JP3904270B2 - Production method of etoposides - Google Patents

Description

（式中Ｒ₁ は水酸基の保護基を示す）で示される４’−デメチル−４−エピポドフィロトキシンと式（２）
【０００６】
【化６】

（式中Ｒ₂ は水酸基の保護基を示しＸ₁ は保持基の付いた水酸基またはアミノ基である）で示されるグルコース誘導体またはグルコサミン誘導体を、有機溶媒及びエーテル類の存在下に反応させて式（３）
【０００７】
【化７】

（式中Ｒ_1,Ｒ₂ およびＸ₁ は前記と同一である）で示される官能基の保護されたエトポシド類を得、必要に応じて脱保護することを特徴とするエトポシド類の製造法。
【０００８】
（２）反応触媒として三ふっ化ほう素ジ低級アルキルエーテル錯体又はトリ（Ｃ１〜Ｃ４）アルキルシリルトリフルオロメタンスルホネートを使用する（１）記載の製造法。
（３）エーテル類が１−５個のエーテル基及び２−６個の、炭素数１−６の鎖状もしくは環状炭化水素残基を含むモノ又はポリエーテルである（１）記載の製造法。
【０００９】
（４）モノ又はポリエーテルが下記式（４）
【化８】

（式中ｎは０ないし４の整数であり、Ｒ₃ 、Ｒ₅ はそれぞれ独立に炭素数１−４のアルキル基、Ｒ₄ は炭素数２−４の直鎖又は分岐のアルキレン基を示す）で示されるエーテルである（３）記載の製造法。
（５）有機溶媒として非ハロゲン系溶媒を用いる（１）記載の製造法
（６）非ハロゲン系有機溶媒としてアセトニトリル単独もしくはアセトニトリルと芳香族系溶媒との混合溶媒を用いる（１）に記載した製造法。
（７）有機溶媒としてアセトニトリル単独もしくはアセトニトリルおよびベンゼンもしくはトルエンもしくはキシレンとの混合溶媒を用いる（６）に記載した製造法。
（８）水酸基の保護基が低級アルキルカルボニル基又は１ないし３個のハロゲン原子で置換された低級アルキルカルボニル基である（１）記載の製造法。
（９）水酸基の保護基がアセチル基又は１ないし３個のハロゲン原子で置換されたアセチル基である（８）記載の製造法。
（１０）Ｒ₁ 及びＲ₂ における水酸基の保護基が１ないし３個のハロゲン原子で置換されたアセチル基、Ｘ₁ が水酸基の場合１ないし３個のハロゲン原子で置換されたアセチル基で保護され、またアミノ基の場合ベンジルオキシカルボニル基で保護され、有機溶媒がアセトニトリル単独もしくは芳香族系溶媒との混合溶媒、エーテル類がエチレングリコールジメチルエーテルであり、反応触媒として、三ふっ化ほう素ジエチルエーテルを使用する（１）記載の製造法。
（１１）エーテル類が（ポリ）アルキレングリコールジアルキルエーテル類であり、その使用量が有機溶媒に対して１〜５０％である（１０）記載の製造法。
（１２）ハロゲン化合物の含量が５０ｐｐｂ以下であるエトポシド。
（１３）４’−デメチル−４−エピポドフィロトキシンの二量体を実質的に含まない（１２）記載のエトポシド。
（１４）エトポシドのα−グルコシド体を実質的に含まない（１２）記載のエトポシド。
【００１０】
【発明の実施の形態】
【００１１】
式（１）の保護された４′−デメチル−４−エピポドフィロトキシンの水酸基の保護基Ｒ₁ としては炭素数１ないし１０のアシル基が好ましく、例えば、低級（Ｃ１〜Ｃ６）アルキルカルボニル基、低級（Ｃ１〜Ｃ６）アルキルオキシカルボニル基あるいはベンゾイル基又は１ないし３個のハロゲン原子で置換された低級（Ｃ１〜Ｃ６）アルキルカルボニル基、低級（Ｃ１〜Ｃ６）アルキルオキシカルボニル基あるいはベンゾイル基又はベンジルオキシカルボニル基等があげられる。グルコース誘導体との反応においてはアセチル基またはモノ、ジもしくはトリハロゲノアセチル基が好ましい。ここではハロゲンはふっ素、塩素または臭素等を示し、特にモノクロロアセチル基またはジクロロアセチル基が好ましい。またグルコサミン（アミノ糖）誘導体との反応においてはベンジルオキシカルボニルが好適に用いられる。
【００１２】
式（２）の保護された糖の水酸基の保護基Ｒ₂ はＲ₁ であげた保護基がいずれも使用でき、例えば、低級（Ｃ１〜Ｃ６）アルキルカルボニル基あるいは低級（Ｃ１〜Ｃ６）アルキルオキシカルボニル基又は１ないし３個のハロゲン原子で置換された低級（Ｃ１〜Ｃ６）アルキルカルボニル基あるいは低級（Ｃ１〜Ｃ６）アルキルオキシカルボニル基があげられる。
ここでハロゲンはふっ素、塩素または臭素等を示し、クロロ−アセチル基が好ましく、特にモノクロロアセチル基またはジクロロアセチル基が好ましい。また、Ｘ₁ は保護基の付いた水酸基またはアミノ基であり、水酸基の保護基としては上記Ｒ₂ と同じものが例えば挙げられる。
またアミノ基の保護基はアミノ基の保護に通常使用される保護基がいずれも使用できるが、好ましくはベンジルオキシカルボニルが用いられる。
【００１３】
反応溶媒は有機溶媒であればいずれも使用できるが、非ハロゲン系溶媒のときに本発明の効果は大きい。非ハロゲン系溶媒としては非ハロゲン化脂肪族極性溶媒単独もしくは該脂肪族極性溶媒と非ハロゲン化芳香族系溶媒との混合溶媒が好ましい。より好ましくはアセトニトリル単独または上述の芳香族系溶媒との混合溶媒が用いられる。芳香族系溶媒としては、反応に影響を与えないものが好ましく、特にトルエンが好ましい。
溶媒の使用量は反応させるものによって異なるが、原料である保護基を付した４′−デメチル−４−エピポドフィロトキシンに対して１〜５０倍容量、特に２〜２０倍容量が好ましい。
【００１４】
エーテル類は１−５個のエーテル基及び２−６個の、炭素数１−６の鎖状もしくは環状炭化水素残基を含むモノ／又はポリエーテルが例えばあげられ、好ましくは式（４）で示されるエーテルである。
【００１５】
エーテル類の両末端の炭素数１−６の鎖状炭化水素残基としては、例えばメチル基、エチル基またはプロピル基等の低級アルキル基が好ましい。エーテル類の中間に存在する炭素数１−６鎖状炭化水素残基としては、例えば分枝していてもよいＣ２〜Ｃ４のアルキレンが好ましく、具体的には、メチレン基、エチレン基、１−メチルエチレン基などがあげられる。環状炭化水素残基としてはフェニル基、またはフェニレン基などがあげられる。
【００１６】
式（４）で示されるエーテルとしては、例えばエチレングリコール、プロピレングリコール、ジエチレングリコールおよびトリエチレングリコールのそれぞれジメチルエーテル、ジエチルエーテルおよびジプロピルエーテルであり、特にエチレングリコールジメチルエーテル、エチレングリコールジエチルエーテルおよびジエチレングリコールジメチルエーテルが好ましい。更に好ましくはエチレングリコールジメチルエーテルである。これらの添加量は触媒の使用量および溶媒量によって異なるが、溶媒に対して１〜５０％、好ましくは１０〜３０％である。
【００１７】
反応触媒としては脱水縮合触媒が使用され、例えば、三ふっ化ほう素ジエチルエーテル錯体等の三ふっ化ほう素ジ低級アルキルエーテル錯体又はトリ（Ｃ１〜Ｃ４）アルキルシリルトリフルオロメタンスルホネートがあげられ、三ふっ化ほう素ジエチルエーテル錯体が比較的安価で、使用し易いため好ましいものとして挙げられる。三ふっ化ほう素ジエチルエーテル錯体の使用量は原料である式（１）で示される化合物に対して１〜１５倍当量、特に１．５〜８倍当量が好ましい。
【００１８】
また、式（１）および（２）で示される各化合物の使用量は、通常式（１）で示される化合物に対し、式（２）で示される化合物が１〜５当量、好ましくは１．２〜３当量である。
【００１９】
この反応は一般的に１０℃以下の低温、好ましくは０〜−３０℃、より好ましくは−５〜−２０℃の冷却下で行われ、反応系は出来るだけ無水状態で行われ、必要に応じてモレキュラーシーブ等の乾燥剤が用いられる。
上記反応で得られた式（３）化合物より保護基を脱離する。
保護基の脱離は、保護基の種類により、加水分解、加アルコール分解等の加溶媒分解または接触還元等の還元などの通常の方法によって行えばよい。例えばアセチル基またはハロゲノアセチル基の脱離はメタノールまたはメタノールを含有する混合溶媒中で通常の脱アシル化触媒である各種酢酸塩あるいはピリジン等塩基性物質の存在下加熱することにより容易に進行する。またベンジルオキシカルボニル基の脱離はパラジウムブラックあるいはパラジウムカーボン等を触媒として接触還元により脱離される。
上記の方法によって得られた粗エトポシドは、メタノール等の低級アルコール類、アセトン等の低級ケトン類、酢酸エチル等の低級カルボン酸エステル類、イソプロピルエーテル等のエーテル系溶媒、ヘキサン等の炭化水素溶媒もしくはこれらの混合溶媒等の非ハロゲン系溶媒で１〜２回再結晶又はこれらのアルコールで１〜２回懸濁処理することによって、精製することができる。
本発明方法によれば精製されたエトポシドにおけるハロゲン化合物の含量を、高感度クロマトグラフィーによる分析で８０ｐｐｂ以下、より好ましくは５０ｐｐｂ以下、更に好ましくは数ｐｐｂ〜３０ｐｐｂ程度にできる。従来のハロゲン系溶媒を用いて合成されたものはハロゲン化溶媒などのハロゲン化合物を百数拾ｐｐｍ以上含むもので、本発明方法で得られたものはそれらとは明らかに差別化できるものである。
尚、ここでハロゲン化合物の含量とは、ハロゲン化合物が２種以上存在した場合にはそれらの合計として表したものである。また、この精製されたエトポシドは原料４’−デメチル−４−エピポドフィロトキシンの二量体及びエトポシドのα−グルコシド体を実質的に含まないものであり、例えばそれらの含量は１％以下、好ましくは０．１％以下である。
本発明において式（１）で示される化合物及び式（２）で示される化合物はどのようにして製造されたものでも特に制限はないが、ハロゲン系溶媒を使用せずに合成されたものを用いることが好ましい。
【００２０】
式（１）で表わされる化合物としては例えば下記のものがあげられる。
（１）４′−ジクロロアセチル４′−デメチル−エピポドフィロトキシン（式（１）のＲ₁ ＝−ＣＯＣＨＣＩ₂ ）
（２）４′−ジブロモアセチル−４′−デメチル−エピポドフィロトキシン（式（１）のＲ₁ ＝−ＣＯＣＨＢr₂）
（３）４′−β，β，β−トリクロロエトキシカルボニル−４′−デメチル−エピポドフィロトキシン（式（１）のＲ₁ ＝−ＣＯＯＣＨ₂ ＣＣｌ₃ ）
（４）４′−β，β，β−トリブロモエトキシカルボニル−４′−デメチル−エピポドフィロトキシン（式（１）のＲ₁ ＝−ＣＯＯＣＨ₂ ＣＢｒ₃ ）
（５）４′−クロロアセチル−４′−デメチル−エピポドフィロトキシン（式（１）のＲ₁ −ＣＯＣＨ₂ Ｃｌ）
（６）４′−ベンジルオキシカルボニル−４′−デメチルエピポドフィロトキシン（式（１）のＲ₁ ＝−ＣＯＯＣＨ₂ Ｃ₆ Ｈ₅ ）
【００２１】
式（２）で表わされる化合物としては例えば下記のものがあげられる。
（１）４，６−Ｏ−エチリデン−２，３−ジ−Ｏ−ジクロロアセチル−β−Ｄ−グルコピラノース（式（２）のＲ₂ ＝−ＣＯＣＨＣｌ₂ 、Ｘ₁ ＝−ＯＣＯＣＨＣｌ₂ ）
（２）４，６−Ｏ−エチリデン−２，３−ジ−Ｏ−ジブロモアセチル−β−Ｄ−グルコピラノース（式（２）のＲ₂ ＝−ＣＯＣＨＢｒ₂ 、Ｘ₁ ＝−ＯＣＯＣＨＢr₂）
（３）４，６−Ｏ−エチリデン−２，３−ジ−Ｏ−トリクロロアセチル−β−Ｄ−グルコピラノース（式（２）のＲ₂ ＝−ＣＯＣＣｌ₃ 、Ｘ₁ ＝−ＯＣＯＣＣｌ₃ ）
（４）４，６−Ｏ−エチリデン−２，３−ジ−Ｏ−β，β，β−トリクロロエトキシカルボニル−β−Ｄ−グルコピラノース（式（２）のＲ₂ ＝−ＣＯＯＣＨ₂ ＣＣｌ₃ 、Ｘ₁ ＝−ＯＣＯＯＣＨ₂ ＣＣｌ₃ ）
（５）４，６−Ｏ−エチリデン−２−ベンジルオキシカルボニルアミノ−２−デオキシ−３−ジクロロアセチル−β−Ｄ−グルコピラノース（式（２）のＲ₂ ＝−ＣＯＣＨＣｌ₂ 、Ｘ₁ ＝−ＮＨＣＯＯＣＨ₂ Ｃ₆ Ｈ_s ）
【００２２】
また両者の反応によって得られた式（３）の官能基の保護されたエトポシド類としては、それぞれ原料に対応した保護基を有するものが得られる。具体的には例えば下記のものがあげられる。
（１）４′−ジクロロアセチル−４′−デメチル−エピポドフィロトキシン−β−Ｄ−２，３−ジ−Ｏ−ジクロロアセチル−４，６−Ｏ−エチリデングルコシド（式（３）のＲ₁ 、Ｒ₂ ＝−ＣＯＣＨＣｌ₂ 、Ｘ₁ ＝−ＯＣＯＣＨＣｌ₂ ）
（２）４′−ジブロモアセチル−４′−デメチル−エピポドフィロトキシン−β−Ｄ−２，３−ジ−Ｏ−ジブロモアセチル−４，６−Ｏ−エチリデングルコシド（式（３）のＲ₁ 、Ｒ₂ ＝−ＣＯＣＨＢr₂、Ｘ₁ ＝−ＯＣＯＣＨＢr₂）
（３）４′−ジクロロアセチル−４′−デメチル−エピポドフィロトキシン−β−Ｄ−２，３−ジ−Ｏ−トリクロロアセチル−４，６−Ｏ−エチリデングルコシド（式（３）のＲ₁ ＝ＣＯＣＨＣｌ₂ 、Ｒ₂ ＝−ＣＯＣＣｌ₃ 、Ｘ₁ ＝−ＯＣＯＣＣｌ₃ ）
（４）４′−クロロアセチル−４′−デメチル−エピポドフィロトキシン−β−Ｄ−２，３−ジ−Ｏ−クロロアセチル−４，６−Ｏ−エチリデングルコシド（式（３）のＲ₁ 、Ｒ₂ ＝−ＣＯＣＨ₂ Ｃｌ、Ｘ₁ ＝−ＯＣＯＣＨ₂ Ｃｌ）
（５）４−Ｏ−（２−ベンジルオキシカルボニルアミノ−２−デオキシ−３−ジクロロアセチル−β−Ｄ−グルコピラノシル）−４′−ベンジルオキシカルボニル−４′−デメチル−エピポドフィロトキシン（式（３）のＲ₁ ＝ベンジルオキシカルボニル、Ｒ₂ ＝−ＣＯＣＨＣｌ₂ 、Ｘ₁ ＝−ＮＨＣＯＯＣＨ₂ Ｃ₆ Ｈ₅ ）
【００２３】
【実施例】
次に本発明を実施例により更に具体的に説明する。
実施例１
エトポシドの合成
式（２）の（１）の化合物（式（２）においてＲ₂ ＝ＣＯＣＨＣ１₂ 、Ｘ₁ ＝ＯＣＯＣＨＣ１₂ ）１．６７ｇとアセトニトリル０．５ｍｌおよびトルエン２．５ｍｌを攪拌混合した。さらにエチレングリコールジメチルエーテル０．５ｍｌを加え、混合液を−１０℃以下に冷却した。これに三ふっ化ほう素ジエチルエーテル錯体０．８３ｇを加えた。次に式（１）の（１）の化合物（式（１）においてＲ₁ ＝ＣＯＣＨＣ１₂ ）１．００ｇを加え反応温度を−１０℃以下に保ちながら３時間反応を続けた。ピリジン０．７ｇを加え反応を停止した。反応液に酢酸エチル２０ｍｌおよび水２０ｍｌを加え攪拌した後分液した。さらに水洗を２回繰り返し、式（３）の（１）の化合物（式（３）においてＲ₁ ＝Ｒ₂ ＝ＣＯＣＨＣ１₂ Ｘ₁ ＝ＯＣＯＣＨＣ１₂ ）を含む有機層を得た。有機層にメタノール３ｍｌおよび酢酸アンモニウム１．５ｇを加え、４０℃で８時間攪拌し表記エトポシドを含む反応液を得た。反応液を高速液体クロマトグラフィーで分析した結果エトポシド１．１１ｇを含有していた。収率９６．９％
またα−グルコシド体はエトポシドに対して１．６５％（面積比）であった。
上記反応液を４０℃に加熱し水を加え晶析させ、２５℃以下に冷却した。水で洗浄し、ろ過し、粗エトポシドを得た。得られたエトポシドは純度約９７．７％で、α−グルコシド体含量、前記２量体含量はいずれも１％未満であった。またハロゲン化合物量は８０ｐｐｂ以下であった。
【００２４】
比較例１
実施例１においてエチレングリコールジメチルエーテルを添加しないで、他は全く同様の操作を行ったところ反応液にはエトポシド１．０４ｇを含有していた。収率９０．５％ またα−グルコシド体はエトポシドに対して６．６２％（面積比）であった。
【００２５】
実施例２
アミノエトポシドの合成
式（１）の（６）の化合物（式（１）においてＲ₁ ＝ベンジルオキシカルボニル）５．００ｇおよび式（２）の（５）の化合物（式（２）においてＲ₂ ＝ＣＯＣＨＣ１₂ 、Ｘ₁ ＝ＮＨＣＯＯＣＨ₂ Ｃ₆ Ｈ₅ ）５．６６ｇとアセトニトリル８０ｍｌおよびエチレングリコールジメチルエーテル２０ｍｌを攪拌混合した。混合液を−１０℃以下に冷却した。これに三ふっ化ほう素ジエチルエーテル錯体３．４０ｇを加えた。反応温度を−１０℃以下に保ちながら１時間反応を続けた。ピリジン２．１９ｇを加え反応を停止した。反応液に酢酸エチル１００ｍｌおよび水１００ｍｌを加え攪拌した後、分液した。さらに水洗を２回繰り返し、式（３）の（５）の化合物（式（３）においてＲ₂ ＝ＣＯＣＨＣ１₂ 、Ｒ₁ ＝ベンジルオキシカルボニル、Ｘ₁ ＝ＮＨＣＯＯＣＨ₂ Ｃ₆ Ｈ₅ ）を含む有機層を得た。有機層にメタノール１５ｍｌ及び酢酸アンモニウム４．０ｇを加え、４０℃で１．５時間攪拌した。反応液を３回水洗し、有機層を濃縮した。蒸発残渣をメタノール１５０ｍｌに溶解し、つぎにパラジウムブラック１．１ｇを加え、オートクレーブ中、６０℃で接触還元した。反応液をろ過し反応液を高速液体クロマトグラフィーで分析した結果アミノエトポシド４．２０ｇを含有していた。 収率７９．７％
またα−グルコシド体はアミノエトポシドに対して３．６７％（面積比）であった。
なお原料として使用する式（２）の（５）の化合物は特開平−２９５９９６に開示されている方法に準じて、２−Ｎ−ベンジルオキシカルボニル−４，６−Ｏ−エチリデン−Ｄ−グルコサミンに、ジクロロアセチルクロライドを反応させることによって得ることができる。
【００２６】
比較例２
実施例２においてエチレングリコールジメチルエーテルを添加しないで、式（１）の（６）の化合物と式（２）の（５）の化合物の反応時間が３０分の他は全く同様の操作を行ったところ反応液はアミノエトポシド３．５９ｇを含有していた。 収率７０．３％
またα−グルコシド体はアミノエトポシドに対して１２．６６％（面積比）であった。
【００２７】
【発明の効果】
本発明によって、有害なハロゲン系溶媒を使用せずかつ副生物を抑え高収率でエトポシド類を得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to (1) 4′-demethyl-4-epipodophyllotoxin-β-D-ethylidene glucoside (hereinafter referred to as etoposide), which is widely used as an antitumor agent, and (2) a hydroxyl group of the sugar moiety. The present invention relates to a method for producing a water-soluble derivative substituted with an amino group (hereinafter referred to as amino etoposide) and (3) those in which the functional group of those compounds is protected.
[0002]
[Prior art]
4'-demethyl-4-epipodophyllotoxin with a protecting group represented by the following formula (1) and a saccharide with a protecting group represented by the following formula (2) are boron trifluoride diethyl ether complex. And the like, and a halogen-based solvent such as dichloromethane or chloroform is preferably used as a solvent in a method for obtaining etoposides having a functional group protected by the following formula (3) (JP-A-2-292295). No. 2-295996, JP-B 63-28438, etc.).
[0003]
[Problems to be solved by the invention]
In recent years, conversion of halogen solvents to non-halogen solvents has been desired because of their carcinogenicity to humans and environmental hazards. However, it was found that when a non-halogen solvent was used in this reaction system and the reaction was carried out under the same conditions, a large amount of α-glucoside was produced as a by-product in addition to the target β-glucoside.
Since the production of α-glucoside forms not only lowers the yield of the target product but also lowers the quality, a means to suppress the production as much as possible is desired.
[0004]
[Means for Solving the Invention]
As a result of various studies on methods for suppressing the production of α-glucosides, the present inventors have found that the production of α-glucosides can be remarkably suppressed by making ethers coexist in the reaction system. Completed.
[0005]
That is, the present invention relates to the following (1) to (14).
(1) Formula (1)
[Chemical formula 5]

(Wherein R ₁ represents a hydroxyl-protecting group) and 4′-demethyl-4-epipodophyllotoxin represented by the formula (2)
[0006]
[Chemical 6]

(Wherein R ₂ represents a hydroxyl-protecting group, and X ₁ represents a hydroxyl group or amino group with a holding group) and a glucose derivative or glucosamine derivative represented by the formula is reacted in the presence of an organic solvent and ethers. (3)
[0007]
[Chemical 7]

(Wherein R _1, R ₂ and X ₁ are the same as those described above) A method for producing etoposides comprising obtaining a protected etoposide having a functional group and deprotecting as necessary.
[0008]
(2) The production method according to (1), wherein boron trifluoride dilower alkyl ether complex or tri (C1-C4) alkylsilyl trifluoromethanesulfonate is used as a reaction catalyst.
(3) The production method according to (1), wherein the ether is a mono- or polyether containing 1-5 ether groups and 2-6 linear or cyclic hydrocarbon residues having 1-6 carbon atoms.
[0009]
(4) Mono or polyether is represented by the following formula (4)
[Chemical 8]

(Wherein n is an integer of 0 to 4, R ₃ and R ₅ each independently represents an alkyl group having 1 to ₄ carbon atoms, and R ₄ represents a linear or branched alkylene group having 2 to ₄ carbon atoms) (3) The manufacturing method of description.
(5) Production method according to (1) using a non-halogen solvent as the organic solvent (6) Production according to (1) using acetonitrile alone or a mixed solvent of acetonitrile and an aromatic solvent as the non-halogen organic solvent Law.
(7) The production method according to (6), wherein acetonitrile is used alone or a mixed solvent of acetonitrile and benzene, toluene or xylene is used as the organic solvent.
(8) The production method according to (1), wherein the hydroxyl protecting group is a lower alkylcarbonyl group or a lower alkylcarbonyl group substituted with 1 to 3 halogen atoms.
(9) The production method according to (8), wherein the hydroxyl-protecting group is an acetyl group or an acetyl group substituted with 1 to 3 halogen atoms.
(10) The hydroxyl protecting group in R ₁ and R ₂ is protected with an acetyl group substituted with 1 to 3 halogen atoms, and when X ₁ is a hydroxyl group, protected with an acetyl group substituted with 1 to 3 halogen atoms. In the case of an amino group, it is protected with a benzyloxycarbonyl group, the organic solvent is acetonitrile alone or a mixed solvent with an aromatic solvent, the ether is ethylene glycol dimethyl ether, and boron trifluoride diethyl ether is used as a reaction catalyst. The production method according to (1) to be used.
(11) The production method according to (10), wherein the ethers are (poly) alkylene glycol dialkyl ethers, and the amount used is 1 to 50% with respect to the organic solvent.
(12) Etoposide having a halogen compound content of 50 ppb or less.
(13) The etoposide according to (12) substantially free from a dimer of 4′-demethyl-4-epipodophyllotoxin.
(14) The etoposide according to (12), which is substantially free of an α-glucoside of etoposide.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
[0011]
The hydroxyl-protecting group R ₁ of the protected 4′-demethyl-4-epipodophyllotoxin of the formula (1) is preferably an acyl group having 1 to 10 carbon atoms, such as lower (C ₁ -C 6) alkylcarbonyl. Group, lower (C1-C6) alkyloxycarbonyl group or benzoyl group or lower (C1-C6) alkylcarbonyl group, lower (C1-C6) alkyloxycarbonyl group or benzoyl group substituted with 1 to 3 halogen atoms Or a benzyloxycarbonyl group etc. are mention | raise | lifted. In the reaction with a glucose derivative, an acetyl group or a mono, di or trihalogenoacetyl group is preferred. Here, halogen represents fluorine, chlorine, bromine or the like, and a monochloroacetyl group or a dichloroacetyl group is particularly preferable. In the reaction with a glucosamine (amino sugar) derivative, benzyloxycarbonyl is preferably used.
[0012]
As the protecting group R _{2 for} the hydroxyl group of the protected sugar of the formula (2), any of the protecting groups mentioned for R ₁ can be used, for example, a lower (C1 to C6) alkylcarbonyl group or a lower (C1 to C6) alkyloxy group. Examples thereof include a carbonyl group or a lower (C1 to C6) alkylcarbonyl group or a lower (C1 to C6) alkyloxycarbonyl group substituted with 1 to 3 halogen atoms.
Here, halogen represents fluorine, chlorine, bromine or the like, and is preferably a chloro-acetyl group, particularly preferably a monochloroacetyl group or a dichloroacetyl group. X ₁ is a hydroxyl group or amino group with a protecting group, and examples of the hydroxyl protecting group include the same groups as those described above for R ₂ .
As the protecting group for the amino group, any protecting group usually used for protecting the amino group can be used, but benzyloxycarbonyl is preferably used.
[0013]
Any reaction solvent can be used as long as it is an organic solvent, but the effect of the present invention is great when it is a non-halogen solvent. As the non-halogen solvent, a non-halogenated aliphatic polar solvent alone or a mixed solvent of the aliphatic polar solvent and a non-halogenated aromatic solvent is preferable. More preferably, acetonitrile alone or a mixed solvent with the above aromatic solvent is used. As the aromatic solvent, those which do not affect the reaction are preferable, and toluene is particularly preferable.
The amount of the solvent to be used varies depending on what is to be reacted, but it is preferably 1 to 50 times, particularly 2 to 20 times the volume of 4′-demethyl-4-epipodophyllotoxin with a protecting group as a raw material.
[0014]
Examples of ethers include mono- and / or polyethers containing 1-5 ether groups and 2-6 linear or cyclic hydrocarbon residues having 1-6 carbon atoms, preferably in formula (4) The ether shown.
[0015]
The chain hydrocarbon residue having 1-6 carbon atoms at both ends of the ether is preferably a lower alkyl group such as a methyl group, an ethyl group or a propyl group. As the C1-C6 hydrocarbon residue present in the middle of ethers, for example, an optionally branched C2-C4 alkylene is preferable, and specifically includes a methylene group, an ethylene group, 1- Examples thereof include a methylethylene group. Examples of the cyclic hydrocarbon residue include a phenyl group and a phenylene group.
[0016]
Examples of the ether represented by the formula (4) include ethylene glycol, propylene glycol, diethylene glycol and triethylene glycol, which are dimethyl ether, diethyl ether and dipropyl ether, respectively, and ethylene glycol dimethyl ether, ethylene glycol diethyl ether and diethylene glycol dimethyl ether are particularly preferable. . More preferred is ethylene glycol dimethyl ether. The amount of addition varies depending on the amount of catalyst used and the amount of solvent, but is 1 to 50%, preferably 10 to 30%, based on the solvent.
[0017]
As the reaction catalyst, a dehydration condensation catalyst is used, and examples thereof include boron trifluoride dilower alkyl ether complexes such as boron trifluoride diethyl ether complex or tri (C1-C4) alkylsilyl trifluoromethanesulfonate. A boron fluoride diethyl ether complex is preferable because it is relatively inexpensive and easy to use. The amount of boron trifluoride diethyl ether complex to be used is preferably 1 to 15 times equivalent, particularly 1.5 to 8 times equivalent to the compound represented by the formula (1) as the raw material.
[0018]
Moreover, the usage-amount of each compound shown by Formula (1) and (2) is 1-5 equivalent for the compound shown by Formula (2) with respect to the compound normally shown by Formula (1), Preferably 1. 2-3 equivalents.
[0019]
This reaction is generally performed at a low temperature of 10 ° C. or lower, preferably 0 to −30 ° C., more preferably −5 to −20 ° C., and the reaction system is performed in an anhydrous state as much as possible. A desiccant such as molecular sieve is used.
The protecting group is eliminated from the compound of formula (3) obtained by the above reaction.
The removal of the protecting group may be carried out by a usual method such as hydrolysis, solvolysis such as alcoholysis or reduction such as catalytic reduction, depending on the type of protecting group. For example, elimination of an acetyl group or a halogenoacetyl group easily proceeds in methanol or a mixed solvent containing methanol by heating in the presence of a basic substance such as various acetates or pyridine, which are ordinary deacylation catalysts. The benzyloxycarbonyl group is eliminated by catalytic reduction using palladium black or palladium carbon as a catalyst.
The crude etoposide obtained by the above method is a lower alcohol such as methanol, a lower ketone such as acetone, a lower carboxylic acid ester such as ethyl acetate, an ether solvent such as isopropyl ether, a hydrocarbon solvent such as hexane, or the like. It can be purified by recrystallization once or twice with a non-halogen solvent such as a mixed solvent or once or twice with these alcohols.
According to the method of the present invention, the content of the halogen compound in the purified etoposide can be reduced to 80 ppb or less, more preferably 50 ppb or less, and even more preferably about several ppb to 30 ppb by analysis by high sensitivity chromatography. Those synthesized using a conventional halogen-based solvent contain one hundred ppm or more of halogen compounds such as halogenated solvents, and those obtained by the method of the present invention can be clearly differentiated from those. .
Here, the content of the halogen compound is expressed as the sum of two or more halogen compounds. The purified etoposide is substantially free from the raw material 4′-demethyl-4-epipodophyllotoxin dimer and the α-glucoside of etoposide. For example, the content thereof is 1% or less. Preferably, it is 0.1% or less.
In the present invention, the compound represented by the formula (1) and the compound represented by the formula (2) are not particularly limited even if they are produced in any way, but those synthesized without using a halogen-based solvent are used. It is preferable.
[0020]
Examples of the compound represented by the formula (1) include the following.
(1) 4'-dichloroacetyl 4'-demethyl-epipodophyllotoxin (R ₁ = -COCHCI _{2 in} formula (1))
(2) 4'-dibromoacetyl-4'-demethyl-epipodophyllotoxin (R ₁ = -COCHBr _{2 in} formula (1))
(3) 4'-β, β, β-trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin (R ₁ = -COOCH ₂ CCl _{3 in} formula (1))
(4) 4'-β, β, β-tribromoethoxycarbonyl-4'-demethyl-epipodophyllotoxin (R ₁ = -COOCH ₂ CBr _{3 in} formula (1))
(5) 4′-chloroacetyl-4′-demethyl-epipodophyllotoxin (R ₁ —COCH ₂ Cl in formula (1))
(6) 4′-benzyloxycarbonyl-4′-demethylepipodophyllotoxin (R ₁ = —COOCH ₂ C ₆ H _{5 in} formula (1))
[0021]
Examples of the compound represented by the formula (2) include the following.
(1) 4,6-O-ethylidene-2,3-di-O-dichloroacetyl-β-D-glucopyranose (R ₂ = -COCHCl ₂ of formula (2), X ₁ = -OCOCHCl ₂ )
(2) 4,6-O-ethylidene-2,3-di-O-dibromoacetyl-β-D-glucopyranose (R ₂ = —COCHBr ₂ of formula (2), X ₁ = —OCOCHBr ₂ )
(3) 4,6-O-ethylidene-2,3-di-O-trichloroacetyl-β-D-glucopyranose (R ₂ = —COCCl ₃ , X ₁ = —OCOCCl _{3 in} formula (2))
(4) 4,6-O-ethylidene-2,3-di-O-β, β, β-trichloroethoxycarbonyl-β-D-glucopyranose (R _{2 of} formula (2) = — COOCH ₂ CCl ₃ , X ₁ = -OCOOCH ₂ CCl ₃₎
(5) 4,6-O-ethylidene-2-benzyloxycarbonylamino-2-deoxy-3-dichloroacetyl-β-D-glucopyranose (R ₂ = —COCHCl ₂ of formula (2), X ₁ = − NHCOOCH ₂ C ₆ H _s )
[0022]
In addition, as the etoposides protected by the functional group of the formula (3) obtained by the reaction of both, those having a protecting group corresponding to the raw material can be obtained. Specific examples include the following.
(1) 4'-dichloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-dichloroacetyl-4,6-O-ethylidene glucoside (R in formula (3) ₁ , R ₂ = -COCHCl ₂ , X ₁ = -OCOCHCl ₂ )
(2) 4'-dibromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-dibromoacetyl-4,6-O-ethylidene glucoside (R in formula (3) ₁ , R ₂ = -COCHBr ₂ , X ₁ = -OCOCHBr ₂ )
(3) 4'-dichloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-trichloroacetyl-4,6-O-ethylidene glucoside (R in formula (3) ₁ = COCHCl ₂ , R ₂ = —COCCl ₃ , X ₁ = —OCOCCl ₃ )
(4) 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-chloroacetyl-4,6-O-ethylidene glucoside (R in formula (3) ₁ , R ₂ = —COCH ₂ Cl, X ₁ = —OCOCH ₂ Cl)
(5) 4-O- (2-benzyloxycarbonylamino-2-deoxy-3-dichloroacetyl-β-D-glucopyranosyl) -4'-benzyloxycarbonyl-4'-demethyl-epipodophyllotoxin (formula (3) R ₁ = benzyloxycarbonyl, R ₂ = —COCHCl ₂ , X ₁ = —NHCOOCH ₂ C ₆ H ₅ )
[0023]
【Example】
Next, the present invention will be described more specifically with reference to examples.
Example 1
Synthesis of Etoposide A compound of formula (2) (1) (R ₂ = COCHC1 ₂ , X ₁ = OCOCHC1 ₂ in formula (2)), 0.5 ml of acetonitrile and 2.5 ml of toluene were mixed with stirring. Further, 0.5 ml of ethylene glycol dimethyl ether was added, and the mixture was cooled to -10 ° C or lower. To this was added 0.83 g of boron trifluoride diethyl ether complex. Next, 1.00 g of the compound of the formula (1) (1) (R ₁ = COCHC1 ₂ in the formula (1)) was added and the reaction was continued for 3 hours while keeping the reaction temperature at −10 ° C. or lower. The reaction was stopped by adding 0.7 g of pyridine. To the reaction solution, 20 ml of ethyl acetate and 20 ml of water were added and stirred for separation. Further, washing with water was repeated twice to obtain an organic layer containing the compound of the formula (1) (1) (R ₁ = R ₂ = COCHC1 ₂ X ₁ = OCOCHC1 _{2 in the} formula (3)). 3 ml of methanol and 1.5 g of ammonium acetate were added to the organic layer and stirred at 40 ° C. for 8 hours to obtain a reaction solution containing the title etoposide. The reaction solution was analyzed by high performance liquid chromatography. As a result, it contained 1.11 g of etoposide. Yield 96.9%
The α-glucoside was 1.65% (area ratio) with respect to etoposide.
The reaction solution was heated to 40 ° C., water was added for crystallization, and the mixture was cooled to 25 ° C. or lower. Washed with water and filtered to obtain crude etoposide. The obtained etoposide had a purity of about 97.7%, and both the α-glucoside content and the dimer content were less than 1%. The amount of halogen compound was 80 ppb or less.
[0024]
Comparative Example 1
The same operation was performed except that ethylene glycol dimethyl ether was not added in Example 1, and the reaction liquid contained 1.04 g of etoposide. Yield 90.5% The α-glucoside was 6.62% (area ratio) with respect to etoposide.
[0025]
Example 2
Synthesis of aminoetoposide Compound (6) of formula (1) (R ₁ = benzyloxycarbonyl in formula (1)) and compound (5) of formula (2) (R ₂ = COCHC1 ₂ , X ₁ = NHCOOCH ₂ C ₆ H ₅ ) 5.66 g, 80 ml of acetonitrile and 20 ml of ethylene glycol dimethyl ether were mixed with stirring. The mixture was cooled to -10 ° C or lower. To this was added 3.40 g of boron trifluoride diethyl ether complex. The reaction was continued for 1 hour while maintaining the reaction temperature at -10 ° C or lower. The reaction was stopped by adding 2.19 g of pyridine. The reaction mixture was stirred after adding 100 ml of ethyl acetate and 100 ml of water. Further, washing with water was repeated twice, and the organic layer containing the compound of formula (3) (5) (in formula (3), R ₂ = COCHC _{1 2} , R ₁ = benzyloxycarbonyl, X ₁ = NHCOOCH ₂ C ₆ H ₅ ) Got. 15 ml of methanol and 4.0 g of ammonium acetate were added to the organic layer and stirred at 40 ° C. for 1.5 hours. The reaction solution was washed with water three times, and the organic layer was concentrated. The evaporation residue was dissolved in 150 ml of methanol, then 1.1 g of palladium black was added, and catalytic reduction was performed at 60 ° C. in an autoclave. The reaction solution was filtered and the reaction solution was analyzed by high performance liquid chromatography. As a result, it contained 4.20 g of aminoetoposide. Yield 79.7%
The α-glucoside was 3.67% (area ratio) with respect to aminoetoposide.
The compound of formula (2) (5) used as a raw material is converted into 2-N-benzyloxycarbonyl-4,6-O-ethylidene-D-glucosamine according to the method disclosed in JP-A-295996. It can be obtained by reacting dichloroacetyl chloride.
[0026]
Comparative Example 2
In Example 2, the same operation was carried out except that the reaction time of the compound of formula (1) (6) and the compound of formula (2) (5) was 30 minutes without adding ethylene glycol dimethyl ether. The reaction solution contained 3.59 g of amino etoposide. Yield 70.3%
The α-glucoside was 12.66% (area ratio) with respect to aminoetoposide.
[0027]
【The invention's effect】
According to the present invention, etoposides can be obtained in high yield without using harmful halogen solvents and suppressing by-products.

Claims (11)

Formula (1)

(Wherein R ₁ represents a hydroxyl-protecting group) and 4′-demethyl-4-epipodophyllotoxin having a protecting group represented by formula (2)

(Wherein R ₂ represents a hydroxyl-protecting group, and X ₁ represents a hydroxyl group or amino group with a protecting group), and the glucose derivative or glucosamine derivative represented by the formula is reacted in the presence of an organic solvent and ethers. (3)

(Wherein R ₁ , R ₂ and X ₁ are the same as those described above) A method for producing etoposides comprising obtaining a protected etoposide having a functional group and deprotecting as necessary. The process according to claim 1, wherein boron trifluoride di-lower alkyl ether complex or tri (C1-C4) alkylsilyl trifluoromethanesulfonate is used as a reaction catalyst. The process according to claim 1, wherein the ether is a mono- or polyether containing 1-5 ether groups and 2-6 linear or cyclic hydrocarbon residues having 1-6 carbon atoms. Mono or polyether is represented by the following formula (4)

(Wherein n is an integer of 0 to 4, R ₃ and R ₅ each independently represents an alkyl group having 1 to ₄ carbon atoms, and R ₄ represents a linear or branched alkylene group having 2 to ₄ carbon atoms) The production method according to claim 3, which is an ether represented by the formula: The production method according to claim 1, wherein a non-halogen organic solvent is used as the organic solvent. The production method according to claim 5, wherein acetonitrile is used alone or a mixed solvent of acetonitrile and an aromatic solvent is used as the non-halogen organic solvent. The process according to claim 6, wherein acetonitrile is used alone or a mixed solvent of acetonitrile and benzene, toluene or xylene is used as the non-halogen organic solvent. The process according to claim 1, wherein the protecting group for the hydroxyl group is a lower alkylcarbonyl group, a lower alkyloxycarbonyl group, or a lower alkylcarbonyl group or a lower alkyloxycarbonyl group substituted with 1 to 3 halogen atoms. 9. The process according to claim 8, wherein the hydroxyl protecting group is an acetyl group or an acetyl group substituted with 1 to 3 halogen atoms. The protecting group for the hydroxyl group in R ₁ and R ₂ is an acetyl group substituted with 1 to 3 halogen atoms, and when X ₁ is a hydroxyl group, it is protected with an acetyl group substituted with 1 to 3 halogen atoms; In the case of a group, it is protected by a benzyloxycarbonyl group, the organic solvent is acetonitrile alone or a mixed solvent with an aromatic solvent, the ether is ethylene glycol dimethyl ether, and boron trifluoride diethyl ether is used as a reaction solvent. Item 1. The production method according to Item 1. The method according to claim 10, wherein the ether is a (poly) alkylene glycol dialkyl ether, and the amount used is 1 to 50% with respect to the organic solvent.