JPH0341081A - Production of dimeric alkaloids - Google Patents
Production of dimeric alkaloidsInfo
- Publication number
- JPH0341081A JPH0341081A JP17564289A JP17564289A JPH0341081A JP H0341081 A JPH0341081 A JP H0341081A JP 17564289 A JP17564289 A JP 17564289A JP 17564289 A JP17564289 A JP 17564289A JP H0341081 A JPH0341081 A JP H0341081A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- phenanthroline
- compound
- lower alkyl
- group
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 229930013930 alkaloid Natural products 0.000 title description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 229910052742 iron Inorganic materials 0.000 claims abstract description 14
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 230000008878 coupling Effects 0.000 claims abstract description 4
- 238000010168 coupling process Methods 0.000 claims abstract description 4
- 125000005157 alkyl carboxy group Chemical group 0.000 claims abstract description 3
- 125000003368 amide group Chemical group 0.000 claims abstract description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- NSMJMUQZRGZMQC-UHFFFAOYSA-N 2-naphthalen-1-yl-1H-imidazo[4,5-f][1,10]phenanthroline Chemical compound C12=CC=CN=C2C2=NC=CC=C2C2=C1NC(C=1C3=CC=CC=C3C=CC=1)=N2 NSMJMUQZRGZMQC-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000003700 epoxy group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- GKWYINOZGDHWRA-UHFFFAOYSA-N catharanthine Natural products C1C(CC)(O)CC(CC2C(=O)OC)CN1CCC1=C2NC2=CC=CC=C12 GKWYINOZGDHWRA-UHFFFAOYSA-N 0.000 abstract description 6
- CXBGOBGJHGGWIE-IYJDUVQVSA-N vindoline Chemical compound CN([C@H]1[C@](O)([C@@H]2OC(C)=O)C(=O)OC)C3=CC(OC)=CC=C3[C@]11CCN3CC=C[C@]2(CC)[C@@H]13 CXBGOBGJHGGWIE-IYJDUVQVSA-N 0.000 abstract description 6
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 abstract description 5
- 229960003048 vinblastine Drugs 0.000 abstract description 5
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 abstract description 5
- WVTGEXAIVZDLCR-UHFFFAOYSA-N Vindoline Natural products CC1C2CN3CCCC14CCC5Nc6ccccc6C25C34 WVTGEXAIVZDLCR-UHFFFAOYSA-N 0.000 abstract description 4
- CMKFQVZJOWHHDV-DYHNYNMBSA-N catharanthine Chemical compound C([C@@H]1C=C([C@@H]2[C@@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC=CC=C12 CMKFQVZJOWHHDV-DYHNYNMBSA-N 0.000 abstract 2
- 239000004593 Epoxy Substances 0.000 abstract 1
- 125000003158 alcohol group Chemical group 0.000 abstract 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000000034 method Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 10
- -1 iron ions Chemical class 0.000 description 9
- 150000003797 alkaloid derivatives Chemical class 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- FFRFGVHNKJYNOV-DOVUUNBWSA-N 3',4'-Anhydrovinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C=C(C2)CC)N2CCC2=C1NC1=CC=CC=C21 FFRFGVHNKJYNOV-DOVUUNBWSA-N 0.000 description 6
- 229950001104 anhydrovinblastine Drugs 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 150000005045 1,10-phenanthrolines Chemical class 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WKBKCMCWVKDZQX-AWARSVQWSA-N methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2(7),3,5,13-tetraene-10-carboxylate hydrochloride Chemical compound Cl.CN([C@H]1[C@](O)([C@@H]2OC(C)=O)C(=O)OC)C3=CC(OC)=CC=C3[C@@]11CCN3CC=C[C@]2(CC)[C@@H]13 WKBKCMCWVKDZQX-AWARSVQWSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野］
本発明はたとえば抗ガン剤として有用なビンブラスチン
等へ容易に変換できるイミニウム中間体化合物の新規な
合成法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel method for synthesizing iminium intermediate compounds that can be easily converted into vinblastine and the like useful as anticancer agents, for example.
（従来の技術〕
従来、アルカロイドをカップリングさせて二量体アルカ
ロイドイミニウム中間体を合成する方法としては、特開
昭５１−８８９９９号に記載のＰｏｌｏｎｏｖｓｌｋｙ
反応を利用したものがあるがアルカロイドを一旦、Ｎ−
オキシドにする必要がある等の欠点がある。(Prior Art) Conventionally, as a method for synthesizing a dimeric alkaloid iminium intermediate by coupling alkaloids, the Polonovslky method described in JP-A-51-88999 has been used.
There are some that utilize the reaction, but once the alkaloid is converted to N-
It has drawbacks such as the need to convert it into an oxide.
又、特願昭６３−１９８８９７号及び特願昭６３−１９
８８９８号には３価の鉄イオンを用いる方法が記載され
ているが、反応速度が遅い等の欠点があり、いずれも工
業的生産方法として問題があった。Also, Japanese Patent Application No. 63-198897 and Japanese Patent Application No. 63-19
No. 8898 describes a method using trivalent iron ions, but it has drawbacks such as slow reaction rate, and both have problems as industrial production methods.
〔発明が解決しようとする課題］
本発明は、たとえば抗ガン剤として有用なビンブラスチ
ン等に容易に変換できる二量体アルカ［ｌイドイミニウ
ム中間体を高収率で生産できる工業的に有利な製造方法
を提供することを目的とするものである。[Problems to be Solved by the Invention] The present invention provides an industrially advantageous production method that can produce in high yield a dimeric alkali diiminium intermediate that can be easily converted into vinblastine, etc. useful as an anticancer agent. The purpose is to provide the following.
本発明、上記目的を達成するためになされたものであっ
てカサランチンあるいはカサランチン誘導体とビンドリ
ンあるいはビンドリン誘導体とのカップリング反応を種
々検討した結果、３価の鉄イオンと式（ＴＶ）で表わさ
れる１、 ｔｏ−フェナントロリン及び／又は
１．１０−フェナントロリン誘導体との錯体を用いるこ
とによって３価の鉄イオンのみで反応させる場合とくら
べてより少量の鉄イオンでより短時間で目的とする二量
体アルカロイドイミニウム中間体を合成できることを見
い出すに至った。The present invention has been made to achieve the above object, and as a result of various studies on coupling reactions between casalanthine or casalanthine derivatives and vindoline or vindoline derivatives, trivalent iron ion and 1 By using a complex with to-phenanthroline and/or 1.10-phenanthroline derivatives, the desired dimeric alkaloid can be produced in a shorter time with a smaller amount of iron ions than when reacting with only trivalent iron ions. We have discovered that it is possible to synthesize iminium intermediates.
本発明は一般式ＣＩ）
（式中ＲＩ＋ Ｒ２，Ｒ３，Ｒ４は水素原子もしくは低
級アルキル基あるいはＲ，Ｒ□又はＲｔ Ｒ４が一緒に
なってエポキシ基もしくは二重結合を形成し、Ｒ５は水
素原子もしくは低級アルキル基を表わし、Ｒ６は水素原
子もしくは低級アルキル基、低級アルコキシ基を表わす
）で表わされる化合物と一般式（）
（式中Ｒ１１は低級アルコキシ基、Ｒ１２は水素原子も
しくは低級アルキル基、ホルミル基を表わし、Ｒ″３は
低級アルコキシカルボキシ基もしくはアミド基を表わし
、Ｒ１４はアルコール）もしくは低級アルキルカルボキ
シ基を表わすで表わされる化合物とを３価の鉄イオンと
１．１０−フェナントロリン及び／又はｌ、１０−フェ
ナントロリン誘導体との錯体を用いてカップリングさせ
一般式（ＩＩ［）（本頁以下余白）
（式中 Ｒ５−Ｒ６は式〔１）に同じＲ１１〜Ｒ′イは
式［１１）に同じ）で表わされる化合物を製造する方法
に関する。The present invention relates to the general formula CI) (where RI+ R2, R3, and R4 are hydrogen atoms or lower alkyl groups, or R, R□, or Rt R4 together form an epoxy group or a double bond, and R5 is a hydrogen atom or a lower alkyl group, R6 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group) and a compound represented by the general formula () (in the formula, R11 is a lower alkoxy group, R12 is a hydrogen atom, a lower alkyl group, or a formyl group). R''3 represents a lower alkoxycarboxy group or an amide group, R14 represents an alcohol) or a lower alkylcarboxy group, and a trivalent iron ion and 1.10-phenanthroline and/or l , coupled using a complex with a 10-phenanthroline derivative to form the general formula (II[) (white space below this page) (wherein R5-R6 are the same as formula [1), R11 to R'i are the same as formula [11] The same applies to a method for producing a compound represented by
上記式（１）の化合物としてはカサランチン、ジヒドロ
カサランチン等が、式（ＩＩ）の化合物としてはビンド
リン、Ｎ−ホルミルビンドリン等が挙げられる。Examples of the compound of formula (1) include casalanthine and dihydrocasalanthine, and examples of the compound of formula (II) include vindoline and N-formylvindoline.
上記式［：ＩＩＩ）の化合物としてはＲ，＝Ｒ，＝Ｒ，
＝Ｈ。The compounds of the above formula [:III) include R, =R, =R,
=H.
ＲｔとＲ４が一緒になって二重結合を形成Ｒ，＝Ｉｌ”
２＝Ｍｅ＋ Ｒ’＋＝−ＯＭｅ、 Ｒ’１＝−ＣＯＪｅ
＋ Ｒ’４＝−ＯＡＣあるいはＲ１＝Ｒｚ ＝ Ｒ２＝
Ｒａ ＝ Ｒｈ ＝ Ｈ＋ ＲＳ ＝ Ｒ’ ｚ ＝
Ｍｅ ＨＲ’ ３ ＝−ＣＯｌＭｅ、 Ｒ’ 、 ＝
−ＯＭｅ＋ Ｒ’ ａ ＝−ＯＡｃである化合物等が
挙げられる。Rt and R4 together form a double bond R,=Il”
2=Me+ R'+=-OMe, R'1=-COJe
+ R'4=-OAC or R1=Rz=R2=
Ra = Rh = H+ RS = R'z =
Me HR' 3 =-COMe, R', =
Examples include compounds where -OMe+ R' a =-OAc.
本発明は３価の鉄イオン−ｌ、１０−フェナントロリン
又は／及びフェナントロリン誘導体錯体、カサランチン
又はカサランチン誘導体又はそれらの塩類、及びとンド
リン又はビンドリン誘導体又はそれらの塩類を溶かす溶
媒を用い、単にこれらの混合溶液を攪拌するというきわ
めて簡単な方法で実施することができる。The present invention uses a solvent that dissolves trivalent iron ion-l, 10-phenanthroline or/and phenanthroline derivative complex, casalanthine or casalanthine derivatives or salts thereof, and indoline or vindoline derivatives or salts thereof, and simply mixes them. This can be carried out by an extremely simple method of stirring the solution.
本発明においては反応系内に３価の鉄イオン源とフェナ
ントロリン及び／又はフェナントロリン誘導体を添加し
て反応系内で錯体を形成させることが特に好ましい。用
いる３価の鉄イオン源としては、フェナントロリン又は
／及びフェナントロリン誘導体と錯体を形成するもので
あればいかなるものでもよいが、特に塩酸塩、硝酸塩が
好ましい。これらの添加量は原料アルカロイドに対して
３価の鉄として０．１〜１０００倍モル、好ましくは１
〜５０倍モルである。In the present invention, it is particularly preferable to add a trivalent iron ion source and phenanthroline and/or a phenanthroline derivative to the reaction system to form a complex within the reaction system. The trivalent iron ion source used may be any source as long as it forms a complex with phenanthroline or/and a phenanthroline derivative, but hydrochloride and nitrate are particularly preferred. The amount of these added is 0.1 to 1000 times mole as trivalent iron to the raw material alkaloid, preferably 1
~50 times the molar amount.
添加する１、１０−フェナントロリン及び／又はｌ。Adding 1,10-phenanthroline and/or l.
１０−フェナントロリン誘導体は３価の鉄イオンに対し
て０．０５〜６倍モル、好ましくは０．１〜３倍モルで
ある。１．１０−フェナントロリン誘導体としては、例
えば４．７−シメチルー１．１０−フェナントロリンが
挙げられるが特にこれらに限定されるものでなくいかな
るものでもよい。なお、この反応においては無置換の１
，１０−フェナントロリンそのものが特に好ましい。The amount of the 10-phenanthroline derivative is 0.05 to 6 times, preferably 0.1 to 3 times, by mole relative to the trivalent iron ion. Examples of the 1.10-phenanthroline derivative include 4.7-dimethyl-1.10-phenanthroline, but are not particularly limited thereto, and any derivative may be used. In addition, in this reaction, unsubstituted 1
, 10-phenanthroline itself is particularly preferred.
このように反応系内で錯体を形成させる方法以外に、反
応前にあらかしめ、錯体を合成し、このものを反応系内
に添加する方法も好ましい方法の一つである。In addition to the method of forming a complex within the reaction system as described above, one preferred method is to prepare a plan before the reaction, synthesize a complex, and add this complex to the reaction system.
この反応に用いる溶媒としては、Ｈ２Ｏ、メタノール、
エタノール等のアルコール類、ＴＩＩＦ、アセトニトリ
ル、Ｄ？ＩＰ、 ＤＭＳＯ等をあげることができる。Solvents used for this reaction include H2O, methanol,
Alcohols such as ethanol, TIIF, acetonitrile, D? Examples include IP, DMSO, etc.
また、これらの２種あるいはそれ以上の混合溶媒を用い
てもよい。好ましくは、Ｈ！Ｏ単独、１１ｔＯ−メタノ
ール混合溶媒が用いられる。Further, a mixed solvent of two or more of these may also be used. Preferably H! O alone or a mixed solvent of 11tO-methanol is used.
反応温度は、反応溶媒の融点以上ないし５０°Ｃ位まで
の広い範囲を採用することができるが好ましくは一２０
°Ｃ〜ｉｏ”ｃである。The reaction temperature can be in a wide range from the melting point of the reaction solvent to about 50°C, but is preferably -20°C.
°C~io”c.
本発明によれば、従来の方法と比較してより少量の試薬
でまり高収率で、たとえば抗ガン剤として有用なビンブ
ラスチン等へ容易に変換できる二量体アルカロイトイミ
ニラム中間体を得ることができる利点がある。ビンブラ
スチン等が非常に高価な抗ガン剤であることを考慮すれ
ば本発明の方法のもたらす効果は非常に大きい。According to the present invention, a dimeric alkaloid iminiram intermediate that can be easily converted into vinblastine, etc., which is useful as an anticancer drug, can be obtained using a smaller amount of reagents and in a higher yield than in conventional methods. There is an advantage that it can be done. Considering that vinblastine and the like are very expensive anticancer drugs, the effects of the method of the present invention are very large.
次に実施例によってこの発明を更に具体的に説明するが
これは本発明を限定するものではない。Next, the present invention will be explained in more detail with reference to examples, but these are not intended to limit the present invention.
実施例１
カサランチン１／２硫酸塩の１２ｍＭ水溶液０．４ ｍ
ｌ 。Example 1 12mM aqueous solution of casalanthine 1/2 sulfate 0.4m
l.
ビンドリン塩酸塩の１２ｍＭ水溶液０．４ｍｆ１．、Ｆ
ｅＣｌ＊・６１１２０の１．２門水？容？ｆｆ１０．０
５ｍ！！及びＬ １０−フェナントロリン０．０３５６
ｇ （１，１０−フェナントロリン／ｐｅ３”−３／１
モル比）を反応器に仕込み０°Ｃで６時間撹拌し二量体
アルカロイドイミニウム中間体を得た。Vindoline hydrochloride 12mM aqueous solution 0.4mf1. ,F
eCl*・61120 1.2 gate water? Yong? ff10.0
5m! ! and L 10-phenanthroline 0.0356
g (1,10-phenanthroline/pe3”-3/1
molar ratio) was charged into a reactor and stirred at 0°C for 6 hours to obtain a dimer alkaloid iminium intermediate.
次いで、ＬＯｍｌｌのｌＩ２０を加えた後ＮａＢＩＩ４
の０．２２７Ｍ水溶液を１ ｍｌ添加し二量体アルカロ
イトイ迅ニウム中間体を１，２−還元し、２成のアンモ
ニア水を加えた後Ａｃ０Ｅｔ １０ｃｃで３回抽出し、
これらを合せ４０°Ｃ以下で減圧乾固した。このものを
高速液体クロマトグラフィーで分析し、アンヒドロビン
ブラスチンとして二量体アルカロイドイミニウム中間体
を定量した。この時アンヒドロビンブラスチンの収率は
６７％であった。Then add LOml of lI20 followed by NaBII4
1 ml of a 0.227M aqueous solution of was added to 1,2-reduce the dimer alkaloid intermediate, and after addition of binary aqueous ammonia, it was extracted 3 times with 10 cc of Ac0Et.
These were combined and dried under reduced pressure at 40°C or less. This product was analyzed by high performance liquid chromatography, and the dimeric alkaloid iminium intermediate was quantified as anhydrovinblastine. At this time, the yield of anhydrovinblastine was 67%.
（分析条件）
カラム： ＹＭＣ−ｐａｃｋｅｄ ｃｏｌｕｍｎ Ａ−
５１２（ＣＮ） ６ Ｘ５０ｍ
ン容 媒 ： ＨｚＯ−ＭｅＯＨ−ＥｔＪ−八ｃＯＨ
＝１５００：１５００：４：１゜６
流速： １ ａｆ／ｗｉｎ
カラム温度：４５℃
検出波長： ２５４ｎｍ
リチンシコンタイム：アンヒドロビンブラスチン４６分
比較例１
実施例１における１、１０−フェナントロリンを添加せ
ず、又ＮａＢＨａ水溶液を加える前にＡｃ０Ｎａの２Ｍ
水溶液を５ ｃｃ加えた以外は実施例１と全く同様に行
った。この時、アンヒドロビンブラスチンの収率は５６
％であった。(Analysis conditions) Column: YMC-packed column A-
512(CN) 6 x 50m capacity Medium: HzO-MeOH-EtJ-8cOH
= 1500:1500:4:1゜6 Flow rate: 1 af/win Column temperature: 45°C Detection wavelength: 254 nm Lithin synthesis time: Anhydrovinblastine 46 minutes Comparative example 1 1,10-phenanthroline in Example 1 was not added , and 2M of Ac0Na before adding the NaBHa aqueous solution.
The same procedure as in Example 1 was carried out except that 5 cc of the aqueous solution was added. At this time, the yield of anhydrovinblastine was 56
%Met.
実施例２〜３
実施例１における、Ｌ １０−フェナントロリンの添加
量を変えた以外は実施例１と全く同様に行った。結果を
第１表に示す。Examples 2 to 3 The same procedure as in Example 1 was conducted except that the amount of L 10-phenanthroline added was changed. The results are shown in Table 1.
第１表
実施例２１
３
実施例４
実施例１における、鉄量を１７５（フェナントロリン／
Ｆｅ”＋比は同じ）にした以外は実施例１と全く同様に
行った。この時、アンヒドロビンブラスチンの収率は４
４％であった。Table 1 Example 21 3 Example 4 In Example 1, the amount of iron was changed to 175 (phenanthroline/
The procedure was carried out in exactly the same manner as in Example 1, except that the Fe"+ ratio was the same. At this time, the yield of anhydrovinblastine was 4.
It was 4%.
実施例５
実施例１におけるカサランチン１／２硫酸塩をジヒドロ
カサランチン塩酸塩に変えた以外は実施例１と全く同様
に行った。この時、デオキシビンブラスチンの収率は５
０％であった。Example 5 The same procedure as in Example 1 was carried out except that casalanthine 1/2 sulfate in Example 1 was changed to dihydrocasalanthine hydrochloride. At this time, the yield of deoxyvinblastine was 5
It was 0%.
実施例６
実施例１における１、 １０−フェナントロリンを４．
７−シメチルー１．１０−フェナントロリンに変えた以
外は実施例１と全く同しに行った。Example 6 1, 10-phenanthroline in Example 1 was added to 4.
The same procedure as in Example 1 was carried out except that 7-dimethyl-1,10-phenanthroline was used.
この時、アンヒドロビンブラスチンの収率は６４％であ
った。At this time, the yield of anhydrovinblastine was 64%.
Claims (1)
くは低級アルキル基あるいはＲ＿１Ｒ＿３又はＲ＿２Ｒ
＿４が一緒になってエポキシ基もしくは二重結合を形成
し、Ｒ＿５は水素原子もしくは低級アルキル基を表わし
、Ｒ＿６は水素原子もしくは低級アルキル基、低級アル
コキシ基を表わす）で表わされる化合物と一般式〔II〕 ▲数式、化学式、表等があります▼〔II〕 （式中Ｒ′＿１、は低級アルコキシ基、Ｒ′＿２は水素
原子もしくは低級アルキル基、ホルミル基を表わし、Ｒ
′＿３は低級アルコキシカルボニル基もしくはアミド基
を表わし、Ｒ′＿４はアルコールもしくは低級アルキル
カルボキシ基を表わす）で表わされる化合物とを３価の
鉄と１，１０−フェナントロリン及び／又は１，１０−
フェナントロリン誘導体との錯体を用いてカップリング
させ一般式〔III〕▲数式、化学式、表等があります▼
〔III〕 （式中Ｒ＿１〜Ｒ＿６は式〔 I 〕に同じＲ′＿１〜Ｒ
′＿４は式〔II〕に同じ）で表わされる化合物を製造す
ることを特徴とする式〔III〕で表わされる化合物の製
造方法。 ２、式〔III〕の化合物がＲ＿１＝Ｈ，Ｒ＿２とＲ＿４
が一緒になって二重結合を形成Ｒ＿３＝Ｈ，Ｒ＿５＝Ｍ
ｅ，Ｒ＿６＝Ｈ，Ｒ′＿１＝−ＯＭｅ，Ｒ′＿２＝Ｍｅ
，Ｒ′＿３＝−ＣＯＯＭｅ，Ｒ′＿４＝−ＯＡｃである
ことを特徴とする請求項１記載の化合物の製造方法。 ３、式〔III〕の化合物がＲ＿１＝Ｒ＿２＝Ｒ＿３＝Ｒ
＿４＝Ｈ，Ｒ＿５＝Ｍｅ，Ｒ＿６＝Ｈ，Ｒ′＿１＝−Ｏ
Ｍｅ，Ｒ′＿２＝Ｍｅ、Ｒ′＿３＝−ＣＯＯＭｅ，Ｒ′
＿４＝−ＯＡｃであることを特徴とする請求項１記載の
化合物の製造方法。[Claims] 1. General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, R_1, R_2, R_3, R_4 are hydrogen atoms, lower alkyl groups, or R_1R_3 or R_2R
_4 together form an epoxy group or a double bond, R_5 represents a hydrogen atom or a lower alkyl group, R_6 represents a hydrogen atom or a lower alkyl group, or a lower alkoxy group) and a compound represented by the general formula [ II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II] (In the formula, R'_1 represents a lower alkoxy group, R'_2 represents a hydrogen atom, a lower alkyl group, or a formyl group,
'_3 represents a lower alkoxycarbonyl group or an amide group, R'_4 represents an alcohol or a lower alkylcarboxy group), trivalent iron, 1,10-phenanthroline and/or 1,10-
Coupling using a complex with a phenanthroline derivative General formula [III] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
[III] (In the formula, R_1 to R_6 are the same R′_1 to R as in the formula [I]
'_4 is the same as formula [II]) A method for producing a compound represented by formula [III]. 2. The compound of formula [III] is R_1=H, R_2 and R_4
together form a double bond R_3=H, R_5=M
e, R_6=H, R'_1=-OMe, R'_2=Me
, R'_3=-COOMe, and R'_4=-OAc. 3. The compound of formula [III] is R_1=R_2=R_3=R
_4=H, R_5=Me, R_6=H, R'_1=-O
Me, R'_2=Me, R'_3=-COOMe, R'
The method for producing the compound according to claim 1, wherein _4=-OAc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17564289A JPH0341081A (en) | 1989-07-10 | 1989-07-10 | Production of dimeric alkaloids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17564289A JPH0341081A (en) | 1989-07-10 | 1989-07-10 | Production of dimeric alkaloids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0341081A true JPH0341081A (en) | 1991-02-21 |
Family
ID=15999657
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17564289A Pending JPH0341081A (en) | 1989-07-10 | 1989-07-10 | Production of dimeric alkaloids |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0341081A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0859610A1 (en) * | 1995-08-08 | 1998-08-26 | Albany Medical College | Ibogamine congeners |
| JP2010504303A (en) * | 2006-09-20 | 2010-02-12 | ピエール、ファーブル、メディカマン | Fluorinated catalanthin derivatives, their production, and their use as vinca dimer alkaloid precursors |
| JP2011140494A (en) * | 1998-06-02 | 2011-07-21 | Roowin Sa | New vinca-alkaloid derivative and method for preparing the same |
-
1989
- 1989-07-10 JP JP17564289A patent/JPH0341081A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0859610A1 (en) * | 1995-08-08 | 1998-08-26 | Albany Medical College | Ibogamine congeners |
| EP0859610A4 (en) * | 1995-08-08 | 2002-05-15 | Albany Medical College | Ibogamine congeners |
| JP2011140494A (en) * | 1998-06-02 | 2011-07-21 | Roowin Sa | New vinca-alkaloid derivative and method for preparing the same |
| JP2010504303A (en) * | 2006-09-20 | 2010-02-12 | ピエール、ファーブル、メディカマン | Fluorinated catalanthin derivatives, their production, and their use as vinca dimer alkaloid precursors |
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