JPH09221495A - Suppression of formation of etoposide isomer - Google Patents
Suppression of formation of etoposide isomerInfo
- Publication number
- JPH09221495A JPH09221495A JP4963896A JP4963896A JPH09221495A JP H09221495 A JPH09221495 A JP H09221495A JP 4963896 A JP4963896 A JP 4963896A JP 4963896 A JP4963896 A JP 4963896A JP H09221495 A JPH09221495 A JP H09221495A
- Authority
- JP
- Japan
- Prior art keywords
- etoposide
- solution
- isomer
- acid
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[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。TECHNICAL FIELD The present invention relates to an isomer of 4′-demethyl-4-epipodophyllotoxin-β-D-ethylidene glucoside (hereinafter referred to as etoposide), which is widely used as an antitumor agent. Generation suppression method.
【０００２】[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２−２
９５９９６、特公昭６３−２８４３８号、特開平２−２
９２２９５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。2. Description of the Related Art Etoposide represented by the formula (1) is synthesized by using, for example, 4'-demethyl-4-epipodophyllotoxin and a glucose derivative as raw materials (JP-A-2-2).
95996, JP-B-63-28438, JP-A-2-2
92295 and others). The crude etoposide thus obtained is usually highly purified by a method such as recrystallization.
【０００３】[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、式（２）Problems to be Solved by the Invention Etoposide is, for example,
It is unstable due to long-term treatment, such as heating and concentration, and as a result, a large part of etoposide becomes
【０００３】[0003]
【化２】 Embedded image
【０００４】で示すピクロ体と呼ばれる、Ｃ環部分（ラ
クトン環）が異性化してＣ（２）−Ｃ（２ａ）及びＣ
（３）−Ｃ（３ａ）結合の配位が、それぞれエトポシド
そのものと逆転した異性体（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。The C ring portion (lactone ring), which is called the picroform, is isomerized to form C (2) -C (2a) and C.
The coordination of the (3) -C (3a) bond is converted into an isomer (stereoisomer) which is the reverse of the etoposide itself, and the purity of the target etoposide is significantly reduced. Therefore, a means for obtaining the desired etoposide with high purity by suppressing the production of picromeric bodies is desired.
【０００５】[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。Means for Solving the Problems The present inventors have conducted various studies in order to suppress the production of picoforms of etoposide. It was discovered that body formation was suppressed, and the present invention was completed.
【０００６】即ち、本発明は次の（１）〜（６）に関す
る。 （１）式（１）That is, the present invention relates to the following (1) to (6). Expression (1)
【化３】 で示されるエトポシドの有機溶媒溶液を有機酸の存在下
で処理することを特徴とする異性体の生成抑制方法。 （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。Embedded image A method for suppressing the formation of isomers, which comprises treating a solution of etoposide represented by the following in an organic solvent in the presence of an organic acid. (2) A method for suppressing the production of isomers, which comprises purifying etoposide 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 a carboxyl group of 1 to 3, a carbon number of 1 to 6, and may be substituted with a hydroxyl group, and the carboxyl group and the hydroxyl group may be condensed to form a ring. The above methods (1) to (4). (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 heat treatment.
【０００７】[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６３−２８
４３８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。BEST MODE FOR CARRYING OUT THE INVENTION The etoposide used in the present invention is the above-mentioned JP-A-2-295996, JP-B-63-28.
Examples thereof include those produced by JP-A No. 438, JP-A-2-292295 and the like, and the obtained crude etoposide may be used as it is, or may be the one obtained by primary purification. The primary purification is performed by heating and refluxing an organic solvent in which crude etoposide is suspended or dissolved to obtain crystals, and then refining with an alcohol solvent to obtain a highly purified product. This means the first purification when purification is performed.
【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。The present invention can be applied to any case of treating an etoposide organic solvent solution, for example, when purifying etoposide. Specifically, the purification of etoposide includes, for example, a method of recrystallizing the above-mentioned crude etoposide or the primary purified product in a suitable organic solvent solution. At this time, if necessary, the solution is heat-treated. For example, when the present invention is applied to such 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 in a short time, for example, about 30 minutes, so the present invention is applicable to such cases. Further, when the temperature of the solution is about 40 ° C., it is more effective when the heat treatment is performed for a longer time, for example, for more than 30 hours. The most general case of the present invention will be explained. In the case where a solution of etoposide in an organic solvent is heat-treated 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 the etoposide production method on a large scale. If necessary, allow to cool to room temperature and take out crystals.
【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。The organic solvent solution of etoposide used in the present invention may be either one in which etoposide is completely dissolved, or one in which etoposide remains undissolved and remains in a suspended state. The organic solvent used is not particularly limited, and examples thereof include alcohol solvents, ethyl acetate, acetone and the like, and alcohol solvents are preferable. More preferably, the aliphatic hydrocarbon residue of the alcohol solvent has 1 to 3 carbon atoms.
Are alkyl groups of, for example, methano-
And ethanol, n-propanol, i-propanol and the like. Here, the aliphatic hydrocarbon residue of the alcohol solvent means a residue obtained by removing a hydroxyl group from the structural formula of the alcohol. When the present invention is used in the final purification such as the secondary purification after the above primary purification,
Particularly preferred is methanol, and the primary purified product used in that case is particularly preferably a purified product in methanol.
【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。The organic acid to be added is not particularly limited as long as it does not usually react when coexisting with etoposide in a solvent. For example, a carboxyl group is 1
Preferred are those having 3 to 3 and 1 to 6 carbon atoms. 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,
Examples thereof include citric acid, lactic acid, fumaric acid, tartaric acid, malic acid, oxalic acid and ascorbic acid. More preferably,
Citric acid, which does not affect the subsequent formulation and is harmless to the human body.
【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。The concentration of the organic acid to be added is not particularly limited, but 0.0001 to 1% by weight with respect to the solvent,
It is preferably 0.001 to 0.01% by weight.
【００１２】[0012]
【実施例】次に実施例をあげて本発明を詳しく説明す
る。EXAMPLES Next, the present invention will be described in detail with reference to examples.
【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。Example 1 10 g of primary purified etoposide described below is dissolved in 350 ml of methanol by heating. To this, 30 mg of citric acid and 1 g of activated carbon are added, and after standing for 10 minutes, the activated carbon is filtered off. After heating for 19 hours on an oil bath with a bath temperature of around 70 ° C, aliquots of the solution were aliquoted and used in a μBondapak Phenyl column (Waters
Company, diameter 3.9 mm, length 300 mm). Area ratio of picomeric isomer to etoposide (%)
Was calculated to be 0.04.
【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。Comparative Example 1 The same treatment as in Example 1 was carried out except that citric acid was not added. The area ratio (%) of the picro isomer, which is an isomer, to etoposide was calculated to be 6.95.
【００１４】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。The primary purified etoposide used in Example 1 and Comparative Example 1 was obtained by the following procedure. 28 ml of 10% water-containing ethanol is added to 12.6 g of dried crude etoposide, and the mixture is heated under reflux for 30 minutes while stirring. After cooling to room temperature, the crystals are taken out. After ethanol washing (12 ml × 2 times), vacuum drying is performed at 50 to 60 ° C. to obtain 11.36 g of ethanol purified product.
【００１５】[0015]
【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。The production rate of the picroform of the present invention was actually suppressed to 1/174 as compared with the case where citric acid was not added. According to the present invention, the target etoposide can be efficiently obtained with high purity.
Claims (7)
で処理することを特徴とする異性体の生成抑制方法。(1) The following formula (1): A method for suppressing the formation of isomers, which comprises treating a solution of etoposide represented by the following in an organic solvent in the presence of an organic acid.
ことを特徴とする異性体の生成抑制方法。2. A method for suppressing the formation of isomers, which comprises purifying etoposide in the presence of an organic acid.
は２記載の方法。3. The method according to claim 1, wherein the solvent is an alcohol solvent.
が、炭素数１ないし３のアルキル基である請求項３記載
の方法。4. The method according to claim 3, wherein the aliphatic hydrocarbon residue of the alcohol solvent is an alkyl group having 1 to 3 carbon atoms.
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請求項１ないし４の方法。5. The organic acid has a carboxyl group of 1 to 3
5. The method according to claim 1, wherein the carbon number is 1 to 6 and may be substituted with a hydroxyl group, and the carboxyl group and the hydroxyl group may be condensed to form a ring.
５記載の方法。6. The method according to claim 1, wherein the organic acid is citric acid.
法。7. The method according to claim 1, wherein the treatment is heat treatment.
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 true JPH09221495A (en) | 1997-08-26 |
| JP3800356B2 JP3800356B2 (en) | 2006-07-26 |
Family
ID=12836763
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 |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3800356B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11349546A (en) * | 1998-05-14 | 1999-12-21 | Dsm Fine Chem Austria Gmbh | Stabilization of cyanohydrin |
-
1996
- 1996-02-14 JP JP04963896A patent/JP3800356B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11349546A (en) * | 1998-05-14 | 1999-12-21 | Dsm Fine Chem Austria Gmbh | Stabilization of cyanohydrin |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3800356B2 (en) | 2006-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2577331C2 (en) | Crystalline base of minocycline and methods for obtaining thereof | |
| US3687982A (en) | Separation of mixed diastereoisomers of zearalanol | |
| JPH08511550A (en) | Process for producing N-acetylneuraminic acid derivative | |
| NO321154B1 (en) | Process for preparing mometasone furoate | |
| ITMI20131307A1 (en) | PROCESS FOR THE PREPARATION OF REFAXIMINA K | |
| JPH09221495A (en) | Suppression of formation of etoposide isomer | |
| JP3896226B2 (en) | Purification method of roxithromycin | |
| EP0101383B1 (en) | 14-amino-steroid derivatives, their therapeutical use and process for their preparation | |
| US20060111560A1 (en) | Process for the preparation of crystalline form II of clarithromycin | |
| CA1173027A (en) | PROCESS FOR THE PREPARATION OF 17.alpha.-HYDROXY-AND 17A.alpha.-HYDROXY-D-HOMOETIOCARBOXYLIC ACIDS | |
| EP0772630B1 (en) | Streptogramine derivatives, preparation of same and pharmaceutical compositions containing same | |
| US2549683A (en) | Oxy substituted aminoindanones | |
| KR100325558B1 (en) | Method for Purifying 7-chloroquinoline-8-carboxylic Acid | |
| CN1031342C (en) | Process for preparing 1,5-benzothiazepine derivatives | |
| EP1697380A1 (en) | The method of manufacturing of 7-ethyl-10-hydroxycamptothecin | |
| JPH0227352B2 (en) | ||
| JPH051053A (en) | New process for producing 6-(3-dimethylamino-propionyl) forskolin | |
| JPS6229595A (en) | 5-o-mycaminosyl-narbonolide derivative and production thereof | |
| JP2000198779A (en) | Purification of 3-alkylflavanol derivative | |
| SU819119A1 (en) | Method of preparing 16-unsaturated pregnane steroids | |
| JPH0881412A (en) | Production of phenoxyalkylcarboxylic acid derivative | |
| WO2002044136A1 (en) | PROCESSES FOR PREPARATION OF N-PROTECTED-ss-AMINO ALCOHOLS AND N-PROTECTED-ss-AMINO EPOXIDES | |
| JPS5879984A (en) | Antipregnant medicinal composition | |
| HU224817B1 (en) | New process for producing 17-betha-hydroxy-17-alpha-methyl-2-oxa-5-alpha-androstan-3-on and intermediate thereof | |
| JPH0586060A (en) | Purification of adenine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20051228 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060224 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20060419 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20060419 |
|
| R150 | Certificate of patent (=grant) or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090512 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120512 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120512 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150512 Year of fee payment: 9 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |