JP3800356B2 - Method for suppressing the formation of etoposide isomers - Google Patents
Method for suppressing the formation of etoposide isomers Download PDFInfo
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- JP3800356B2 JP3800356B2 JP04963896A JP4963896A JP3800356B2 JP 3800356 B2 JP3800356 B2 JP 3800356B2 JP 04963896 A JP04963896 A JP 04963896A JP 4963896 A JP4963896 A JP 4963896A JP 3800356 B2 JP3800356 B2 JP 3800356B2
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- acid
- etoposide
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Description
【０００１】
【発明の属する技術分野】
本発明は、抗腫瘍剤として広く使用されている、４’−デメチル−４−エピポドフィロトキシン−β−Ｄ−エチリデングルコシド（以下、エトポシドと称す）の異性体生成抑制法に関する。
【０００２】
【従来の技術】
式（１）で示されるエトポシドは、例えば４’−デメチル−４−エピポドフィロトキシンと、グルコース誘導体を原料として合成される（特開平２−２９５９９６、特公昭６３−２８４３８号、特開平２−２９２２９５号他）。得られた粗エトポシドは、通常、再結晶等の方法により高純度に精製される。
【０００３】
【発明が解決しようとする課題】
エトポシドは例えば、長時間にわたる処理例えば加熱濃縮等によって不安定であり、その結果エトポシドのかなりの部分が、
【０００４】
ピクロ体と呼ばれる異性体（立体異性体）へ変換してしまい、目的のエトポシドの純度が著しく低下してしまう。従って、ピクロ体の生成を抑えて、目的のエトポシドを高純度で得る手段が望まれる。
【０００５】
【課題を解決するための手段】
本発明者らは、エトポシドのピクロ体生成を抑えるべく、様々な検討を行った結果、エトポシドの有機溶媒溶液を有機酸の存在下で処理することで著しくピクロ体生成が抑えられることを発見し、本発明の完成に至った。
【０００６】
即ち、本発明は次の（１）〜（６）に関する。
（１）式（１）
【化２】
（２）エトポシドの精製時を有機酸の存在下で行うことを特徴とする異性体の生成抑制方法。
（３）溶媒がアルコール系溶媒である上記（１）又は（２）記載の方法。
（４）アルコール系溶媒の脂肪族炭化水素残基が、炭素数１ないし３のアルキル基である上記（３）記載の方法。
（５）有機酸が、カルボキシル基が１ないし３で、炭素数１ないし６で、水酸基で置換されていてもよく、カルボキシル基と水酸基は縮合して環を形成していてもよいものである上記（１）ないし（４）の方法。
（６）有機酸が、クエン酸である上記（１）ないし（５）記載の方法。
（７）処理が加熱処理である上記（１）記載の方法。
【０００７】
【発明の実施の形態】
本発明で使用されるエトポシドは、前述の特開平２−２９５９９６、特公昭６３−２８４３８号、特開平２−２９２２９５号等によって製造されたものが例えばあげられ、得られた粗エトポシドのままでもよいし、第一次精製を行ったものでもよい。第一次精製とは、粗エトポシドを懸濁又は溶解させた有機溶媒を加熱還流し結晶を得た後、高純度品を得るために更にアルコール系溶媒などで精製を行うような、複数回の精製を行う場合の最初の精製のことをいう。
【０００８】
本発明はエトポシド有機溶媒溶液を処理する場合にはいずれの場合にも適用することができ、例えばエトポシドの精製時に適用できる。エトポシドの精製とは具体的には上述の粗エトポシドあるいは第一次精製品を適当な有機溶媒溶液とし、例えば再結晶する方法等があげられる。この時必要があれば該溶液を加熱処理する。例えばこのような加熱処理行う場合に本発明が適用される場合、加熱処理される時間は特に限定はなく、その加熱処理条件等により異なる。例えば、エトポシド有機溶媒溶液の温度が８０℃を超える高温では短時間例えば３０分程度でも異性体の生成が増加するのでそのような場合にも本発明は適用可能である。また溶液の温度が４０℃程度の場合には、より長時間例えば３０時間を超える加熱処理の場合により有効である。本発明の最も一般的な場合について説明すると、エトポシドの有機溶媒溶液を溶液の温度が５０〜８０℃、好ましくは７０℃前後で１０ないし３０時間、通常１５ないし２５時間加熱処理するような場合に、その加熱処理前にエトポシド有機溶媒溶液中に、有機酸を添加し、有機酸の存在下で加熱処理するようにすればよい。通常大規模スケールでのエトポシド製造法における精製時に有効である。必要があれば室温まで放冷後、結晶を取り出す。
【０００９】
本発明で使用されるエトポシドの有機溶媒溶液としては、エトポシドが完全に溶解しているものかあるいは、エトポシドが溶けきらずに一部残存したり懸濁状態であるもののどちらでもよい。使用される有機溶媒としては特に限定されないが、例えばアルコ−ル系溶媒や、酢酸エチル、アセトン等があげられるが、好ましくはアルコール系溶媒である。より好ましくは、アルコ−ル系溶媒の脂肪族炭化水素残基が、炭素数１ないし３のアルキル基であるものが挙げられ、例えば、メタノ−ル、エタノ−ル、ｎ−プロパノール、ｉ−プロパノール等が挙げられる。なおここでアルコ−ル系溶媒の脂肪族炭化水素残基とは、該アルコ−ルの構造式から水酸基を除いた残基のことである。本発明が上述の第一次精製後の第二次精製などの最終精製時に使用される場合には、特にメタノールが好ましく、その場合に用いる第一次精製品はメタノールでの精製品が特に好ましい。
【００１０】
添加する有機酸は、溶媒中で、エトポシドと共存した場合、通常で反応しにくいものであれば、特に限定されることはないが、例えばカルボキシル基が１ないし３で炭素数が１ないし６のものが好ましい。これらの有機酸は水酸基を置換基として有していてもよい。
またカルボキシル基と水酸基は縮合して環を形成していてもよい。好ましい有機酸としては例えばギ酸、酢酸、クエン酸、乳酸、フマル酸、酒石酸、リンゴ酸、シュウ酸、アスコルビン酸等が挙げられる。より好ましくは、のちの製剤化に影響を与えず、人体に無害であるクエン酸である。
【００１１】
添加する有機酸の濃度は特に限定されるものではないが、溶媒に対して０．０００１〜１重量％、好ましくは０．００１〜０．０１重量％である。
【００１２】
【実施例】
次に実施例をあげて本発明を詳しく説明する。
【００１３】
実施例 １
後記する第一次精製エトポシド１０ｇを３５０ｍｌのメタノ−ルに加熱溶解する。これにクエン酸 ３０ｍｇ及び活性炭 １ｇを加えて１０分放置後、活性炭を濾別する。浴温７０℃前後の油浴上で、１９時間加熱後、溶液の一定量を分取し、μBondapak Phenyl カラム（Waters社、直径３．９ｍｍ、長さ３００ｍｍ）で分析する。異性体であるピクロ体のエトポシドに対する面積比（％）を計算すると、０．０４であった。
【００１４】
比較例 １
実施例 １においてクエン酸を添加しないで、他は全て同様に処理した。異性体であるピクロ体のエトポシドに対する面積比（％）を計算すると、６．９５であった。
【００１５】
尚、実施例 １及び比較例 １において使用した第一次精製エトポシドは次の操作により得られたものである。乾燥粗エトポシド１２．６ｇに１０％含水エタノ−ル２８ｍｌを加えて、攪拌しながら３０分間加熱還流する。室温まで放冷後、結晶を取り出す。エタノール洗（１２ｍｌ×２回）後、５０〜６０℃で真空乾燥して、エタノール精製品１１．３６ｇを得る。
【００１６】
【発明の効果】
クエン酸を添加しなかった場合に対する、本発明のピクロ体の生成率は実に１７４分の１に抑えられていた。本発明によると、効率よくかつ高純度で目的のエトポシドを得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for inhibiting isomer formation of 4′-demethyl-4-epipodophyllotoxin-β-D-ethylidene glucoside (hereinafter referred to as etoposide), which is widely used as an antitumor agent.
[0002]
[Prior art]
The etoposide represented by the formula (1) is synthesized using, for example, 4'-demethyl-4-epipodophyllotoxin and a glucose derivative as raw materials (Japanese Patent Laid-Open No. Hei 2-295996, Japanese Patent Publication No. 63-28438, Japanese Patent Laid-Open No. Hei 2). -292295 and others). The obtained crude etoposide is usually purified to a high purity by a method such as recrystallization.
[0003]
[Problems to be solved by the invention]
Etoposide is unstable, for example, by prolonged processing, such as heat concentration, so that a significant portion of etoposide is
[0004]
It is converted into an isomer called a picro isomer (stereoisomer), and the purity of the target etoposide is significantly reduced. Therefore, a means for suppressing the production of picro form and obtaining the target etoposide with high purity is desired.
[0005]
[Means for Solving the Problems]
As a result of various studies to suppress the formation of etoposide picro form, the present inventors have found that ecroposide formation can be remarkably suppressed by treating an organic solvent solution of etoposide in the presence of an organic acid. The present invention has been completed.
[0006]
That is, the present invention relates to the following (1) to (6).
(1) Formula (1)
[Chemical 2 ]
(2) A method for suppressing the formation of isomers, wherein etoposide is purified in the presence of an organic acid.
(3) The method according to (1) or (2) above, wherein the solvent is an alcohol solvent.
(4) The method according to (3) above, wherein the aliphatic hydrocarbon residue of the alcohol solvent is an alkyl group having 1 to 3 carbon atoms.
(5) The organic acid has 1 to 3 carboxyl groups and 1 to 6 carbon atoms and may be substituted with a hydroxyl group. The carboxyl group and the hydroxyl group may be condensed to form a ring. Method (1) to (4) above.
(6) The method according to (1) to (5) above, wherein the organic acid is citric acid.
(7) The method according to (1) above, wherein the treatment is a heat treatment.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
Examples of etoposide used in the present invention include those produced by the above-mentioned JP-A-2-295996, JP-B-63-28438, JP-A-2-292295, etc., and the obtained crude etoposide may be used as it is. However, it may be subjected to primary purification. In the primary purification, an organic solvent in which crude etoposide is suspended or dissolved is heated to reflux to obtain crystals, and then purified with an alcohol solvent or the like to obtain a high-purity product. This refers to the initial purification when performing purification.
[0008]
The present invention can be applied to any case where an etoposide organic solvent solution is treated, for example, at the time of purification of etoposide. The purification of etoposide specifically includes a method of recrystallizing the above crude etoposide or primary purified product into an appropriate organic solvent solution. At this time, if necessary, the solution is heated. For example, when the present invention is applied to such a heat treatment, the heat treatment time is not particularly limited and varies depending on the heat treatment conditions and the like. For example, when the temperature of the etoposide organic solvent solution exceeds 80 ° C., the production of isomers increases even for a short time, for example, about 30 minutes, so that the present invention is also applicable to such a case. Further, when the temperature of the solution is about 40 ° C., it is more effective in the case of heat treatment for a longer time, for example, more than 30 hours. The most general case of the present invention will be described. In the case where an organic solvent solution of etoposide is heated at a temperature of 50 to 80 ° C., preferably around 70 ° C. for 10 to 30 hours, usually 15 to 25 hours. Before the heat treatment, an organic acid may be added to the etoposide organic solvent solution and the heat treatment may be performed in the presence of the organic acid. It is usually effective during purification in a large-scale etoposide production process. If necessary, the crystals are taken out after being allowed to cool to room temperature.
[0009]
The organic solvent solution of etoposide used in the present invention may be either a solution in which etoposide is completely dissolved, or a solution in which etoposide is not completely dissolved but remains in a suspended state. The organic solvent to be used is not particularly limited, and examples thereof include an alcohol solvent, ethyl acetate, acetone and the like, and an alcohol solvent is preferable. More preferably, the aliphatic hydrocarbon residue of the alcohol solvent is an alkyl group having 1 to 3 carbon atoms, such as methanol, ethanol, n-propanol, i-propanol. Etc. Here, the aliphatic hydrocarbon residue of the alcohol solvent is a residue obtained by removing the hydroxyl group from the structural formula of the alcohol. When the present invention is used at the time of final purification such as secondary purification after the above-mentioned primary purification, methanol is particularly preferable, and the primary purified product used in that case is particularly preferably a purified product with methanol. .
[0010]
The organic acid to be added is not particularly limited as long as it is usually nonreactive when coexisting with etoposide in a solvent. For example, the organic acid has 1 to 3 carboxyl groups and 1 to 6 carbon atoms. Those are preferred. These organic acids may have a hydroxyl group as a substituent.
Moreover, the carboxyl group and the hydroxyl group may be condensed to form a ring. Preferred organic acids include formic acid, acetic acid, citric acid, lactic acid, fumaric acid, tartaric acid, malic acid, oxalic acid, ascorbic acid and the like. More preferred is citric acid which does not affect the subsequent formulation and is harmless to the human body.
[0011]
The concentration of the organic acid to be added is not particularly limited, but is 0.0001 to 1% by weight, preferably 0.001 to 0.01% by weight, based on the solvent.
[0012]
【Example】
Next, the present invention will be described in detail with reference to examples.
[0013]
Example 1
10 g of primary purified etoposide described later is dissolved by heating in 350 ml of methanol. To this, 30 mg of citric acid and 1 g of activated carbon are added and allowed to stand for 10 minutes, and then the activated carbon is filtered off. After heating for 19 hours on an oil bath at a bath temperature of around 70 ° C., a certain amount of the solution is taken and analyzed with a μBondapak Phenyl column (Waters, diameter 3.9 mm, length 300 mm). The area ratio (%) of the isomeric picro form to etoposide was calculated to be 0.04.
[0014]
Comparative Example 1
In Example 1, the same treatment was performed except that citric acid was not added. The area ratio (%) of the isomeric picro form to etoposide was calculated to be 6.95.
[0015]
The primary purified etoposide used in Example 1 and Comparative Example 1 was obtained by the following operation. Add 28 ml of 10% aqueous ethanol to 12.6 g of dry crude etoposide and heat to reflux for 30 minutes with stirring. After cooling to room temperature, the crystals are taken out. After washing with ethanol (12 ml × 2 times), vacuum drying is performed at 50 to 60 ° C. to obtain 11.36 g of an ethanol purified product.
[0016]
【The invention's effect】
The production rate of the picro form of the present invention compared to the case where citric acid was not added was actually suppressed to 1/174. According to the present invention, the target etoposide can be obtained efficiently and with high purity.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04963896A JP3800356B2 (en) | 1996-02-14 | 1996-02-14 | Method for suppressing the formation of etoposide isomers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04963896A JP3800356B2 (en) | 1996-02-14 | 1996-02-14 | Method for suppressing the formation of etoposide isomers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09221495A JPH09221495A (en) | 1997-08-26 |
| JP3800356B2 true JP3800356B2 (en) | 2006-07-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04963896A Expired - Lifetime JP3800356B2 (en) | 1996-02-14 | 1996-02-14 | Method for suppressing the formation of etoposide isomers |
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| Country | Link |
|---|---|
| JP (1) | JP3800356B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT408883B (en) * | 1998-05-14 | 2002-03-25 | Dsm Fine Chem Austria Gmbh | METHOD FOR STABILIZING CYANHYDRINES |
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1996
- 1996-02-14 JP JP04963896A patent/JP3800356B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| JPH09221495A (en) | 1997-08-26 |
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