触媒(通常は例えば炭素のような支持体上に担持)中の金属の量は、一般的には式(II)の化合物の量に対して0.05から0.7重量%、好ましくは、0.05から0.3%、より好ましくは0.1から0.2%である。好ましい触媒は、パラジウム、例えば炭素のような不活性担体上の微細分割パラジウムを含有している。これにより好都合な反応速度および最小限の副反応の双方が可能となる。即ち、式(II)の化合物が3−クロロ−2−シアノ−5−トリフルオロメチルピリジンである場合、本発明の方法を用いれば脱塩素化が最小限となる。好ましい触媒のその他の例には上記した金属の酸化物または他の化合物が包含される。
【0019】
この方法は、典型的にはアルコール(例えばメタノール、エタノール、プロパノールまたはブタノール)、または、酢酸エチルのようなエステル、または、テトラヒドロフランのようなエーテルのような溶媒の存在下に行なう。アルコール溶媒が好ましい(メタノールが最も好ましい)。この方法は好ましくは塩酸、臭化水素酸、硫酸またはリン酸のような強酸(好ましくは塩酸)の存在下で行なう。酸の存在は、式(I)の生成物のアミノ基による触媒の汚染を防止する作用があり、さらにまた、そうでない場合にはニトリルの接触水素化中に起こることが知られているアミノ中間体のカップリングを防止する。
【0020】
反応条件は典型的には適切な反応容器中で全ての反応体を混合すること、および例えば0から60℃、好ましくは20から30℃の温度で攪拌することを含む。この方法の別の利点は1から4気圧の水素圧を一般的に用いて、低い圧力を使用する点である(この方法は好ましくは1気圧で行なう)。
【0021】
この反応は、場合により、副反応として起こる場合がある脱ハロゲン化の程度を低減することにより反応の選択性を更に向上させる触媒阻害剤の存在下に行なう。このような触媒阻害剤は、例えばP.N.ライランダー(P.N.Rylander)の「水素化方法(Hydrogenation Methods, Best Synthetic Series, Academic Press, 1985)」の125から126頁に記載されている通り当該分野で知られており、アルカリ金属の臭化物またはヨウ化物、例えば臭化カリウムおよびヨウ化カリウム、または臭化アンモニウムまたはヨウ化アンモニウム、または臭化水素またはヨウ化水素、またはトリフェニルホスフィイト、次亜リン酸、リン酸またはアルキルホスフィン酸のようなリン化合物、またはチオグリコール(2,2’−チオジエタノール)、またはチオ尿素またはイオウを包含する。好ましくは触媒阻害剤は、アルカリ金属の臭化物またはヨウ化物、臭化アンモニウムまたはヨウ化アンモニウムおよびヨウ化水素から選択される。
【0022】
即ち、本発明は2−アミノメチルピリジンの調製のための高収率で選択性のある好都合な方法を提供する。
【0023】
塩、とりわけ塩酸塩の形態で式(I)の化合物を生成することが特に好都合である。農薬の製造における中間体として使用する場合は、塩は相当する遊離アミンを予め単離することなく、直接、次の反応工程に付すことができる。従って、塩の形成とその後の反応は一容器で好都合に行なうことができる。特に好ましい塩は2−アミノメチル−3−クロロ−5−トリフルオロメチルピリジン塩酸塩である。
【0024】
本発明の更に別の態様によれば、上述において定義した式(II)の化合物の調製方法(B)であって、下記式(III):
【0025】
【化10】
[式中、X、Yおよびnは上述において定義する通りである]の化合物を水性の溶媒中または溶媒を用いることなくシアン化物源と触媒とで処理することを包含する方法であり、シアン化物源はシアン化水素、アルカリ金属シアン化物、アルカリ土類金属シアン化物または場合により置換されたシアン化アンモニウムである上記調製方法が提供される。
【0026】
触媒は、一般に相転移触媒、例えば、ベンジルトリメチルアンモニウムクロリド、トリカプリルメチルアンモニウムクロリド、テトラメチルアンモニウムクロリド、テトラ−n−プロピルアンモニウムブロミド、n−ドデシルトリメチルアンモニウムクロリド、テトラ−n−ブチルアンモニウムクロリド、テトラ−n−ブチルアンモニウムブロミド、テトラ−n−オクチルアンモニウムブロミドまたはn−テトラデシルトリメチルアンモニウムブロミドのようなテトラアルキルアンモニウム塩、またはテトラ−n−ブチルホスホニウムブロミドまたはテトラフェニルホスホニウムブロミドのようなテトラアルキルホスホニウム塩、または、クラウンエーテルまたはそのアクリル系類縁体、例えばTDA−1(トリス[2−(2−メトキシエトキシ)エチル]アミン)、または4−ジメチルアミノピリジンのようなアミンである。
【0027】
好ましくは触媒は、トリカプリルメチルアンモニウムクロリドおよびテトラ−n−オクチルアンモニウムブロミドから選択される。
【0028】
使用する触媒の量は、一般に約0.01から10モル%、好ましくは約0.1から5モル%、より好ましくは約1から5モル%である。
【0029】
化合物(III)は好ましくは3−クロロ−2−フルオロ−5−トリフルオロメチルピリジンである。
【0030】
本発明の上記方法(B)は、2−シアノピリジン類の調製のための高収率の方法であり、容易に行なうことができ、中等度の温度で操作され、多くの従来技術の方法の難点を有さない。特に本発明の方法は、工業的規模で使用された場合に毒性のある流出物を生じたり回収することが困難な銅またはニッケルのシアン化物のような重金属のシアン化物を必要としない。本発明の方法(B)は容易に処理できる排液を生じる。
【0031】
更にまた、この方法は、多くの従来技術の方法で必要とされていた高い変換率のための活性化ピリジンN−オキシドまたはN−アルキルピリジンの調製を必要としない。本発明の方法(B)は、4−ジメチルアミノピリジンのような活性化剤を必要とせず、このため、更に回収や再使用の工程を行なわなくてよい。本発明の方法(B)の別の利点は、反応に有機溶媒を使用しない点であり、これによりジメチルスルホキシドのような高価な溶媒を再使用する必要がない。
【0032】
シアン化物源は、好ましくはシアン化ナトリウムまたはシアン化カリウム、好ましくはシアン化カリウムである。使用するシアン化物源の量は、一般的には約1.0から約2.0モル等量(しかしながら所望によりより多い量を使用してもよい)、好ましくは1.0から1.5モル等量、より好ましくは1.0から1.1モル等量である。
【0033】
反応は、一般的に好ましくは水を溶媒として用いながら行なわれるが、溶媒の非存在下で行なってもよい。
【0034】
この反応条件は、典型的には適切な反応容器中で全ての反応体を混合すること、および、0から60℃、好ましくは20から40℃の温度で攪拌することを含む。
【0035】
即ち、本発明は2−シアノピリジンの調製のための高収率の方法(B)を提供する。この反応は中等度の反応温度を使用するため、必要とされるものは単純で安価な反応器および下流処理装置のみである。更にまた、反応体は容易に入手できるため、この方法は安価に実施できる。更に、本発明の方法は容易に処理できる排液を生じる。
【0036】
本発明の更に別の態様によれば、方法(B)および(A)を組み合わせて式(III)の化合物から式(I)の化合物を調製することができる。
【0037】
本発明の更に別の態様によれば方法(A)または(B)および(A)の組み合せ方法の後、更に、下記式(IV):
【0038】
【化11】
[式中、Lは脱離基であり、R1およびR2は各々同じかまたは異なるハロゲンであり、そしてmは0、1または2である]のベンゾイル化合物で式(I)の化合物をアシル化することにより、下記式(V):
【0039】
【化12】
の化合物を得ることを包含す方法(C)をおこなう。
【0040】
好ましくはLは塩素である。
【0041】
式(V)の化合物は例えば国際特許公開WO99/42447に開示されている価値ある農薬活性成分である。
【0042】
式(V)の好ましい化合物は、下記物質:
N−[(3−クロロ−5−トリフルオロメチル−2−ピリジル)メチル]−2,6−ジクロロベンズアミド;
N−[(3−クロロ−5−トリフルオロメチル−2−ピリジル)メチル]−2,6−ジフルオロベンズアミド;
N−[(3−クロロ−5−トリフルオロメチル−2−ピリジル)メチル]−2−クロロ−6−フルオロベンズアミド;
N−[(3−クロロ−5−トリフルオロメチル−2−ピリジル)メチル]−2,3−ジフルオロベンズアミド;
N−[(3−クロロ−5−トリフルオロメチル−2−ピリジル)メチル]−2,4,6−トリフルオロベンズアミド、または、
N−[(3−クロロ−5−トリフルオロメチル−2−ピリジル)メチル]−2−ブロモ−6−フルオロベンズアミド;
である。
【0043】
方法(C)は国際特許公開WO99/42447に記載されている。
【0044】
本発明の更に別の特徴によれば、方法(B)または(B)および(A)の組み合せ方法または(B)、(A)および(C)の組み合せを、下記式(VI):
【0045】
【化13】
[式中X、Yおよびnは前述の通り定義される]の化合物のフッ素化を包含する前の方法(D)と組み合わせることができる。
【0046】
方法(D)は一般的にはアルカリ金属フッ化物、好ましくはフッ化カリウムまたはフッ化ナトリウムのような適当なフッ素化試薬を用いて、ジメチルスルホキシドまたはスルホランのような非プロトン性の溶媒中、50から150℃の温度で行なう。
【0047】
本発明の上記方法により得られる式(I)および(II)の化合物は以下の反応スキームに従う式(V)の殺カビ活性2−ピリジルメチルアミン誘導体の調製において特に有用である。
【0048】
【化14】
【0049】
本発明を以下の調製実施例により更に説明する。
【0050】
実施例1(方法A)
3−クロロ−2−シアノ−5−トリフルオロメチルピリジン(5.1g)および5%Pd/C(金属Pdとして5.1mg)の混合物を水素1気圧下メタノールおよび濃塩酸(2.5ml)と共に20℃で攪拌した。4時間後、HPLCによれば反応が完了していた。混合物をセラトム(Celatom)で濾過し、メタノールおよび水で洗浄し、蒸発させて2−アミノメチル−3−クロロ−5−トリフルオロメチルピリジン塩酸塩を95から97%の収率で得た。
NMR(重水中)4.6(s,2H),8.35(s,1H),8.9(s,1H)。
【0051】
実施例2(方法B)
水(215g)中のシアン化カリウム(71.6g)の溶液を30℃の3−クロロ−2−フルオロ−5−トリフルオロメチルピリジン(199.5g)およびAliquat336(トリカプリリルメチルアンモニウムクロリド、12.1g)の攪拌混合物に1時間かけて添加した。この温度で攪拌を4時間継続した時点で、原料のフッ化物の量はHPLCによれば1%未満となった。下層の有機層を分離し、塩化ナトリウム水溶液で洗浄し、蒸留して15mbarでの沸点が90℃の3−クロロ−2−シアノ−5−トリフルオロメチルピリジン(185.5g、90%収率)を得た。この生成物の純度は98%であった。
【0052】
実施例3(方法B)
固体のシアン化ナトリウム(0.29g)を20から25℃の3−クロロ−2−フルオロ−5−トリフルオロメチルピリジン(0.8g)とテトラブチルアンモニウムブロミド(0.06g)の攪拌混合物に添加し、23時間攪拌して3−クロロ−2−シアノ−5−トリフルオロメチルピリジン(0.68g、HPLCによる収率82%)を得た。
【0053】
方法(D)の実施例
2,3−ジクロロ−5−トリフルオロメチルピリジン(800g)を110℃の無水フッ化カリウム(320g)と無水ジメチルスルホキシドの攪拌混合物に添加し、次に2時間加熱し、そして減圧下に分別蒸留し、3−クロロ−2−フルオロ−5−トリフルオロメチルピリジン(685g)を収率92%で得た(純度98%)。[0001]
The present invention is useful for the new preparation of 2-aminomethylpyridines (especially 2-aminomethyl-3-chloro-5-trifluoromethylpyridine), which are useful as intermediates for the production of pesticides, and It relates to a new process for the preparation of 2-cyanopyridines used in its preparation.
[0002]
It is known that aminomethylpyridine can be obtained by catalytic hydrogenation of cyanopyridine. However, if the cyanopyridine compound contains additional halogen atoms, this reduction may be complicated by competing dehalogenation reactions. P. N. According to PNRylander's “Hydrogenation Methods, Best Synthetic Series, Academic Press, 1985”, page 148, palladium is usually the catalyst of choice when it is desired to carry out a dehalogenation reaction, and Platinum and rhodium are relatively ineffective and are therefore frequently used for hydrogenation when it is desired to preserve the halogen.
[0003]
Contrary to the prior art teaching described above, we have found that the use of a palladium catalyst gives particularly good results in the reduction of cyanopyridines containing additional halogenated atoms. We have developed a new method for the preparation of 2-aminomethylpyridines with another halogen atom that can be applied to industrial scale processes with minimal dehalogenation.
[0004]
Many methods for introducing a cyano group at the 2-position of the pyridine moiety have been reported. These typically involve substitution of halogens, in particular bromine or fluorine, in polar solvents such as dimethyl sulfoxide or dimethylformamide. Furthermore, there are many methods using activated pyridine N-oxide or N-alkylpyridine as a raw material. Many of these cyanide pathways use heavy metal reagents including copper or nickel. For example, EP 0034917 discloses the preparation of 2-cyano-3-chloro-5-trifluoromethylpyridine from 2-bromo analogs by reaction with copper cyanide in dimethylformamide at 120 ° C.
[0005]
However, many of these prior art methods involve several difficulties, including the use of heavy metals that result in low yields, toxic effluents, or the use of polar solvents that are difficult to recover. Furthermore, the process involving the formation of pyridine N-oxide or N-alkylpyridine involves several steps. These difficulties become even more critical when scaling up to an industrial scale.
[0006]
German Offenlegungsschrift 117970 describes the cyanation of 2-halopyridine compounds using an activator and a cyanide source in a polar solvent, thereby avoiding many of the disadvantages mentioned above. However, this method of operation still requires the reuse of activator and aprotic solvent to minimize the cost for industrial scale processes.
[0007]
We have now developed an alternative and advanced method for the preparation of 2-cyanopyridines that can be applied to industrial scale processes.
[0008]
According to a first aspect of the present invention, the following formula (I):
[0009]
[Chemical 8]
A method for preparing a compound represented by formula (A), or a salt thereof, comprising:
[0010]
[Chemical 9]
Catalytic hydrogenation of a compound or salt thereof wherein X is halogen, each Y is the same or different and is halogen, haloalkyl, alkoxycarbonyl or alkylsulfonyl, and n is 0 to 3 The above preparation method is provided.
[0011]
In the present invention, halogen means a fluorine, chlorine or bromine atom, and a preferred halogen atom is chlorine.
[0012]
Haloalkyl typically means a C 1 to C 6 alkyl moiety substituted with one or more halogen atoms. For example, the C 1 to C 6 alkyl moiety may be methyl, ethyl, n-propyl or i-propyl, preferably methyl. The C 1 to C 6 alkyl moiety is preferably substituted with one or more chlorine or fluorine atoms. A more preferred haloalkyl group is trifluoromethyl.
[0013]
The alkoxycarbonyl group is typically a C 1 to C 6 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or i-propoxycarbonyl.
[0014]
Alkylsulfonyl group is typically a C 6 alkylsulfonyl C 1 to C 6 moiety is defined as described above from C 1.
[0015]
Preferably X is chlorine.
[0016]
Y halogen or haloalkyl (more preferably trifluoromethyl) is preferred.
[0017]
Compound (II) is preferably 3-chloro-2-cyano-5-trifluoromethylpyridine.
[0018]
The catalyst generally contains a metal selected from palladium, platinum, ruthenium, nickel and cobalt. The amount of metal in the catalyst used (usually supported on a support such as carbon) is generally 0.05 to 0.7% by weight, preferably based on the amount of compound of formula (II) Is from 0.05 to 0.3%, more preferably from 0.1 to 0.2%. Preferred catalysts contain finely divided palladium on an inert support such as palladium, eg carbon. This allows for both favorable reaction rates and minimal side reactions. That is, when the compound of formula (II) is 3-chloro-2-cyano-5-trifluoromethylpyridine, dechlorination is minimized using the method of the present invention. Other examples of preferred catalysts include the metal oxides or other compounds described above.
[0019]
This process is typically carried out in the presence of a solvent such as an alcohol (eg methanol, ethanol, propanol or butanol) or an ester such as ethyl acetate or an ether such as tetrahydrofuran. Alcohol solvents are preferred (methanol is most preferred). This process is preferably carried out in the presence of a strong acid (preferably hydrochloric acid) such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. The presence of the acid serves to prevent the contamination of the catalyst by the amino group of the product of formula (I), and is also known to occur during the catalytic hydrogenation of the nitrile otherwise. Prevent body coupling.
[0020]
Reaction conditions typically include mixing all the reactants in a suitable reaction vessel and stirring, for example, at a temperature of 0 to 60 ° C, preferably 20 to 30 ° C. Another advantage of this method is that it typically uses a hydrogen pressure of 1 to 4 atmospheres and uses a lower pressure (this method is preferably performed at 1 atmosphere).
[0021]
This reaction is optionally carried out in the presence of a catalyst inhibitor that further improves the selectivity of the reaction by reducing the degree of dehalogenation that may occur as a side reaction. Such catalyst inhibitors are exemplified by P.I. N. Known in the art as described in PNRylander, “Hydrogenation Methods, Best Synthetic Series, Academic Press, 1985”, pages 125 to 126, bromides or iodides of alkali metals, For example, potassium bromide and potassium iodide, or ammonium bromide or ammonium iodide, or hydrogen bromide or hydrogen iodide, or phosphorus compounds such as triphenyl phosphite, hypophosphorous acid, phosphoric acid or alkylphosphinic acid Or thioglycol (2,2′-thiodiethanol), or thiourea or sulfur. Preferably the catalyst inhibitor is selected from alkali metal bromides or iodides, ammonium bromide or ammonium iodide and hydrogen iodide.
[0022]
That is, the present invention provides a convenient method with high yield and selectivity for the preparation of 2-aminomethylpyridine.
[0023]
It is particularly advantageous to produce the compound of formula (I) in the form of a salt, in particular the hydrochloride. When used as an intermediate in the production of agricultural chemicals, the salt can be directly subjected to the next reaction step without prior isolation of the corresponding free amine. Thus, salt formation and subsequent reaction can be conveniently performed in a single vessel. A particularly preferred salt is 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride.
[0024]
According to yet another aspect of the present invention, there is provided a process (B) for the preparation of a compound of formula (II) as defined above, wherein
[0025]
[Chemical Formula 10]
A process comprising treating a compound of [wherein X, Y and n are as defined above] with an cyanide source and a catalyst in an aqueous solvent or without using a solvent. The above preparation method is provided wherein the source is hydrogen cyanide, alkali metal cyanide, alkaline earth metal cyanide or optionally substituted ammonium cyanide.
[0026]
The catalyst is generally a phase transfer catalyst such as benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, tetramethylammonium chloride, tetra-n-propylammonium bromide, n-dodecyltrimethylammonium chloride, tetra-n-butylammonium chloride, tetra A tetraalkylammonium salt such as n-butylammonium bromide, tetra-n-octylammonium bromide or n-tetradecyltrimethylammonium bromide, or a tetraalkylphosphonium salt such as tetra-n-butylphosphonium bromide or tetraphenylphosphonium bromide Or crown ethers or acrylic analogs thereof, such as TDA-1 (Tris [2- (2-methoxyeth ) Ethyl] amine), or an amine such as 4-dimethylaminopyridine.
[0027]
Preferably the catalyst is selected from tricaprylmethylammonium chloride and tetra-n-octylammonium bromide.
[0028]
The amount of catalyst used is generally about 0.01 to 10 mol%, preferably about 0.1 to 5 mol%, more preferably about 1 to 5 mol%.
[0029]
Compound (III) is preferably 3-chloro-2-fluoro-5-trifluoromethylpyridine.
[0030]
The above method (B) of the present invention is a high yield method for the preparation of 2-cyanopyridines, can be performed easily, is operated at moderate temperatures, and is Has no difficulties. In particular, the process of the present invention does not require heavy metal cyanides such as copper or nickel cyanides that are toxic effluents and difficult to recover when used on an industrial scale. The method (B) of the present invention produces a drain that can be easily treated.
[0031]
Furthermore, this method does not require the preparation of activated pyridine N-oxides or N-alkylpyridines for the high conversion required by many prior art methods. The method (B) of the present invention does not require an activating agent such as 4-dimethylaminopyridine, and therefore there is no need for further recovery and reuse steps. Another advantage of the method (B) of the present invention is that no organic solvent is used in the reaction, thereby eliminating the need to reuse expensive solvents such as dimethyl sulfoxide.
[0032]
The cyanide source is preferably sodium cyanide or potassium cyanide, preferably potassium cyanide. The amount of cyanide source used is generally from about 1.0 to about 2.0 molar equivalents (but higher amounts may be used if desired), preferably 1.0 to 1.5 molar. An equivalent amount, more preferably 1.0 to 1.1 molar equivalent.
[0033]
The reaction is generally preferably performed using water as a solvent, but may be performed in the absence of a solvent.
[0034]
The reaction conditions typically include mixing all the reactants in a suitable reaction vessel and stirring at a temperature of 0 to 60 ° C, preferably 20 to 40 ° C.
[0035]
That is, the present invention provides a high yield method (B) for the preparation of 2-cyanopyridine. Since this reaction uses moderate reaction temperatures, all that is required is a simple and inexpensive reactor and downstream processing equipment. Furthermore, since the reactants are readily available, this method can be carried out inexpensively. Furthermore, the method of the present invention produces a drain that can be easily processed.
[0036]
According to yet another aspect of the invention, methods (B) and (A) can be combined to prepare compounds of formula (I) from compounds of formula (III).
[0037]
According to yet another aspect of the present invention, after the method (A) or the combined method of (B) and (A), the following formula (IV):
[0038]
Embedded image
Wherein L is a leaving group, R 1 and R 2 are each the same or different halogen, and m is 0, 1 or 2; The following formula (V):
[0039]
Embedded image
Process (C) comprising obtaining a compound of
[0040]
Preferably L is chlorine.
[0041]
The compound of formula (V) is a valuable agrochemical active ingredient as disclosed, for example, in International Patent Publication WO 99/42447.
[0042]
Preferred compounds of formula (V) are the following substances:
N-[(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,6-dichlorobenzamide;
N-[(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,6-difluorobenzamide;
N-[(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2-chloro-6-fluorobenzamide;
N-[(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,3-difluorobenzamide;
N-[(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2,4,6-trifluorobenzamide, or
N-[(3-chloro-5-trifluoromethyl-2-pyridyl) methyl] -2-bromo-6-fluorobenzamide;
It is.
[0043]
Method (C) is described in International Patent Publication WO 99/42447.
[0044]
According to still another aspect of the present invention, a method (B) or a combination method of (B) and (A) or a combination of (B), (A) and (C) is represented by the following formula (VI):
[0045]
Embedded image
It can be combined with the previous method (D) involving fluorination of a compound of the formula wherein X, Y and n are defined as above.
[0046]
Method (D) is generally carried out in an aprotic solvent such as dimethyl sulfoxide or sulfolane using a suitable fluorinating reagent such as an alkali metal fluoride, preferably potassium fluoride or sodium fluoride. To 150 ° C.
[0047]
The compounds of formulas (I) and (II) obtained by the above method of the invention are particularly useful in the preparation of fungicidal 2-pyridylmethylamine derivatives of formula (V) according to the following reaction scheme.
[0048]
Embedded image
[0049]
The invention is further illustrated by the following preparative examples.
[0050]
Example 1 (Method A)
A mixture of 3-chloro-2-cyano-5-trifluoromethylpyridine (5.1 g) and 5% Pd / C (5.1 mg as metal Pd) together with methanol and concentrated hydrochloric acid (2.5 ml) under 1 atm of hydrogen. Stir at 20 ° C. After 4 hours, the reaction was complete according to HPLC. The mixture was filtered through Celatom, washed with methanol and water and evaporated to give 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride in 95-97% yield.
NMR (in heavy water) 4.6 (s, 2H), 8.35 (s, 1H), 8.9 (s, 1H).
[0051]
Example 2 (Method B)
A solution of potassium cyanide (71.6 g) in water (215 g) was added at 30 ° C. with 3-chloro-2-fluoro-5-trifluoromethylpyridine (199.5 g) and Aliquat 336 (tricaprylylmethylammonium chloride, 12.1 g ) Was added to the stirred mixture over 1 hour. When stirring was continued for 4 hours at this temperature, the amount of the raw material fluoride was less than 1% according to HPLC. The lower organic layer was separated, washed with aqueous sodium chloride solution and distilled to 3-chloro-2-cyano-5-trifluoromethylpyridine (185.5 g, 90% yield) having a boiling point of 90 ° C. at 15 mbar. Got. The purity of this product was 98%.
[0052]
Example 3 (Method B)
Solid sodium cyanide (0.29 g) is added to a stirred mixture of 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.8 g) and tetrabutylammonium bromide (0.06 g) at 20-25 ° C. The mixture was stirred for 23 hours to obtain 3-chloro-2-cyano-5-trifluoromethylpyridine (0.68 g, yield 82% by HPLC).
[0053]
Method 2, Example 2,3-Dichloro-5-trifluoromethylpyridine (800 g) was added to a stirred mixture of anhydrous potassium fluoride (320 g) and anhydrous dimethyl sulfoxide at 110 ° C. and then heated for 2 hours. And fractional distillation under reduced pressure gave 3-chloro-2-fluoro-5-trifluoromethylpyridine (685 g) in 92% yield (purity 98%).
Claims (28)
下記式(II):
Formula (II) below:
該触媒が相転移触媒またはクラウンエーテルまたはそのアクリル系類縁体またはアミンである上記調製方法。A process for preparing a compound of formula (II) according to any one of claims 1 to 4, comprising the following formula (III):
The above preparation method, wherein the catalyst is a phase transfer catalyst or a crown ether or an acrylic analog or amine thereof.
工程(A)の後に、下記式(II) After step (A), the following formula (II)
下記式(III):Formula (III) below:
但し、シアン化物源がシアン化水素、アルカリ金属シアン化物、アルカリ土類金属シアン化物または場合により置換されたシアン化アンモニウムであり、該触媒が相転移触媒またはクラウンエーテルまたはそのアクリル系類縁体またはアミンである前記工程(B);Provided that the cyanide source is hydrogen cyanide, alkali metal cyanide, alkaline earth metal cyanide or optionally substituted ammonium cyanide, and the catalyst is a phase transfer catalyst or crown ether or an acrylic analog or amine thereof. The step (B);
工程(B)の後に、下記式(I): After step (B), the following formula (I):
下記式(II): Formula (II) below:
工程(C)の後に、下記式(IV): After step (C), the following formula (IV):
を特徴とする式(V)の化合物の調製方法。A process for the preparation of a compound of formula (V) characterized by
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GB0021066A GB0021066D0 (en) | 2000-08-25 | 2000-08-25 | Novel process |
GB0025616A GB0025616D0 (en) | 2000-10-19 | 2000-10-19 | Novel process |
GB0025616.4 | 2000-10-19 | ||
EP01420128.9 | 2001-06-07 | ||
EP01420128A EP1199305A1 (en) | 2000-10-19 | 2001-06-07 | Process for the preparation of 2-aminomethylpyridines |
PCT/EP2001/010984 WO2002016322A2 (en) | 2000-08-25 | 2001-08-21 | Process for the preparation of 2-aminoethylpyridines |
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US4159382A (en) * | 1978-06-28 | 1979-06-26 | The Dow Chemical Company | Process for preparing picolylamine |
JPS5663949A (en) * | 1979-10-29 | 1981-05-30 | Kuraray Co Ltd | Preparation of nitrile compound |
JPS56118066A (en) * | 1980-02-21 | 1981-09-16 | Ishihara Sangyo Kaisha Ltd | 2-cyano-3-halogeno-5-trifluoromethylpyridine and its preparation |
DE3165316D1 (en) * | 1980-02-21 | 1984-09-13 | Ishihara Sangyo Kaisha | 2-substituted-5-trifluoromethylpyridines and a process for producing the same |
IL68822A (en) * | 1982-06-18 | 1990-07-12 | Dow Chemical Co | Pyridyl(oxy/thio)phenoxy compounds,herbicidal compositions and methods of using them |
JPH06749B2 (en) * | 1985-04-30 | 1994-01-05 | 広栄化学工業株式会社 | Method for producing aminomethylpyridine |
US4766219A (en) * | 1985-06-03 | 1988-08-23 | The Dow Chemical Company | Preparation of 2-cyano-6-chloropyridine compounds |
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DE4132808A1 (en) * | 1991-10-02 | 1993-04-08 | Hoechst Ag | PROCESS FOR THE PREPARATION OF 2-AMINOMETHYLPIPERIDINE |
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