JP3126799B2 - Optically active camptothecin derivative and method for producing the same - Google Patents
Optically active camptothecin derivative and method for producing the sameInfo
- Publication number
- JP3126799B2 JP3126799B2 JP04076978A JP7697892A JP3126799B2 JP 3126799 B2 JP3126799 B2 JP 3126799B2 JP 04076978 A JP04076978 A JP 04076978A JP 7697892 A JP7697892 A JP 7697892A JP 3126799 B2 JP3126799 B2 JP 3126799B2
- Authority
- JP
- Japan
- Prior art keywords
- ethyl
- compound
- methoxycamptothecin
- acyl
- producing
- 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.)
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Description
【０００１】[0001]
【産業上の利用分野】本発明は光学活性２０−Ｏ−アシ
ル−７−エチル−１０−メトキシカンプトテシン及びそ
の製法に関し、更に詳しくは合成抗癌剤として有用なカ
ンプトテシン誘導体製造のための合成中間体である該化
合物及びその製法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active 20-O-acyl-7-ethyl-10-methoxycamptothecin and a method for producing the same, and more particularly to a synthetic intermediate for producing a camptothecin derivative useful as a synthetic anticancer agent. The present invention relates to the compound and a method for producing the compound.
【０００２】[0002]
【従来の技術及び発明が解決しようとする課題】下記化
学式（３）BACKGROUND OF THE INVENTION The following chemical formula (3)
【０００３】[0003]
【化３】 Embedded image
【０００４】で表わされるカンプトテシン誘導体は抗癌
剤として有用なものであることが知られている。It is known that the camptothecin derivative represented by the formula is useful as an anticancer agent.
【０００５】そこで、上記カンプトテシン誘導体（３）
の製造に有用な中間体を穏和な条件下で簡便に得る方法
の開発が望まれていた。Therefore, the camptothecin derivative (3)
It has been desired to develop a method for easily obtaining an intermediate useful for the production of a compound under mild conditions.
【０００６】[0006]
【課題を解決するための手段】本発明者らはかかる実情
に鑑み鋭意検討した結果、ＳＨ酵素がカンプトテシン誘
導体のＲ体にのみ作用して分解し、Ｓ体を残存させるこ
とを見出し、本発明を完成するに至った。Means for Solving the Problems The present inventors have conducted intensive studies in view of the above circumstances, and as a result, have found that the SH enzyme acts only on the R-form of a camptothecin derivative to decompose it, leaving the S-form, and the present invention. Was completed.
【０００７】すなわち、本発明は、光学活性２０−Ｏ−
アシル−７−エチル−１０−メトキシカンプトテシンを
提供するものである。That is, the present invention provides an optically active 20-O-
Acyl-7-ethyl-10-methoxycamptothecin.
【０００８】更に、本発明は、下記一般式（２）で表わ
される２０−Ｏ−アシル−７−エチル−１０−メトキシ
カンプトテシンのラセミ体にＳＨ酵素を反応させる光学
活性２０−Ｏ−アシル−７−エチル−１０−メトキシカ
ンプトテシンの製法を提供するものである。Further, the present invention relates to an optically active 20-O-acyl-7 obtained by reacting an SH enzyme with a racemic 20-O-acyl-7-ethyl-10-methoxycamptothecin represented by the following general formula (2). -Ethyl-10-methoxycamptothecin.
【０００９】[0009]
【化４】 Embedded image
【００１０】（式中、ＲＣＯはアシル基を示す）(Wherein RCO represents an acyl group)
【００１１】上記光学活性２０−Ｏ−アシル−７−エチ
ル−１０−メトキシカンプトテシンは、特に下記一般式
（１）The above-mentioned optically active 20-O-acyl-7-ethyl-10-methoxycamptothecin is particularly represented by the following general formula (1):
【００１２】[0012]
【化５】 Embedded image
【００１３】（式中、ＲＣＯはアシル基を示す）で表わ
される（２０Ｓ）−２０−Ｏ−アシル−７−エチル−１
０−メトキシカンプトテシンであることが好ましい。(Wherein RCO represents an acyl group) (20S) -20-O-acyl-7-ethyl-1
Preferably, it is 0-methoxycamptothecin.
【００１４】本発明に使用される上記一般式（２）、ひ
いては一般式（１）で表わされる化合物のアシル基ＲＣ
ＯのＲは炭素数１〜６のアルキル基が好ましく、なかで
もメチル基、エチル基、ｎ−プロピル基等が特に好まし
い。The acyl group RC of the compound represented by the above general formula (2) and the general formula (1) used in the present invention.
R in O is preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably a methyl group, an ethyl group, an n-propyl group and the like.
【００１５】本発明に使用されるＳＨ酵素は、活性中心
にＳＨ基を有するものであり、植物由来、動物由来、微
生物由来のものがあるが、植物由来又は動物由来のもの
が好ましく、特に植物由来のものが、中でもパパイン、
フィシン等が好ましい。The SH enzyme used in the present invention has an SH group at its active center and is of plant, animal or microbial origin, but is preferably of plant or animal origin. Of origin, especially papain,
Ficin and the like are preferred.
【００１６】化合物（１）を得るには、まず化合物
（２）のラセミ体を水、水と有機溶媒（水と混和するも
の；メタノール、エタノール等）との混合溶媒又は水と
有機溶媒（水と混和しないもの；酢酸エチル、イソプロ
ピルエーテル、ｎ−ヘキサン、トルエン等）との混合溶
媒に懸濁した後、上記ＳＨ酵素を静かに添加して攪拌し
反応させる。In order to obtain the compound (1), first, the racemic compound (2) is mixed with water, a mixed solvent of water and an organic solvent (miscible with water; methanol, ethanol, etc.) or water and an organic solvent (water And the mixture is suspended in a mixed solvent of ethyl acetate, isopropyl ether, n-hexane, toluene, etc.), and the SH enzyme is gently added, followed by stirring and reaction.
【００１７】反応は、通常５〜６０℃、好ましくは３０
〜５０℃、pH４〜９、好ましくは６〜７で１０〜７２時
間程度攪拌することにより行う。The reaction is carried out usually at 5 to 60 ° C., preferably at 30 ° C.
It is carried out by stirring at ５０50 ° C., pH 4-9, preferably 6-7 for about 10-72 hours.
【００１８】本発明に使用される化合物（２）のラセミ
体の濃度は０．１〜１重量％（以下単に％という）が好
ましく、０．１〜０．２％が特に好ましい。The concentration of the racemic compound (2) used in the present invention is preferably from 0.1 to 1% by weight (hereinafter simply referred to as%), particularly preferably from 0.1 to 0.2%.
【００１９】使用されるＳＨ酵素量は特に限定されない
が、化合物（２）のラセミ体に対し、重量比で１〜５０
倍であることが好ましい。The amount of the SH enzyme to be used is not particularly limited, but is 1 to 50 by weight based on the racemic compound (2).
Preferably it is twice.
【００２０】上記反応終了後、反応液に濾過、減圧濃
縮、カラムクロマトグラフィー等の公知の手段を施すこ
とにより目的の化合物（１）を単離することができる。After completion of the above reaction, the desired compound (1) can be isolated by subjecting the reaction solution to known means such as filtration, concentration under reduced pressure, column chromatography and the like.
【００２１】得られた化合物（１）を公知の方法により
脱アシル化した後、更に公知の方法、例えば特開昭６３
−１５２３８２号公報記載の方法により前記化合物
（３）に導くことができる。After the obtained compound (1) is deacylated by a known method, it is further subjected to a known method, for example,
Compound (3) can be derived by the method described in JP-A-152382.
【００２２】[0022]
【発明の効果】本発明は、穏和な条件下でかつ簡便に反
応を行わせることができるものであり、しかも副反応を
ほとんど誘発することなく、高純度の目的化合物を得る
ことができる。According to the present invention, the reaction can be easily carried out under mild conditions, and the desired compound of high purity can be obtained without inducing any side reaction.
【００２３】[0023]
【実施例】以下に本発明を実施例により具体的に説明す
るが、本発明はこれらに限定されるものではない。EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.
【００２４】参考例 ２０−Ｏ−アセチル−７−エチル−１０−メトキシカン
プトテシン（化合物（２））の製造 ４−Ｏ−アセチル−４−エチル−６，６−（エチレンジ
オキシ）−７，８−ジヒドロ−１Ｈ−ピラノ〔３，４−
ｆ〕インドリジン−３，１０（４Ｈ）−ジオン３５０mg
を酢酸２ml、濃塩酸１mlの混合溶媒に溶解し室温で１時
間放置した。反応液に水１０mlを加え、クロロホルムで
抽出した。有機層を水洗後乾燥し、減圧下溶媒を留去し
た。この残渣をトルエン２０mlに溶解し、２−アミノ−
５−メトキシプロピオフェノン１８０mgを加え、１時間
加熱還流した。放冷後、トシル酸（１水和物）２５mgを
加え、更に１時間加熱還流した。反応液を氷冷し、析出
する沈澱を濾取、洗浄（冷トルエン５ml）することによ
り標記の化合物（ラセミ体）３７０mg（収率８３％）を
得た。Reference Example 20 Preparation of 20-O-acetyl-7-ethyl-10-methoxycamptothecin (Compound (2)) 4-O-acetyl-4-ethyl-6,6- (ethylenedioxy) -7,8 -Dihydro-1H-pyrano [3,4-
f] Indolizine-3,10 (4H) -dione 350mg
Was dissolved in a mixed solvent of 2 ml of acetic acid and 1 ml of concentrated hydrochloric acid and left at room temperature for 1 hour. 10 ml of water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. This residue was dissolved in 20 ml of toluene, and 2-amino-
180 mg of 5-methoxypropiophenone was added, and the mixture was heated under reflux for 1 hour. After cooling, 25 mg of tosylic acid (monohydrate) was added, and the mixture was further heated under reflux for 1 hour. The reaction solution was ice-cooled, and the resulting precipitate was collected by filtration and washed (5 ml of cold toluene) to obtain 370 mg (yield: 83%) of the title compound (racemic product).
【００２５】FT-NMR、MS各データを以下に示す。 FT-NMR(CDCl3 中のδ値(ppm) ）： 0.96(3H,t,J=7Hz) 1.42(3H,t,J=7Hz) 2.19(3H,s) 2.0-2.3(2H,m) 3.18(2H,m) 4.02(3H,s) 5.29(2H,s) 5.53(2H,dd,J=17.1Hz) 7.26(1H,s) 7.35(1H,d,J=3Hz) 7.48(1H,d,J=9Hz) 7.95(1H,d,J=9Hz) MS(m/z):448(M+)FT-NMR and MS data are shown below. FT-NMR (δ value in CDCl 3 (ppm)): 0.96 (3H, t, J = 7 Hz) 1.42 (3H, t, J = 7 Hz) 2.19 (3H, s) 2.0-2.3 (2H, m) 3.18 (2H, m) 4.02 (3H, s) 5.29 (2H, s) 5.53 (2H, dd, J = 17.1Hz) 7.26 (1H, s) 7.35 (1H, d, J = 3Hz) 7.48 (1H, d, J = 9Hz) 7.95 (1H, d, J = 9Hz) MS (m / z): 448 (M + )
【００２６】実施例１ （２０Ｓ）−２０−Ｏ−アセチル−７−エチル−１０−
メトキシカンプトテシン（化合物（１））の製造 参考例で得られた２０−Ｏ−アセチル−７−エチル−１
０−メトキシカンプトテシン（化合物（２））１５０mg
を０．１Ｍリン酸緩衝液（pH６．５、５０mMの２−メル
カプトエタノール及び１０％メタノールを含有する）１
５０mlに懸濁し、パパイン（シグマ社製）４．５ｇを加
え、３７℃で３日間攪拌した。反応液にメタノール−酢
酸混液（１：１）１５０mlを加え、変性蛋白をセライト
濾過により除いた。濾液を濃縮乾固後、残渣をシリカゲ
ルカラムで精製することにより上記化合物６０mg（収率
４０％）を得た。目的化合物の光学純度は９５％e.e.で
あった。Example 1 (20S) -20-O-acetyl-7-ethyl-10-
Production of methoxycamptothecin (compound (1)) 20-O-acetyl-7-ethyl-1 obtained in Reference Example
0-methoxycamptothecin (Compound (2)) 150 mg
In 0.1 M phosphate buffer (pH 6.5, containing 50 mM 2-mercaptoethanol and 10% methanol) 1
The suspension was suspended in 50 ml, and 4.5 g of papain (manufactured by Sigma) was added, followed by stirring at 37 ° C. for 3 days. 150 ml of a methanol-acetic acid mixture (1: 1) was added to the reaction solution, and the denatured protein was removed by celite filtration. The filtrate was concentrated to dryness, and the residue was purified by a silica gel column to obtain the above compound (60 mg, yield 40%). The optical purity of the target compound was 95% ee.
【００２７】分析条件を下記に示す。 カラム：キラルセルＯＤ（ダイセル化学工業社製） 移動相：ｎ−ヘキサン：エタノール＝１：１（含０．２
％ ジメチルアミン） 流速 ：１．０ml／分 波長 ：３６０nmThe analysis conditions are shown below. Column: Chiral Cell OD (manufactured by Daicel Chemical Industries, Ltd.) Mobile phase: n-hexane: ethanol = 1: 1 (including 0.2
% Dimethylamine) Flow rate: 1.0 ml / min Wavelength: 360 nm
【００２８】実施例２ （２０Ｓ）−２０−Ｏ−アセチル−７−エチル−１０−
メトキシカンプトテシン（化合物（１））の製造 参考例で得られた２０−Ｏ−アセチル−７−エチル−１
０−メトキシカンプトテシン（化合物（２））１００mg
を２０％酢酸エチル（０．１Ｍリン酸緩衝液、pH６．
５、５０mMの２−メルカプトエタノールを含有する）１
００mlに懸濁し、パパイン（シグマ社製）４．０ｇを加
え３７℃で２日間攪拌した。反応液にメタノール−酢酸
混液（１：１）１００mlを加え、変性蛋白をセライト濾
過により除いた。濾液を濃縮乾固後、残渣をシリカゲル
カラムで精製することにより上記化合物４２mg（収率４
２％）を得た。目的化合物の光学純度は９０％e.e.であ
った。分析は実施例１と同様の条件で行った。Example 2 (20S) -20-O-acetyl-7-ethyl-10-
Production of methoxycamptothecin (compound (1)) 20-O-acetyl-7-ethyl-1 obtained in Reference Example
100 mg of 0-methoxycamptothecin (compound (2))
In 20% ethyl acetate (0.1 M phosphate buffer, pH 6.
5, containing 50 mM 2-mercaptoethanol)
The suspension was suspended in 00 ml, and 4.0 g of papain (manufactured by Sigma) was added, followed by stirring at 37 ° C. for 2 days. 100 ml of a mixture of methanol and acetic acid (1: 1) was added to the reaction solution, and the denatured protein was removed by filtration through celite. The filtrate was concentrated to dryness, and the residue was purified by a silica gel column to give 42 mg of the above compound (yield 4).
2%). The optical purity of the target compound was 90% ee. The analysis was performed under the same conditions as in Example 1.
【００２９】実施例３ （２０Ｓ）−２０−Ｏ−アセチル−７−エチル−１０−
メトキシカンプトテシン（化合物（１））の製造 参考例で得られた２０−Ｏ−アセチル−７−エチル−１
０−メトキシカンプトテシン（化合物（２））１００mg
を０．１Ｍリン酸緩衝液（pH６．５、５０mMの２−メル
カプトエタノール及び１０％メタノールを含有する）１
００mlに懸濁し、フィシン（長瀬産業（株）製）４．０
ｇを加え３７℃で３日間攪拌した。実施例１と同様の操
作を行い上記化合物４４mg（収率４４％）を得た。目的
化合物の光学純度は８８％e.e.であった。分析は実施例
１と同様の条件で行った。Example 3 (20S) -20-O-acetyl-7-ethyl-10-
Production of methoxycamptothecin (compound (1)) 20-O-acetyl-7-ethyl-1 obtained in Reference Example
100 mg of 0-methoxycamptothecin (compound (2))
In 0.1 M phosphate buffer (pH 6.5, containing 50 mM 2-mercaptoethanol and 10% methanol) 1
Suspended in 00 ml, and Ficin (manufactured by Nagase & Co., Ltd.) 4.0
g was added and stirred at 37 ° C. for 3 days. The same operation as in Example 1 was performed to obtain 44 mg of the above compound (yield 44%). The optical purity of the target compound was 88% ee. The analysis was performed under the same conditions as in Example 1.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 井村 明弘 東京都江戸川区北葛西１丁目16番13号 第一製薬株式会社 東京研究開発センタ ー内 (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 491/22 C12P 41/00 ＢＩＯＳＩＳ（ＤＩＡＬＯＧ) ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Akihiro Imura 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (58) Fields surveyed (Int. Cl. 7 , DB name) C07D 491/22 C12P 41/00 BIOSIS (DIALOG) CA (STN) REGISTRY (STN)
Claims (3)
１０−メトキシカンプトテシン。(1) (20S) -O-acyl-7-ethyl-
10-methoxycamptothecin.
Ｏ−アシル−７−エチル−１０−メトキシカンプトテシ
ンのラセミ体にパパイン又はフィシンを反応させること
を特徴とする下記一般式（１） 【化２】 （式中、ＲＣＯはアシル基を示す）で表わされる（２０
Ｓ）−Ｏ−アシル−７−エチル−１０−メトキシカンプ
トテシンの製法。2. The following general formula (2): (Wherein RCO represents an acyl group)
The following general formula (1) characterized in that papain or ficin is reacted with a racemic O-acyl-7-ethyl-10-methoxycamptothecin. (Wherein RCO represents an acyl group)
S) A method for producing -O-acyl-7-ethyl-10-methoxycamptothecin.
Ｏ−アシル−７−エチル−１０−メトキシカンプトテシ
ンのラセミ体にパパイン又はフィシンを反応させてＲ体
のみを分解してＳ体を残存させ、Ｒ体の分解物とＳ体を
分離することを特徴とする下記一般式（１） 【化４】 （式中、ＲＣＯはアシル基を示す）で表わされる（２０
Ｓ）−Ｏ−アシル−７−エチル−１０−メトキシカンプ
トテシンの製法。3. The following general formula (2): (Wherein RCO represents an acyl group)
It is characterized by reacting papain or ficin with a racemic O-acyl-7-ethyl-10-methoxycamptothecin to decompose only the R-form to leave the S-form and separating the R-form and the S-form. The following general formula (1) (Wherein RCO represents an acyl group)
S) A method for producing -O-acyl-7-ethyl-10-methoxycamptothecin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04076978A JP3126799B2 (en) | 1992-03-31 | 1992-03-31 | Optically active camptothecin derivative and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04076978A JP3126799B2 (en) | 1992-03-31 | 1992-03-31 | Optically active camptothecin derivative and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05279370A JPH05279370A (en) | 1993-10-26 |
| JP3126799B2 true JP3126799B2 (en) | 2001-01-22 |
Family
ID=13620877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04076978A Expired - Fee Related JP3126799B2 (en) | 1992-03-31 | 1992-03-31 | Optically active camptothecin derivative and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3126799B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5731316A (en) * | 1996-01-30 | 1998-03-24 | The Stehlin Foundation For Cancer Research | Derivatives of camptothecin and methods of treating cancer using these derivatives |
| SG116433A1 (en) * | 1996-10-30 | 2005-11-28 | Tanabe Seiyaku Co | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof. |
| ID23424A (en) | 1997-05-14 | 2000-04-20 | Bayer Ag | GLIKOKONJUGUS OF 20 (S) -CAMPTOTESIN |
-
1992
- 1992-03-31 JP JP04076978A patent/JP3126799B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05279370A (en) | 1993-10-26 |
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