JP3998074B2 - Method for demethylation of podophyllotoxin - Google Patents
Method for demethylation of podophyllotoxin Download PDFInfo
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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’ーデメチルー４ーエピポドフィロトキシンーβーＤ−エチリデングルコシド（一般名エトポシド）の主要原料である４’ーデメチルー４ーエピポドフィロトキシンの製造法に関するものである。
【０００２】
【従来の技術】
後記式（１）で示されるポドフィロトキシンを臭化水素により４’位のメチル基を脱離し、次いで加水分解して後記式（３）で示される４’ーデメチルー４ーエピポドフィロトキシンを得る方法において、臭化水素による処理の際に用いる溶媒としてジクロロエタン等のハロゲン系溶媒が好適に使用されている。（特公昭４３ー６４６９）
【０００３】
【発明が解決しようとする課題】
近年、ハロゲン系溶媒の人に対する発癌性や環境への有害性から非ハロゲン系有機溶媒への変換が望まれている。しかしながら本反応の場合、臭化水素を高濃度に安定的に溶解し、反応をスムーズに進行させるためにはハロゲン系溶媒を使用する必要があると考えられていた。
【０００４】
【課題を解決するための手段】
本発明者は該反応に使用される溶媒としてハロゲン系溶媒に替わる非ハロゲン系有機溶媒での反応を種々検討した結果、ケトン化合物等の非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合溶媒が特に優れており、非ハロゲン系有機溶媒中でも反応を行うことが可能であることを見い出し本発明の完成にいたった。
【０００５】
即ち、本発明は次の（１）〜（９）に関する。
（１）式（１）
【０００６】
【化４】
で示されるポドフィロトキシンを非ハロゲン系有機溶媒中、臭化水素により脱メチル化して式（２）
【０００８】
【化５】
で示される反応中間体を得、これを加水分解することを特徴とする式（３）
【００１０】
【化６】
で示される４’ーデメチルー４ーエピポドフィロトキシンの製造法。
【００１２】
（２）非ハロゲン系有機溶媒が非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合溶媒である（１）記載の製造法。
【００１３】
（３）非ハロゲン系脂肪族溶媒がケトン化合物である（２）記載の製造法。
【００１４】
（４）ケトン化合物がカルボニル基の両側に炭素数１ないし５のアルキル基を有するケトン化合物である（３）記載の製造法。
【００１５】
（５）非ハロゲン系芳香族溶媒が、置換基として炭素数１ないし４のアルキル基及び／又はニトロ基を１ないし３個有していてもよいベンゼンである（２）、（３）又は（４）記載の製造法。
【００１６】
（６）非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合比（容量比）が０．５：９．５から８：２の範囲内である（２）、（３）、（４）又は（５）記載の製造法。
【００１７】
（７）非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合溶媒の使用量が式（１）で示される化合物１重量部に対して１ないし９容量部の範囲内である（２）、（３）、（４）、（５）又は（６）記載の製造法。
【００１８】
（８）臭化水素の使用量が溶媒１容量部に対して０．１〜１．０重量部の範囲内である（１）、（２）、（３）、（４）、（５）、（６）又は（７）記載の製造法。
【００１９】
（９）式（２）で示される反応中間体をアルカリ金属またはアルカリ土類金属の炭酸水素塩または炭酸塩の水溶液により加水分解する（１）記載の製造法。
【００２０】
（１０）式（１）の化合物を非ハロゲン系有機溶媒中、臭化水素により脱メチル化して式（２）で示される反応中間体を得る行程を含むことを特徴とする式（３）で示される４’ーデメチルー４ーエピポドフィロトキシンの製造法。
【００２１】
【発明の実施の形態】
本発明の反応は系内の水分により大きく阻害される。式（１）で示される化合物は通常数パーセントの水分を含有しているので予め十分脱水して使用するのが好ましい。例えば１００℃ないし１０５℃で十分脱水した該化合物を用いるとよい。非ハロゲン系有機溶媒としては、臭化水素の溶解性に優れているものであれば特に制限されないが、非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合溶媒が好ましい。
【００２２】
非ハロゲン系脂肪族溶媒としてはケトン化合物が好ましく、特にカルボニル基の両側の脂肪族炭化水素残基が炭素数１ないし５のアルキル基であるものが好ましく、例えばアセトン、メチルエチルケトン、メチルプロピルケトン（２ーペンタノン）、メチルイソプロピルケトン、３ーペンタノン、メチルイソブチルケトン、メチルブチルケトン（２ーヘキサノン）または３ーヘキサノン等が挙げられる。また非ハロゲン系芳香族溶媒としては非置換ベンゼンまたは置換基として炭素数１ないし４のアルキル基及び／又はニトロ基を１〜３個有するベンゼンが挙げられ、例えばベンゼン、トルエン、キシレン、エチルベンゼン、プロピルベンゼン、ブチルベンゼン類、トリメチルベンゼン類、ニトロベンゼン、およびニトロトルエン類が挙げられる。上記の反応溶媒中、特に好ましくは非ハロゲン系脂肪族溶媒はメチルエチルケトン、２ーペンタノン、メチルイソプロピルケトン、３ーペンタノン、メチルイソブチルケトン、２ーヘキサノンおよび３ーヘキサノンからなる群から選ばれる溶媒であり、非ハロゲン系芳香族溶媒はトルエン、キシレン、エチルベンゼンおよびニトロベンゼンからなる群から選ばれる溶媒である。
【００２３】
ここでケトン化合物は臭化水素を極めて大量に溶解する溶媒である。ケトン化合物のカルボニル基と臭化水素は付加体を形成しこのものが臭化水素に対する良好な溶媒となっていると考えられる。しかし、ケトン化合物を大量に使用するとこの付加体形成により臭化水素が大量に費やされるために反応をスムーズに進行させるためには極めて大量の臭化水素が必要となる。従って、ケトン化合物はできるだけ少なく使用することが望ましい。一方、反応溶媒は反応操作を円滑に進めるためには一定の容量および反応物に対する溶解性が必要である。臭化水素のケトン化合物に対する溶解性を活用しこれらの条件を満足する希釈溶媒として非ハロゲン系芳香族化合物が優れている。
【００２４】
非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合比（容量比）は反応性および反応物の溶解性から０．５：９．５から８：２の範囲内が好ましく、特に好ましくは、１：９から６：４である。溶媒の使用量は、臭化水素の濃度が高いほど反応速度が速くなるので、少ないほど臭化水素の使用量が相対的に少なくなり好ましいが、操作性を考慮して式（１）で示される化合物１重量部に対して１ないし９容量部が好ましく、特に１．５ないし７容量部が好ましい。ケトン化合物等の非ハロゲン系脂肪族溶媒と非ハロゲン系芳香族溶媒との混合溶媒に式（１）の化合物を懸濁させる。そこに臭化水素ガスを導入すると内容物は溶解し反応が進行する。反応の進行につれて式（２）の化合物が結晶として析出するため副反応が防止できる。
【００２５】
臭化水素の使用量は溶媒の種類、使用量、混合比（容量比）および反応温度によって異なるが、溶媒１容量部に対して通常０．１ないし１．０重量部が好ましく、特に０．２ないし０．６重量部が好ましい。反応温度は通常ー１５℃ないし４０℃、好ましくはー１０℃ないし３０℃、より好ましくはー５℃ないし２０℃である。式（１）で示される化合物を脱メチル化して得られた式（２）で示される反応中間体を加水分解することにより式（３）で示される目的物を得る。加水分解は通常の方法によりおこなわれる。例えば式（１）で示される化合物を脱メチル化して得られた反応液にアセトン等の水溶性の溶媒を添加し、炭酸ナトリウム、炭酸カルシウム、炭酸バリウム等の炭酸塩あるいは炭酸水素カリウム、炭酸水素ナトリウム等の炭酸水素塩の水溶液を加え、加熱することにより容易に加水分解される。
【００２６】
【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
ポドフィロトキシン〔式（１）の化合物〕１．００ｇをトルエン５ｍｌおよびメチルエチルケトン１ｍｌの混合溶媒に懸濁し、反応器を氷浴中に浸した。反応器にガス導入管を通して臭化水素２．１２ｇを導入した。吹き込み終了後氷浴中８時間反応した。反応液を高速液体クロマトグラフィーにより分析した結果、式（２）の脱メチル体が６０．４％の収率（液クロ面比純度）で生成していた。尚、これを用い実施例４と同様に行うことにより、４’ーデメチルー４ーエピポドフィロトキシン〔式（３）の化合物〕の目的物を得ることができる。
【００２７】
実施例２
ポドフィロトキシン〔式（１）の化合物〕１．００ｇをトルエン３．０ｍｌおよびメチルイソブチルケトン２．０ｍｌの混合溶媒に懸濁し、反応器を氷浴中に浸した。反応器にガス導入管を通して臭化水素２．２１ｇを導入した。吹き込み終了後氷浴中９時間反応した。反応液を高速液体クロマトグラフィーにより分析した結果、式（２）の脱メチル体が７３．０％の収率（液クロ面比純度）で生成していた。尚、これを用い実施例４と同様に行うことにより、４’ーデメチルー４ーエピポドフィロトキシン〔式（３）の化合物〕の目的物を得ることができる。
【００２８】
実施例３
ポドフィロトキシン〔式（１）の化合物〕２．００ｇをトルエン４．２ｍｌおよびメチルイソブチルケトン１．８ｍｌの混合溶媒に懸濁し、反応器を１５℃とした。反応器にガス導入管を通して臭化水素１．６９ｇを導入した。吹き込み終了後反応液を１５℃に保ち、８時間反応した。反応液を高速液体クロマトグラフィーにより分析した結果、式（２）の脱メチル体が６５．３％の収率（液クロ面比純度）で生成していた。尚、これを用い実施例４と同様に行うことにより、４’ーデメチルー４ーエピポドフィロトキシン〔式（３）の化合物〕の目的物を得ることができる。
【００２９】
実施例４
ポドフィロトキシン〔式（１）の化合物〕２．００ｇをトルエン４．２ｍｌおよびメチルイソブチルケトン１．８ｍｌの混合溶媒に懸濁し、反応器を氷浴中に浸した。反応器にガス導入管を通して臭化水素２．７０ｇを導入した。吹き込み終了後８時間反応した。反応液を高速液体クロマトグラフィーにより分析した結果、式（２）の脱メチル体が７０．８％の収率で生成していた。反応器を冷蔵庫に入れ、翌日、反応液を高速液体クロマトグラフィーにより分析した結果、式（２）の脱メチル体が７６．８％の収率（液クロ面比純度）で生成していた。反応液にアセトン５ｍｌ添加し、１０％炭酸ソーダ水溶液を２０ｍｌ滴下し、４０℃、３時間加水分解し、反応物を濾過することにより、４’ーデメチルー４ーエピポドフィロトキシン〔式（３）の化合物〕の粗結晶１．０２ｇが得られた。純度８８．５％、目的物の含量０．８３ｇ（収率４４．５％）であった。
【００３０】
【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エトポシドの原料である４’ーデメチルー４ーエピポドフィロトキシンを公知の方法に比べて副反応生成物含量が少ない高純度でかつ高収率で得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to 4′-demethyl-4-epipodophyllotoxin, which is a main raw material of 4′-demethyl-4-epipodophyllotoxin-β-D-ethylideneglucoside (generic name etoposide), which is widely used as an antitumor agent. It relates to the manufacturing method.
[0002]
[Prior art]
4'-methyl-4-epipodophyllotoxin represented by the following formula (3) is hydrolyzed by removing the 4'-position methyl group of the podophyllotoxin represented by the following formula (1) with hydrogen bromide. In the method for obtaining the above, a halogen-based solvent such as dichloroethane is preferably used as a solvent used in the treatment with hydrogen bromide. (Japanese Patent Publication No. 43-6469)
[0003]
[Problems to be solved by the invention]
In recent years, conversion from halogen-based solvents to non-halogen-based organic solvents has been desired due to carcinogenicity to humans and environmental hazards. However, in this reaction, it was considered necessary to use a halogen-based solvent in order to stably dissolve hydrogen bromide at a high concentration and allow the reaction to proceed smoothly.
[0004]
[Means for Solving the Problems]
As a result of various investigations of reactions with non-halogen organic solvents instead of halogen-based solvents as solvents used in the reaction, the present inventors have found that non-halogen-based aliphatic solvents such as ketone compounds and non-halogen-based aromatic solvents The present inventors have found that a mixed solvent is particularly excellent and that the reaction can be carried out even in a non-halogen organic solvent, thereby completing the present invention.
[0005]
That is, the present invention relates to the following (1) to (9).
(1) Formula (1)
[0006]
[Formula 4]
The podophyllotoxin represented by formula (2) is demethylated with hydrogen bromide in a non-halogen organic solvent.
[0008]
[Chemical formula 5]
A reaction intermediate represented by formula (3), which is hydrolyzed
[0010]
[Chemical 6]
A process for producing 4′-demethyl-4-epipodophyllotoxin represented by the formula:
[0012]
(2) The production method according to (1), wherein the non-halogen organic solvent is a mixed solvent of a non-halogen aliphatic solvent and a non-halogen aromatic solvent.
[0013]
(3) The production method according to (2), wherein the non-halogen aliphatic solvent is a ketone compound.
[0014]
(4) The process according to (3), wherein the ketone compound is a ketone compound having an alkyl group having 1 to 5 carbon atoms on both sides of the carbonyl group.
[0015]
(5) The non-halogen type aromatic solvent is benzene which may have 1 to 3 alkyl groups and / or nitro groups having 1 to 4 carbon atoms as a substituent (2), (3) or ( 4) The manufacturing method as described.
[0016]
(6) The mixing ratio (volume ratio) of the non-halogen aliphatic solvent and the non-halogen aromatic solvent is in the range of 0.5: 9.5 to 8: 2, (2), (3), ( 4) or the production method according to (5).
[0017]
(7) The amount of the mixed solvent of the non-halogen aliphatic solvent and the non-halogen aromatic solvent is in the range of 1 to 9 parts by volume with respect to 1 part by weight of the compound represented by the formula (1) (2 ), (3), (4), (5) or (6).
[0018]
(8) The amount of hydrogen bromide used is in the range of 0.1 to 1.0 part by weight with respect to 1 part by volume of the solvent (1), (2), (3), (4), (5) (6) or the manufacturing method of (7) description.
[0019]
(9) The process according to (1), wherein the reaction intermediate represented by the formula (2) is hydrolyzed with an alkali metal or alkaline earth metal hydrogencarbonate or an aqueous solution of carbonate.
[0020]
(10) In the formula (3), comprising the step of demethylating the compound of the formula (1) with hydrogen bromide in a non-halogen organic solvent to obtain a reaction intermediate represented by the formula (2) Process for the production of 4′-demethyl-4-epipodophyllotoxin shown.
[0021]
DETAILED DESCRIPTION OF THE INVENTION
The reaction of the present invention is greatly inhibited by moisture in the system. Since the compound represented by the formula (1) usually contains several percent of water, it is preferably used after sufficiently dehydrating. For example, the compound which has been sufficiently dehydrated at 100 ° C. to 105 ° C. may be used. The non-halogen organic solvent is not particularly limited as long as it has excellent hydrogen bromide solubility, but a mixed solvent of a non-halogen aliphatic solvent and a non-halogen aromatic solvent is preferable.
[0022]
As the non-halogen aliphatic solvent, a ketone compound is preferable, and in particular, an aliphatic hydrocarbon residue on both sides of the carbonyl group is preferably an alkyl group having 1 to 5 carbon atoms. For example, acetone, methyl ethyl ketone, methyl propyl ketone (2 -Pentanone), methyl isopropyl ketone, 3-pentanone, methyl isobutyl ketone, methyl butyl ketone (2-hexanone) or 3-hexanone. Examples of the non-halogen aromatic solvent include unsubstituted benzene or benzene having 1 to 4 alkyl groups and / or nitro groups as a substituent, such as benzene, toluene, xylene, ethylbenzene, propyl. Examples include benzene, butylbenzenes, trimethylbenzenes, nitrobenzene, and nitrotoluenes. Among the above reaction solvents, the non-halogen aliphatic solvent is particularly preferably a solvent selected from the group consisting of methyl ethyl ketone, 2-pentanone, methyl isopropyl ketone, 3-pentanone, methyl isobutyl ketone, 2-hexanone and 3-hexanone. The aromatic solvent is a solvent selected from the group consisting of toluene, xylene, ethylbenzene and nitrobenzene.
[0023]
Here, the ketone compound is a solvent that dissolves hydrogen bromide in a very large amount. The carbonyl group and hydrogen bromide of the ketone compound form an adduct, which is considered to be a good solvent for hydrogen bromide. However, when a large amount of a ketone compound is used, a large amount of hydrogen bromide is required for the reaction to proceed smoothly because a large amount of hydrogen bromide is consumed due to this adduct formation. Therefore, it is desirable to use as little ketone compound as possible. On the other hand, the reaction solvent needs to have a certain volume and solubility in the reactants in order to facilitate the reaction operation. Non-halogen aromatic compounds are excellent as a diluting solvent that utilizes the solubility of hydrogen bromide in ketone compounds and satisfies these conditions.
[0024]
The mixing ratio (volume ratio) of the non-halogen aliphatic solvent and the non-halogen aromatic solvent is preferably in the range of 0.5: 9.5 to 8: 2, particularly preferably from the viewpoint of reactivity and solubility of the reactants. Is from 1: 9 to 6: 4. As the amount of the solvent used, the higher the concentration of hydrogen bromide, the faster the reaction rate. Therefore, the smaller the amount, the smaller the amount of hydrogen bromide used, which is preferable. 1 to 9 parts by volume is preferable with respect to 1 part by weight of the compound to be prepared, and 1.5 to 7 parts by volume is particularly preferable. The compound of formula (1) is suspended in a mixed solvent of a non-halogen aliphatic solvent such as a ketone compound and a non-halogen aromatic solvent. When hydrogen bromide gas is introduced there, the contents dissolve and the reaction proceeds. As the reaction proceeds, the compound of formula (2) precipitates as crystals, so that side reactions can be prevented.
[0025]
The amount of hydrogen bromide used varies depending on the type of solvent, the amount used, the mixing ratio (volume ratio), and the reaction temperature, but it is usually preferably 0.1 to 1.0 parts by weight, especially 0. 2 to 0.6 parts by weight are preferred. The reaction temperature is usually -15 ° C to 40 ° C, preferably -10 ° C to 30 ° C, more preferably -5 ° C to 20 ° C. The target product represented by the formula (3) is obtained by hydrolyzing the reaction intermediate represented by the formula (2) obtained by demethylating the compound represented by the formula (1). Hydrolysis is performed by conventional methods. For example, a water-soluble solvent such as acetone is added to the reaction solution obtained by demethylating the compound represented by the formula (1), and carbonates such as sodium carbonate, calcium carbonate, barium carbonate, potassium hydrogen carbonate, hydrogen carbonate It is easily hydrolyzed by adding an aqueous solution of bicarbonate such as sodium and heating.
[0026]
【Example】
Next, the present invention will be described more specifically with reference to examples.
Example 1
1.00 g of podophyllotoxin [compound of formula (1)] was suspended in a mixed solvent of 5 ml of toluene and 1 ml of methyl ethyl ketone, and the reactor was immersed in an ice bath. 2.12 g of hydrogen bromide was introduced into the reactor through a gas introduction tube. After completion of blowing, the reaction was carried out in an ice bath for 8 hours. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of formula (2) was produced in a yield of 60.4% (liquid surface area specific purity). By using this in the same manner as in Example 4, the target product of 4′-demethyl-4-epipodophyllotoxin [compound of formula (3)] can be obtained.
[0027]
Example 2
1.00 g of podophyllotoxin [compound of formula (1)] was suspended in a mixed solvent of 3.0 ml of toluene and 2.0 ml of methyl isobutyl ketone, and the reactor was immersed in an ice bath. 2.21 g of hydrogen bromide was introduced into the reactor through a gas introduction tube. After completion of the blowing, the reaction was performed for 9 hours in an ice bath. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of the formula (2) was produced in a yield of 73.0% (liquid surface area specific purity). By using this in the same manner as in Example 4, the target product of 4′-demethyl-4-epipodophyllotoxin [compound of formula (3)] can be obtained.
[0028]
Example 3
2.00 g of podophyllotoxin [compound of formula (1)] was suspended in a mixed solvent of 4.2 ml of toluene and 1.8 ml of methyl isobutyl ketone, and the reactor was kept at 15 ° C. 1.69 g of hydrogen bromide was introduced into the reactor through a gas introduction tube. After completion of the blowing, the reaction solution was kept at 15 ° C. and reacted for 8 hours. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of the formula (2) was produced with a yield of 65.3% (liquid surface area specific purity). By using this in the same manner as in Example 4, the target product of 4′-demethyl-4-epipodophyllotoxin [compound of formula (3)] can be obtained.
[0029]
Example 4
2.00 g of podophyllotoxin [compound of formula (1)] was suspended in a mixed solvent of 4.2 ml of toluene and 1.8 ml of methyl isobutyl ketone, and the reactor was immersed in an ice bath. 2.70 g of hydrogen bromide was introduced into the reactor through a gas introduction tube. Reaction was performed for 8 hours after the completion of the blowing. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of formula (2) was produced in a yield of 70.8%. The reactor was put into a refrigerator, and the reaction solution was analyzed by high performance liquid chromatography the next day. As a result, the demethylated product of formula (2) was produced in a yield of 76.8% (liquid chromatography surface specific purity). 5 ml of acetone was added to the reaction solution, 20 ml of 10% sodium carbonate aqueous solution was added dropwise, hydrolyzed at 40 ° C. for 3 hours, and the reaction product was filtered to give 4′-demethyl-4-epipodophyllotoxin [formula (3) Of the compound] was obtained. The purity was 88.5% and the content of the target product was 0.83 g (yield 44.5%).
[0030]
【The invention's effect】
According to the present invention, 4'-demethyl-4-epipodophyllotoxin, which is a raw material of etoposide without using a harmful halogen-based solvent, is obtained in high purity and high yield with less side reaction product content than known methods. Obtainable.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21837397A JP3998074B2 (en) | 1997-07-30 | 1997-07-30 | Method for demethylation of podophyllotoxin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21837397A JP3998074B2 (en) | 1997-07-30 | 1997-07-30 | Method for demethylation of podophyllotoxin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1149774A JPH1149774A (en) | 1999-02-23 |
| JP3998074B2 true JP3998074B2 (en) | 2007-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21837397A Expired - Lifetime JP3998074B2 (en) | 1997-07-30 | 1997-07-30 | Method for demethylation of podophyllotoxin |
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| Country | Link |
|---|---|
| JP (1) | JP3998074B2 (en) |
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1997
- 1997-07-30 JP JP21837397A patent/JP3998074B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| JPH1149774A (en) | 1999-02-23 |
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