JPH023797B2 - - Google Patents
Info
- Publication number
- JPH023797B2 JPH023797B2 JP10138982A JP10138982A JPH023797B2 JP H023797 B2 JPH023797 B2 JP H023797B2 JP 10138982 A JP10138982 A JP 10138982A JP 10138982 A JP10138982 A JP 10138982A JP H023797 B2 JPH023797 B2 JP H023797B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- demethyl
- epipodophyllotoxin
- methanol
- 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.)
- Expired
Links
- 229930182478 glucoside Natural products 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 238000006136 alcoholysis reaction Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- -1 ethylidene glycoside Chemical class 0.000 description 4
- 229930182470 glycoside Natural products 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- FOVRGQUEGRCWPD-UHFFFAOYSA-N (5aR)-9t-beta-D-Glucopyranosyloxy-5t-(4-hydroxy-3,5-dimethoxy-phenyl)-(5ar,8at)-5,8,8a,9-tetrahydro-5aH-furo[3',4';6,7]naphtho[2,3-d][1,3]dioxol-6-on Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(OC3C(C(O)C(O)C(CO)O3)O)C3C2C(OC3)=O)=C1 FOVRGQUEGRCWPD-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YVCVYCSAAZQOJI-JHQYFNNDSA-N 4'-demethylepipodophyllotoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YVCVYCSAAZQOJI-JHQYFNNDSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940057499 anhydrous zinc acetate Drugs 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 241000332712 Sinopodophyllum hexandrum Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Substances FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- YVUZUKYBUMROPQ-UHFFFAOYSA-N mercury zinc Chemical compound [Zn].[Hg] YVUZUKYBUMROPQ-UHFFFAOYSA-N 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
本発明は4′−ハロゲノエトキシカルボニル−
4′−デメチル−エピポドフイロトキシン−β−D
−2.3−ジ−O―アシル−4.6−エチリデングルコ
シドのアシル基をアルコリシスにより、又ハロゲ
ノエトキシカルボニル基を還元により除去するこ
とを特徴とする4′−デメチルエピポドフイロトキ
シン−β−D−エチリデングリコシドの製造法
に関する。
〔式中Acはアシル基を、meはメチル基を、X
はハロゲンを示し、mは0−2の整数、nは1−
3の整数であり、かつm+n=3である〕
上記式で示されらる化合物は抗腫瘍活性を有
する植物成分ポドフイロキシンから誘導される新
規物質であり、又、上記式で示される化合物は
VP−16と呼ばれ抗腫瘍活性を有し、制癌剤とし
て有用な物質である。
化合物の製造法としては次の工程によるもの
が既に知られている。(特公昭46−37837号公報参
照)
(式中Rはホルミル又はアセチル、meは前記
と同じ、φはフエニル基を示す。)
しかしながらこの方法はカルボベンゾキシ基を
除去するに当り、パラジウム−木炭を触媒に用い
る為に、大量の合成の場合反応が完結しにくかつ
たり、又触媒除去の降発火等の危険性があらる等
の欠点を有しており、工業的製法としては好まし
くない。
そこで本発明者らは上記欠点のない化合物の
製法について種々検討した結果、式で示される
化合物を原料とすると、大量合成の場合でも容易
に、しかも安全に、収率よく化合物が製造でき
ることを見い出した。
本発明は上記知見に基づいて完成されたもので
ある。
本発明において、2位および3位のアシル基と
しては例えばアセチル基、ホルミル基などがあげ
られる。
又、4′−位のハロゲノエトキシカルボニル基と
してはそのβ−位に塩素、臭素、ヨウ素を1−3
個有するものが好ましく、例えばβ−アイオドエ
トキシカルボニル基、β,β−ジクロロエトキシ
カルボニル基、β,β,β−トリクロロエトキシ
カルボニル基、β,β,β−トリブロモエトキシ
カルボニル基などがあげられるが、β,β,β−
トリクロロエトキシカルボニル基が好ましい。
本発明におけるアルコリシスおよび還元は任意
の順序で、又は両者同時に行うことができる。
アルコリシスは例えばメタノール、エタノール
などのアルコール類、又はそれらとジオキサン、
テトラヒドロフランなどとの混合溶媒中、無水酢
酸亜鉛の存在下に20―30時間加熱還流することに
より行なわれる。
還元は例えば電解還元法により、又は亜鉛系の
触媒を用いる方法などにより行なわれる。亜鉛系
の触媒としては例えば亜鉛末、亜鉛−銅、亜鉛−
銀、亜鉛−水銀などをあげることができる。その
使用量は化合物に対し、50−100w/w%程度
で充分である。又、触媒としては酢酸、メタノー
ル、エタノールが使用され、場合により補助溶媒
として水、ジオキサン、テトラヒドロフランなど
を用いてもよい。反応温度は特に限定されないが
酢酸の場合は0℃〜室温、アルコールの場合は還
流温度で行なわれらる。反応に要する時間は用い
る溶媒、温度により異なるが15分〜2時間であ
る。
又、アルコリシスおよび還元を同時に実する場
合は、例えば化合物を亜鉛末および無水酢酸亜
鉛の存在下、メタノールなどのアルコール類又は
それらとジオキサン、テトラヒドロフランとの混
合溶媒中で20〜30時間加熱還流すればよい。
本発明において出発原料として使用する式の
化合物は植物podophyllum emodi wallが生産す
る抗腫瘍活性物質ポドフイロトキシンから得られ
る4′−デメチル−エピポドフイロトキシン(特
公昭43−6469号公報参照))を原料とし、例えば
次の反応経路を経て成される。
〔式中Ac,meは前記と同じ〕
即ち、4′−デメチル−エピポドフイロトキシン
に不活性溶媒中でβ,β,β−トリクロルエト
キシカルボニルクロリドを反応させて得られる
4′−β,β,β−トリクロルエトキシカルボニル
−4′−デメチル−エピポドフイロトキシンVを三
弗化硼素エチルエーテレート存在下、不活性な有
機溶媒中、0℃より低い温度で4,6−O−エチ
リデン−2,3−ジ−O−アシル−β−D−グリ
コピラノ−スと縮合させることによりを合成し
た。
以下に実施例並びに参考例を挙げて本発明を具
体的に説明する。
実施例 1
4′−デメチル−エピポドフイロトキシン−β−
D−エチリデングリコシドの製法
4′−β,β,β−トリクロルエトキシカルボニ
ル−4′−デメチル−エピポドフイロトキシン−β
−D−2.3−ジ−O−アセチル−4,6−エチリ
デングリコシド(100mg)、亜鉛末(100mg)およ
び無水水酢酸亜鉛(15mg)のメタノール(4m
)の溶液を22時間加熱還流する。反応終了後ク
ロロホルム(15m)を加えてろ過し、亜鉛末を
除く。クロロホルム層を水(2m×2)で洗い、
無水硫酸ナトリウムで乾燥する。乾燥後溶媒を減
圧下留去して得られる残留物をシリカゲルカラム
クロマトグラフイー(流出溶媒:クロロホルム:
メタノール=20:1)により精製する。収量
40mg(収率57%)
m.p 248−252℃ Rf=0.21(クロロホルム:メタ
ノール=20:1)
IRνnujol nax3650,3400,1766,1610.1110,980cm-1
実施例 2
a 4′−デメチル−エピポドフイロトキシン−β
−D−2,3−ジ−O−アセチル−4,6−エ
チリデングリコシドの製法
(1) 亜鉛末−酢酸を用いるβ,β,β−トリクロ
ルエトキシカルボニル基の脱離
4′−β,β,β―トリクロルエトキシカルボニ
ル−4′−デメチル−エピポドフイロトキシン−β
−D−2.3−ジ−O−アセチル−4.6−エチリデン
グルコシド(200mg)円酢酸−ジオキシン(4m
,1:1)に溶解させ、その溶液に亜鉛末
(200mg)を加えて室温で1時間撹拌する。反応
終了後酢酸エチル(15m)を加えてろ過する。
酢酸エチル層を水(5m×2)で洗い無水硫酸
ナトリウムで乾燥する。乾燥後溶媒を減圧下留去
して得られる油状物質に少量のメタノールを加え
ると結晶化する。収量140mg。(収率88%)
m.p。275−277℃
I.R.νNujol nax3475,1775,1755,1740,1615cm-1
N.M.R(CDCI3)ζ1.33(3.d.J=4Hz)
The present invention provides 4'-halogenoethoxycarbonyl-
4'-demethyl-epipodophyllotoxin-β-D
4'-demethylepipodophyllotoxin-β-D- characterized in that the acyl group of -2.3-di-O-acyl-4.6-ethylidene glucoside is removed by alcoholysis and the halogenoethoxycarbonyl group is removed by reduction. This invention relates to a method for producing ethylidene glycoside. [In the formula, Ac represents an acyl group, me represents a methyl group, and X
indicates halogen, m is an integer of 0-2, n is 1-
is an integer of 3, and m+n=3] The compound represented by the above formula is a new substance derived from the plant component podophyloxin that has antitumor activity, and the compound represented by the above formula is
It is called VP-16, has antitumor activity, and is a useful substance as an anticancer agent. The following process is already known as a method for producing a compound. (Refer to Special Publication No. 46-37837) (In the formula, R is formyl or acetyl, me is the same as above, and φ is a phenyl group.) However, this method requires a large amount of synthesis because palladium-charcoal is used as a catalyst to remove the carbobenzoxy group. In this case, the reaction is difficult to complete and there is a risk of ignition due to catalyst removal, which is not preferred as an industrial production method. The inventors of the present invention have conducted various studies on methods for producing compounds that do not have the above disadvantages, and have discovered that if the compound represented by the formula is used as a raw material, the compounds can be produced easily, safely, and in good yields even in the case of large-scale synthesis. Ta. The present invention was completed based on the above findings. In the present invention, examples of the acyl groups at the 2- and 3-positions include an acetyl group and a formyl group. In addition, as the halogenoethoxycarbonyl group at the 4'-position, 1-3 chlorine, bromine, or iodine is added at the β-position.
Examples of preferred examples include β-iodoethoxycarbonyl group, β,β-dichloroethoxycarbonyl group, β,β,β-trichloroethoxycarbonyl group, β,β,β-tribromoethoxycarbonyl group, etc. is β, β, β−
Trichloroethoxycarbonyl group is preferred. Alcoholysis and reduction in the present invention can be performed in any order or both at the same time. Alcoholysis is, for example, alcohols such as methanol and ethanol, or their combination with dioxane,
This is carried out by heating under reflux for 20 to 30 hours in a mixed solvent such as tetrahydrofuran in the presence of anhydrous zinc acetate. The reduction is carried out, for example, by an electrolytic reduction method or by a method using a zinc-based catalyst. Examples of zinc-based catalysts include zinc powder, zinc-copper, and zinc-based catalysts.
Examples include silver, zinc-mercury, etc. The amount used is approximately 50-100 w/w% based on the compound. In addition, acetic acid, methanol, and ethanol are used as catalysts, and water, dioxane, tetrahydrofuran, etc. may be used as auxiliary solvents in some cases. The reaction temperature is not particularly limited, but in the case of acetic acid, it is carried out at 0°C to room temperature, and in the case of alcohol, it is carried out at reflux temperature. The time required for the reaction varies depending on the solvent and temperature used, but is from 15 minutes to 2 hours. If alcoholysis and reduction are to be carried out simultaneously, for example, the compound can be heated under reflux for 20 to 30 hours in an alcohol such as methanol or a mixed solvent of alcohols such as methanol and dioxane or tetrahydrofuran in the presence of zinc dust and anhydrous zinc acetate. good. The compound of formula used as a starting material in the present invention is 4'-demethyl-epipodophyllotoxin obtained from podophyllotoxin, an antitumor active substance produced by the plant podophyllum emodi wall (see Japanese Patent Publication No. 43-6469). ) as a raw material, for example, through the following reaction route. [In the formula, Ac and me are the same as above] That is, obtained by reacting 4'-demethyl-epipodophyllotoxin with β, β, β-trichloroethoxycarbonyl chloride in an inert solvent.
4'-β,β,β-Trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin V in the presence of boron trifluoride ethyl etherate in an inert organic solvent at a temperature below 0°C. It was synthesized by condensation with 6-O-ethylidene-2,3-di-O-acyl-β-D-glycopyranose. The present invention will be specifically explained below with reference to Examples and Reference Examples. Example 1 4'-demethyl-epipodophyllotoxin-β-
Process for producing D-ethylidene glycoside 4'-β,β,β-trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin-β
-D-2.3-di-O-acetyl-4,6-ethylidene glycoside (100 mg), zinc dust (100 mg) and anhydrous zinc acetate (15 mg) in methanol (4
) is heated to reflux for 22 hours. After the reaction is complete, add chloroform (15m) and filter to remove zinc dust. Wash the chloroform layer with water (2 m x 2),
Dry with anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (effluent solvent: chloroform:
Purify with methanol = 20:1). yield
40mg (yield 57%) mp 248-252℃ Rf=0.21 (chloroform:methanol=20:1) IRν nujol nax 3650, 3400, 1766, 1610.1110, 980cm -1 Example 2 a 4'-demethyl-epipodof Irotoxin-β
-D-2,3-di-O-acetyl-4,6-ethylidene glycoside production method (1) Elimination of β, β, β-trichloroethoxycarbonyl group using zinc dust-acetic acid 4'-β, β, β-Trichloroethoxycarbonyl-4′-demethyl-epipodophyllotoxin-β
-D-2.3-di-O-acetyl-4.6-ethylidene glucoside (200mg) acetic acid-dioxin (4m
, 1:1), add zinc powder (200 mg) to the solution, and stir at room temperature for 1 hour. After the reaction is complete, add ethyl acetate (15m) and filter.
The ethyl acetate layer was washed with water (5 m x 2) and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and a small amount of methanol is added to the resulting oily substance, which crystallizes. Yield 140mg. (yield 88%) mp. 275−277℃ IRν Nujol nax 3475, 1775, 1755, 1740, 1615cm -1 NMR (CDCI 3 ) ζ1.33 (3.dJ=4Hz)
【式】1.83(3H.S)[Formula] 1.83 (3H.S)
【式】 2.05(3H.S)【formula】 2.05 (3H.S)
【式】3.77(6H.S)−OCH3
×2
(2) 亜鉛末−メタノールを用いるβ,β,β−ト
リクロルエトキシカルボニル基の脱離、
4′−β,β,β−トリクロルエトキシカルボニ
ル−4′−デメチル−エピポドフイロトキシン−β
−D−2,3−ジ−O−アセチル−4.6−エチリ
デングルコシド(100mg)、亜鉛末(100mg)お
よびメタノール(4ml)の混合液を15分間加熱還
流する。反応後酢酸エチル(10mlを加えてろ過
し、亜鉛末を除く。酢酸エチル層を水(3ml×
2)で洗い無水硫酸ナトリウムで乾燥する。乾燥
後溶媒を減圧下留去して得られる油状物質に少量
のメタノールを加えると結晶化する。収量57mg
(収率72%)
この化合物は(1)で得られた化合物とm.p.,I.
R.,,N.P.R.とも一致した。
b4′−デメチル−エピポドフイロトキシン−β−
D−エチリデングルコシド製法
上記a)で得られた4′−デメチル−エピポドフ
イロトキシン−β−D−2,3−ジ−O−アセチ
ル−4.6−エチリデングルコシド(15mg)のメタ
ノール−テトラヒドロフラン(5ml 4:1)の
溶液を22時間加熱還流する。反応終了後クロロホ
ルム(20ml)を加える。有機層を水(3ml×2)
で洗い無水硫酸ナトリウムで乾燥する。乾燥後溶
媒を減圧下留去して得られる残留物をシリカゲル
カラムクロマトグラフイー(流出溶媒:クロロホ
ルム:メタノール=20:1)により精製する。収
量49mg(収率71%)
参考例
4′−β,β,β−トリクロルエトキシカルボニ
ル−4′−デメチル−エピポドフイロトキシン−
β−D−2.3−ジ−O−アセチル−4,6−エ
チリデングルコシドの製法
(a) 4′−β,β,β−トリクロルエトキシカルボ
ニル−4′−デメチル−エピポドフイロトキシン
の製法D−2.3−ジ−アシル−4.6−エチリデン
グルコシド
4′−デメチル−エピポドフイロトキシン(2g)
を無水塩化エチレン(35ml)に懸籟させ、ついで
無水ピリジン(440mg)を加えた後−20℃に冷や
す。この液にβ,β,β−トリクロルエトキシカ
ルボニルクロリド(1.17g)の無水塩化エチレン
(3ml)の溶液を30分間を要して滴下し、更に30
分間撹拌反応させる。反応終了後、反応溶液を水
(20ml×2)で洗い有機層を無水硫酸ナトリウム
で乾燥する。乾燥後減圧下に溶媒を留去して得ら
れらる粗粗粗製精製物をアセトン/エーテルから
再結晶する。収量2.64g(収率92%)。更に精製す
るにはメタノールから再結晶す。m.p.141−142℃
と219−220℃の二重融点をもつ
I.R.νNuji nax、3540,3425,1785,1760,1610cm-1
N.M.R(CDCI3)δ3.73(6H,s)−CH3×2,4.83
(2H,S)[Formula] 3.77(6H.S)-OCH 3 ×2 (2) Zinc dust - elimination of β, β, β-trichloroethoxycarbonyl group using methanol, 4′-β, β, β-trichloroethoxycarbonyl- 4′-demethyl-epipodophyllotoxin-β
A mixture of -D-2,3-di-O-acetyl-4,6-ethylidene glucoside (100 mg), zinc dust (100 mg) and methanol (4 ml) is heated under reflux for 15 minutes. After the reaction, add ethyl acetate (10 ml) and filter to remove zinc dust. The ethyl acetate layer is diluted with water (3 ml
Wash with 2) and dry with anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and a small amount of methanol is added to the resulting oily substance, which crystallizes. Yield 57mg
(Yield 72%) This compound is the compound obtained in (1) and mp, I.
It was also consistent with R., NPR. b4'-demethyl-epipodophyllotoxin-β-
D-ethylidene glucoside production method 4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-acetyl-4.6-ethylidene glucoside (15 mg) obtained in a) above was dissolved in methanol-tetrahydrofuran (5 ml). 4:1) solution is heated to reflux for 22 hours. After the reaction is complete, add chloroform (20ml). Add the organic layer to water (3 ml x 2)
Wash with water and dry with anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (effluent solvent: chloroform:methanol = 20:1). Yield 49 mg (yield 71%) Reference example 4'-β,β,β-trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin-
Process for producing β-D-2.3-di-O-acetyl-4,6-ethylidene glucoside (a) Process for producing 4'-β, β, β-trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin D- 2.3-di-acyl-4.6-ethylidene glucoside 4'-demethyl-epipodophyllotoxin (2g)
was suspended in anhydrous ethylene chloride (35 ml), then anhydrous pyridine (440 mg) was added, and the mixture was cooled to -20°C. A solution of β, β, β-trichloroethoxycarbonyl chloride (1.17 g) in anhydrous ethylene chloride (3 ml) was added dropwise to this solution over a period of 30 minutes.
Stir and react for a minute. After the reaction is completed, the reaction solution is washed with water (20 ml x 2) and the organic layer is dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure, and the resulting crude product is recrystallized from acetone/ether. Yield: 2.64g (92% yield). For further purification, recrystallize from methanol. mp141−142℃
and IRnuji nax with dual melting points of 219-220℃, 3540, 3425, 1785, 1760, 1610 cm -1 NMR (CDCI 3 ) δ3.73 (6H, s) - CH 3 ×2, 4.83
(2H, S)
【式】
(b) 4′ーβ,β,β−トリクロルエトキシカルボ
ニル−4′−デメチル−エピポドフイロトキシン
−β−D−2.3−ジ−O−アセチル−4.6−エチ
リデングルコシドの製造
4′−β,β,β−トリクロルエトキシカルボニ
ル−4′−デメチル−エピポドフイロトキシン
(575.4mg)を無水塩化エチレン(4ml)に加熱
して溶媒させ次いでこの溶液を20℃に冷却し、撹
拌しながら4.6−O−エチリデン−2.3−ジ−O−
アセチル−β−D−グリコピラノース(320mg)
を加え糖成分が溶解するまで20℃で撹拌する。溶
解したら反応液を直ちに−20℃に冷却し三弗化ホ
ウ素エーテレート(0.35ml,48%BF3)を滴下
し、ついで−20℃で40分間撹拌する。無水ピリジ
ン(0.35ml)の塩化エチレン(1ml)の溶液を撹
拌、冷却しながら聳下する。反応液に塩化エチレ
ン(10ml)を加え、水(10ml×3)げ洗い有機層
を無水硫酸ナトリウムで乾燥する。乾燥後溶媒を
減圧下で留去し得られる粘稠性物質をシリカゲル
クロマトグラフイー(流出溶媒:トルエン:酢酸
エチル=4:1)により精製すると目的物が白い
泡として得られる。収量790mg(収率93%)
更に精製するにはメタノールから再結晶を行
う。
m.p. 166−168℃
I.R.νNujol nax 1780,1755,1605cm-1
N.M.R.(CDCI3)δ1.33(3H.d.J=4Hz)
[Formula] (b) Production of 4′-β,β,β-trichloroethoxycarbonyl-4′-demethyl-epipodophyllotoxin-β-D-2.3-di-O-acetyl-4.6-ethylidene glucoside 4′ - β, β, β-Trichloroethoxycarbonyl-4'-demethyl-epipodophyllotoxin (575.4 mg) was heated to dissolve in anhydrous ethylene chloride (4 ml), and the solution was cooled to 20°C and stirred. while 4.6-O-ethylidene-2.3-di-O-
Acetyl-β-D-glycopyranose (320mg)
Add and stir at 20℃ until the sugar component is dissolved. Once dissolved, the reaction solution was immediately cooled to -20°C, boron trifluoride etherate (0.35 ml, 48% BF 3 ) was added dropwise, and then stirred at -20°C for 40 minutes. A solution of anhydrous pyridine (0.35 ml) in ethylene chloride (1 ml) was poured under stirring and cooling. Add ethylene chloride (10 ml) to the reaction solution, wash with water (10 ml x 3), and dry the organic layer over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure and the resulting viscous substance is purified by silica gel chromatography (eluent: toluene:ethyl acetate = 4:1) to obtain the desired product as a white foam. Yield: 790 mg (yield: 93%) For further purification, recrystallize from methanol. mp 166−168℃ IRν Nujol nax 1780, 1755, 1605cm -1 NMR (CDCI 3 ) δ1.33 (3H.dJ=4Hz)
【式】1.83(3H.S)[Formula] 1.83 (3H.S)
【式】 2.05(3H.S)【formula】 2.05 (3H.S)
【式】3.70(6H.S)−OCH3 ×24.83(2H.S)[Formula] 3.70 (6H.S) − OCH 3 × 24.83 (2H.S)
Claims (1)
はハロゲンを示し、mは0−2の整数、nは1−
3の整数であり、かつm+n=3である〕 で表わされる4′−ハロゲノエトキシカルボニル−
4′−デメチル−エピポドフイロトキシン−β−D
−2.3−ジ−o−アシル−4.6−エチリデングルコ
シドのアシル基をアルコリシスにより、又ハロゲ
ノエトキシカルボニル基を還元により除去するこ
とを特徴とする式 〔式中meは前記と同じ〕で表わされる4′−デ
メチルエピポドフイロトキシン−β−D−エチリ
デングルコシドの製造法。[Claims] 1 formula [In the formula, Ac represents an acyl group, me represents a methyl group, and X
indicates halogen, m is an integer of 0-2, n is 1-
4'-halogenoethoxycarbonyl-, which is an integer of 3, and m+n=3]
4'-demethyl-epipodophyllotoxin-β-D
A formula characterized in that the acyl group of -2.3-di-o-acyl-4.6-ethylidene glucoside is removed by alcoholysis and the halogenoethoxycarbonyl group is removed by reduction. A method for producing 4'-demethylepipodophyllotoxin-β-D-ethylidene glucoside represented by [where me is the same as above].
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10138982A JPS58219196A (en) | 1982-06-15 | 1982-06-15 | Production of 4'-demethyl-epipodophyllotoxin-beta-d- ethylideneglucoside |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10138982A JPS58219196A (en) | 1982-06-15 | 1982-06-15 | Production of 4'-demethyl-epipodophyllotoxin-beta-d- ethylideneglucoside |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS58219196A JPS58219196A (en) | 1983-12-20 |
JPH023797B2 true JPH023797B2 (en) | 1990-01-24 |
Family
ID=14299394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP10138982A Granted JPS58219196A (en) | 1982-06-15 | 1982-06-15 | Production of 4'-demethyl-epipodophyllotoxin-beta-d- ethylideneglucoside |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS58219196A (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60246393A (en) * | 1984-05-22 | 1985-12-06 | Nippon Kayaku Co Ltd | Novel preparation of etoposide |
US4935504A (en) * | 1987-12-18 | 1990-06-19 | Bristol-Myers Company | Epipodophyllotoxin glucoside 4'-acyl derivatives |
US5036055A (en) * | 1989-06-07 | 1991-07-30 | Bristol-Myers Company | Acylated derivatives of etoposide |
US5066645A (en) * | 1989-09-01 | 1991-11-19 | Bristol-Myers Company | Epipodophyllotoxin altroside derivatives |
FR2655047A1 (en) * | 1989-11-24 | 1991-05-31 | Pf Medicament | ETOPOSIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS SYNTHESIS INTERMEDIATES. |
PA8855801A1 (en) | 2008-12-23 | 2010-07-27 | SYNTHESIS OF PURINE NUCLEOSIDS | |
MX2011006891A (en) | 2008-12-23 | 2011-10-06 | Pharmasset Inc | Nucleoside phosphoramidates. |
UY33311A (en) | 2010-03-31 | 2011-10-31 | Pharmasset Inc | NUCLEOSID PHOSPHORAMIDATES |
-
1982
- 1982-06-15 JP JP10138982A patent/JPS58219196A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS58219196A (en) | 1983-12-20 |
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