JPH02191294A - Acyl derivative of 4'-dimethyl-epipodophyllotoxin-beta-d-ethylidene glucoside - Google Patents
Acyl derivative of 4'-dimethyl-epipodophyllotoxin-beta-d-ethylidene glucosideInfo
- Publication number
- JPH02191294A JPH02191294A JP31768789A JP31768789A JPH02191294A JP H02191294 A JPH02191294 A JP H02191294A JP 31768789 A JP31768789 A JP 31768789A JP 31768789 A JP31768789 A JP 31768789A JP H02191294 A JPH02191294 A JP H02191294A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- epipodophyllotoxin
- halogenoacetyl
- ethylidene
- formula
- 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
- 229930182478 glucoside Natural products 0.000 title claims abstract description 17
- 125000002252 acyl group Chemical group 0.000 title 1
- 239000000126 substance Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 41
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Substances FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 abstract description 3
- 229910015900 BF3 Inorganic materials 0.000 abstract description 2
- 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 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 229960002246 beta-d-glucopyranose Drugs 0.000 abstract 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 5
- -1 ethylidene glucoside Chemical class 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 3
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000008131 glucosides Chemical class 0.000 description 3
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 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 2
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- WGPAQYSVWYWZKT-UHFFFAOYSA-N [C].[Ra] Chemical compound [C].[Ra] WGPAQYSVWYWZKT-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 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
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000012777 commercial manufacturing Methods 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
- 150000004985 diamines Chemical class 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 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
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical group CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、制癌剤として有用な物質を収率よく製造する
ための原料に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a raw material for producing a substance useful as an anticancer drug in good yield.
（従来の技術）
制癌剤として有用な化合物である、４′−デメ〔式中、
Ｒは式−ＣＯＣＲ，Ｘ （式中Ｘは〕１０ゲンを示す）
で表わされるノ・ログノアセチル基を示す〕で表わされ
る４′−ノ・ログノアセチル−４′−テメチルーエビポ
ドフィロトキシンーβ−Ｄ−２，３−ジーＯ−ハロゲノ
アセチルー４６−３７８３７号が知られている。(Prior art) 4'-Deme [formula:
R is the formula -COCR,X (in the formula, X represents] 10 gen)
4'-no-lognoacetyl-4'-temethyl-epipodophyllotoxin-β-D-2,3-di-O-halogenoacetyl group 46 -37837 is known.
（発明が解決しようとする課題）
しかしながらこれらの方法においてはアグリコンの保護
基と糖のそれとが異なるため、それらの除去には２工程
を要する。即ちアグリコンの４′位の保護基であるベン
ジルオキシカルボニル基を除去するのにパラジウム−炭
素を触媒として水素添加分解を行い、糖の保護基である
アセチル基またはホルミル基の除去に酢酸亜鉛を用いて
いる。％に糖の保護基の除去には高温かつ長時間を必要
とし、例えば、２０〜３０時間反応させても反応は完結
せず、更に反応させると副生物が増加するため収率が低
下し工業的製法としては好ましくない。(Problems to be Solved by the Invention) However, in these methods, since the protecting group of the aglycone and that of the sugar are different, two steps are required for their removal. That is, hydrogenolysis is performed using palladium-carbon as a catalyst to remove the benzyloxycarbonyl group, which is the protecting group at the 4' position of the aglycone, and zinc acetate is used to remove the acetyl or formyl group, which is the protecting group of the sugar. ing. % Removal of sugar protecting groups requires high temperature and long time; for example, even if the reaction is allowed to proceed for 20 to 30 hours, the reaction will not be completed, and if the reaction is continued further, by-products will increase, resulting in a decrease in yield and industrial This is not preferred as a commercial manufacturing method.
（課題を解決するための手段）
そこで本発明者らは上記欠点を克服するために種々検討
した結果、特定の原料化合物とアミンおよび／またはア
ンモニアを０６〜室温で数時間反応させることにより、
アグリコ／の４′位および糖の２位、３位の保護基が一
挙にしかも安全に除去でき、高純度の４′−デメチル−
エピポドフィロトキシン−β−り一エチリデングルコシ
ドを高収率で得ることができることを見出し本発明を完
成した。(Means for Solving the Problems) Therefore, the present inventors conducted various studies to overcome the above drawbacks, and found that by reacting a specific raw material compound with an amine and/or ammonia at room temperature for several hours,
Protecting groups at the 4'-position of aglyco/ and the 2- and 3-positions of the sugar can be safely removed at once, resulting in highly pure 4'-demethyl-
The present invention was completed by discovering that epipodophyllotoxin-β-ethylidene glucoside can be obtained in high yield.
即ち、本発明は４′−ハロゲノアセチル−４′−デメチ
ル−エピポドフィロトキシン−β−Ｄ−２．３−ジー０
−ハロゲノアセチル−４，６−０−エチリデングルコシ
ド（１）に関し、これをアミンおよび／またはアンモニ
アと反応させることによりハロゲノアセチル基を除去し
４′−デメチル−エピポドフィロトキシン−β−Ｄ−エ
チリデングルコシド（Ｕ）とすることが出来る。That is, the present invention provides 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2.3-di0
- Halogenoacetyl-4,6-0-ethylidene glucoside (1) is reacted with amine and/or ammonia to remove the halogenoacetyl group and 4'-demethyl-epipodophyllotoxin-β-D- It can be ethylidene glucoside (U).
〔式中、Ｒは−ＣＯＣＨ，Ｘ （式中Ｘはハロゲンを
示す）で表わされるハロゲノアセチル基を示す〕上記式
＋ＩＩ）で示される化合物はＶＰ１６−２１３と呼ばれ
、抗腫瘍活性を示し制癌剤として有用な物質である。[In the formula, R represents a halogenoacetyl group represented by -COCH, It is a useful substance as
本発明においてアグリコンの４′位および糖の２位、３
位のハロゲノアセチル基Ｒは同一であってもよく、又、
異なっていてもよい。Ｘのノ・ロゲンとしては、塩素、
臭素が挙げられる。In the present invention, the 4' position of the aglycone and the 2 and 3 positions of the sugar
The halogenoacetyl groups R at the positions may be the same, and
May be different. As the norogen of X, chlorine,
Examples include bromine.
、化合物＋１）と反応させるアミンとしては、メチルア
ミン、エチルアミン、ｎ−プロピルアミン、ｎ−ブチル
アミンなどの脂肪族−級アミン、ジメチルアミン、ジエ
チルアミン、ジ−ｎ−プロピルアミン、ジ−ｎ−ブチル
アミンなどの脂肪族二級アミン、ピロリジン、ピペリジ
／、モルホリンなどの環状アミンおよびエチレンジアミ
ンなどの脂肪族ジアミン等が挙げられる。これらのアミ
ンおよび／またはアンモニアを使用する場合、そのまま
反応系に加えてもよいのは当然であるが、例えばピリジ
ン、トリエチルアミンなどの塩基共存下に、アミ／およ
び／またはアンモニアの酢飯塩、塩酸塩などを加えて反
応系内で遊離のアミンおよび／またはアンモニアを調製
して反応させてもよい。その使用量は化合物（１）に対
して３〜１０モル倍が適当である。, as the amine to be reacted with compound +1), aliphatic amines such as methylamine, ethylamine, n-propylamine, n-butylamine, dimethylamine, diethylamine, di-n-propylamine, di-n-butylamine, etc. Examples include aliphatic secondary amines such as pyrrolidine, piperidine, cyclic amines such as morpholine, and aliphatic diamines such as ethylenediamine. When using these amines and/or ammonia, it is of course possible to add them to the reaction system as they are, but for example, in the presence of a base such as pyridine or triethylamine, vinegar salts of amines and/or ammonia, hydrochloric acid, etc. Free amine and/or ammonia may be prepared in the reaction system by adding a salt or the like and reacted. The appropriate amount to be used is 3 to 10 times the mole of compound (1).
反応温度はアミンの種類によって変りうるが一１０〜１
００°Ｃが好ましく、特に０〜７０℃が適している。反
応に要する時間はアミンの種類、反応温度によって異な
るが、通常０．５〜５時間である。The reaction temperature may vary depending on the type of amine, but it may vary from 10 to 1.
00°C is preferred, and 0 to 70°C is particularly suitable. The time required for the reaction varies depending on the type of amine and the reaction temperature, but is usually 0.5 to 5 hours.
使用する溶媒としては、反応に悪影響を与えないもので
あれば特に制限はないが、例えば、クロロホルム、塩化
エチレン、メタノール、エタノール、ピリジンなどが挙
げられる。The solvent to be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include chloroform, ethylene chloride, methanol, ethanol, and pyridine.
この方法によれば、ハロゲノアセチル基Ｒの除去が短時
間かつ温和な条件下で容易に行われ、化合物（１）から
化合物（Ｉｌｌを高収率で得ることができる。その為、
反１応終了後の精製も容易であり、例えば、反応液を水
洗し、簡単な再結晶を行うだけで純粋な化合物（ｉｆ）
が得られるので工業的製法として極めて有利な方法であ
る。According to this method, the halogenoacetyl group R can be easily removed in a short time and under mild conditions, and compound (Ill) can be obtained from compound (1) in high yield.Therefore,
Purification after completion of reaction 1 is also easy; for example, pure compound (if) can be obtained by simply washing the reaction solution with water and performing simple recrystallization.
This method is extremely advantageous as an industrial production method.
本発明の式＋１３の化合物は、植物Ｐｏｄｏｐｈｙｌ
ＩＬｕｎａｎｏｄｉＷ３１１ が生産する抗腫瘍活性物
質ポドフィロトキシンから得られる４′−デメチル−エ
ピポドフィロトキシンｔｌ） （％公明４３−６４６９
号公報参照）を原料として、例えば次の反応経録を経〔
式中Ｒは前記と同じ〕
即ち、４′−デメチル−エピポドフィロトキシン（ｍｌ
に不活性溶媒中で）・ロゲノアセチルクロリドを反応さ
せて１辱られる４′−ノ・ログノアセチル−４′−デメ
チルーエピポドフイロトキシン（１ν）を不活性溶媒中
、三弗化硼素エチルエーテラートの存在下、０℃より低
い温度で４．６−０−エチリデン−２，３−ジー０−ノ
・ロゲノアセテルーβ−Ｄ−グルコビラノース凹と縮合
させることにより化合物＋１＋が得られる。ここで化合
物間は新規化合物であり、４．６−０−エチリデン−１
−〇−ベンジルオキシカルボニルーβ−Ｄ−グルコビラ
ノース（ＶＤを原料として、例えば次の反応経路を経て
合成される。The compound of formula +13 of the present invention is derived from the plant Podophyl
4'-demethyl-epipodophyllotoxin tl) obtained from the antitumor active substance podophyllotoxin produced by ILunanodiW311 (%Komei 43-6469
For example, using the following reaction history [
In the formula, R is the same as above] That is, 4'-demethyl-epipodophyllotoxin (ml
In an inert solvent, 4'-logonoacetyl-4'-demethyl-epipodophyllotoxin (1ν) was trifluorinated by reacting with logenoacetyl chloride (in an inert solvent). Condensation of 4.6-0-ethylidene-2,3-di-0-logenoaceter with β-D-glucobylanose concavity at temperatures below 0°C in the presence of boron ethyl etherate gives compound +1+ . Here, between the compounds is a new compound, 4.6-0-ethylidene-1
-0-benzyloxycarbonyl-β-D-glucobylanose (synthesized using VD as a raw material, for example, through the following reaction route.
（ＶＤ
＊＊ｍｍ”１ （至）
〔式中Ｒは前記と同じ〕
即ち、４．６−０−エチリデン−１−〇−ベンジルオキ
シカルボニルーβ−Ｄ−グルコビラノース（ＶＤを不活
性溶媒中、ハロゲノアセチルクロリドと反応させて得ら
れる４、６−０−エチリデン−１−０−ベンジルオキシ
カルボニル−２，３−ジー０−ハロゲノアセチル−β−
Ｄ−グルコビラノース（ｖｌを水素添加分解することに
より化合物間が得られる。(VD **mm”1 (to) [In the formula, R is the same as above] That is, 4.6-0-ethylidene-1-〇-benzyloxycarbonyl-β-D-glucobylanose (VD is replaced with an inert solvent Among them, 4,6-0-ethylidene-1-0-benzyloxycarbonyl-2,3-di-0-halogenoacetyl-β- obtained by reacting with halogenoacetyl chloride.
Compounds are obtained by hydrogenolysis of D-glucobylanose (vl).
（実施例） 以下に実施例を挙げて本発明を具体的に説明する。(Example) The present invention will be specifically described below with reference to Examples.
実施例１゜
４′−デメチル−エピポドフィロトキシン−β−Ｄ−エ
チリデングルコシドｔｌｌ）の製法４″−クロロアセチ
ル−４′−デメチルーエビポドフィロトキシ／−β−Ｄ
−２，３−ジーＯ−クロロアセテルー４．６−０−エ
チリデングルコシド（Ｉｔ （Ｒ＝ −（？０ＣＩＩ□
Ｃ１） ８．２ ｇをピリジ７５Ｑｍｉに溶解し０℃に
冷却する。７０％エチルアミン４．５ｇを滴下し０°Ｃ
で１時間攪拌する。反応終了後クロロホルム２ｏｏｍｔ
を加えて２Ｎ塩酸で中和し水洗後無水硫酸す） ＩＪウ
ムで乾燥する。Example 1 Preparation of 4'-demethyl-epipodophyllotoxin-β-D-ethylidene glucoside 4'-chloroacetyl-4'-demethyl-epipodophyllotoxy/-β-D
-2,3-di-O-chloroacetyl-4.6-0-ethylidene glucoside (It (R= -(?0CII□
C1) Dissolve 8.2 g in Pyridi 75Qmi and cool to 0°C. Drop 4.5g of 70% ethylamine at 0°C.
Stir for 1 hour. After the reaction is complete, add 2 oomt of chloroform.
Neutralize with 2N hydrochloric acid, wash with water, and dry with anhydrous sulfuric acid.
溶媒を減圧上留去して得られた粗結晶をクロロホルムか
ら再結晶して結晶４．９ｇを得た。（収率８３．１％）
ここで得た結晶のＴ Ｌ ＣのＲｆ値（シリカゲル、展
開溶媒クロロホルム：メタノール＝９：１）、ＩＲ，Ｎ
ＭＲ，旋光度は特公昭４６−３７８３７号の方法により
得られた物質のそれと同一であった。The crude crystals obtained by distilling off the solvent under reduced pressure were recrystallized from chloroform to obtain 4.9 g of crystals. (Yield 83.1%) Rf value of TLC of the crystal obtained here (silica gel, developing solvent chloroform:methanol = 9:1), IR, N
The MR and optical rotation were the same as those of the material obtained by the method of Japanese Patent Publication No. 46-37837.
ｍ、ｐ、２５９〜２６２°Ｃ，Ｒｆ＝０．４４実施例２
゜
４′−デメチルーエビポドフィロトキシ７−β−Ｄ−エ
チリデングルコシド叩の製法
実施例１においてエチルアミンの代りにピロリシフ ４
．５ ｇを用いて実施例１と同様にして反応を行ったと
ころ、化合物（■１４．６ｇを得た。m, p, 259-262°C, Rf=0.44 Example 2
゜Preparation of 4'-demethyl-epipodophyllotoxy 7-β-D-ethylidene glucoside In Example 1, pyrolisif 4 was substituted for ethylamine.
．． When the reaction was carried out in the same manner as in Example 1 using 5 g, 14.6 g of the compound (■) was obtained.
（収率７８．０％）
実施例３゜
４’ −テメチルーエビボドフィロトキシ／−β−Ｄ−
エテリデ／グルコシドｔＵｔの製法実施例１においてエ
チルアミンの代りに９８チェチレンジアミン２．Ｏｇを
用いて実施例１と同様にして反応を行ったところ、化合
物ｔｌｌ）４．９ｇを得た。（収率８３．１％）
実施例４゜
４’ −テメチルーエピボドフィロトキシンーβ−Ｄ−
エチリデングルコシド（Ｉｌｌの製法化合物＋１１ （
Ｒ＝−ＣＯＣＨ２ＣＩン８．２ｇをクロロホルム１５０
ｍｌとメタノール５０ ｍｅの混合溶媒に溶解し、ジ
エチルアミン６．６ｇを加えて室温で４時間攪拌する。(Yield 78.0%) Example 3゜4'-temethyl-evibodophyllotoxy/-β-D-
Preparation of etheride/glucoside tUt In Example 1, 98 chelyl diamine was substituted for ethylamine.2. When the reaction was carried out in the same manner as in Example 1 using Og, 4.9 g of compound tll) was obtained. (Yield 83.1%) Example 4゜4'-temethyl-epibodophyllotoxin-β-D-
Ethylidene glucoside (Ill's manufacturing method compound +11 (
8.2 g of R=-COCH2CI was added to 150 g of chloroform.
ml of methanol and 50 me of methanol, 6.6 g of diethylamine was added thereto, and the mixture was stirred at room temperature for 4 hours.
反応終了後実施例１と同様に処理して化合物＋Ｉｌｌ
３．６ ｇを碍た。（収率６１．０％）
実施例５゜
４′−デメチル−エピポドフィロトキシン−β−Ｄ−エ
チリデングルコシド＋Ｉ１１の製法化合物＋１） （Ｒ
＝ −ＣｏＣＨ２Ｃ１） ８．２ ｇをメタノール１５
０ ｍｌに懸濁し、ピリジンｌ Ｑ ｍｌおよび酢酸ア
ンモニウム５．０ｇを加えて１時間還流する。メタノー
ルを減圧下留去した後実施例１と同様に処理して化合物
＋Ｉｌｌ ４．５ ｇを得た。（収率７６．３％）
実施例６゜
４′−デメチル−エピポドフィロトキシン−β−Ｄ−エ
チリデ／グルコシド（ＩＩ）の製法化合物（Ｉｔ （Ｒ
＝ −ＣＯＣＨ２Ｃｌ） ８．２ ｇをクロロホルム１
５０＃／とメタノール５０ｍｔの混合溶媒に溶解し、ト
リエチルアミンＬＯｍｔおよび塩化アンモニウム３．５
ｇを加えて室温で４時間攪拌する。反応終了後実施例１
と同様に処理して化合物叩４．９ｇを得た。（収率８３
．１％）実施例７゜
４′−デメチル−エピポドフィロトキシン−β−〇−エ
チリデングルコシド（Ｉｌｌの製法実施例６において化
合物１１） （Ｒ＝ −ＣＯＣＨ，ＣＩ）の代りに４′
−ブロモアセチル−４′−デメチル−エピポドフィロト
キシン−β−Ｄ −２，３−ジル０−ブロモアセチル−
４，６−０−エチリデングルコシド（１） （Ｒ＝ −
ＣＯＣＨ２Ｂｒ ） ９．５ ｇを用いて実施例６と同
様にして反応を行ったところ、化合物（１１） ４．８
ｇを得た。（収率８１．８チ）実施例Ａ
４′−クロロアセチル−４′−デメチル−エピポドフィ
ロトキシン−β−Ｄ−２．３−ジー０−クロロアセチル
−４，６−０−エチリデングルコシド（１１（Ｒ＝−ｅ
Ｏｃｌ−１，Ｃｌンの製法ｆａ） ４’−クロロアセ
チル−４′−デメテルーエビポド７４０トキ’／７１Ｊ
シｌ （Ｒ＝ −ＣＯＣＨ，ＣＩ ） ノ製法
４′−テメチルーエピボドフィロトキシンｆｆｆｌ）４
０．０ｇを無水塩化エチレン７５０ｍ１に懸濁させ、無
水ピリジン１１．９ｇを加えた後−２０００に冷却する
。この液に９５％塩化クロロアセチル１５．４ｇを１．
５時曲を要して滴下し、更に０．５時間攪拌する。反応
終了後、反応液を水洗し有機層を無水硫酸ナトリウムで
乾燥する。溶媒を減圧下留去して得られた粗生成物をメ
タノールから再結晶して化合物ｑν）（Ｒ＝ −ＣＯＣ
Ｈ２Ｃｌ ） ４３．４ｇを得た。（収率９１．１％）
ｍ、ｐ、 ２３８〜２４０°Ｃ
Ｂｒ
Ｉｒｔ ν ３５５０．１７８３．１７６５（Ｓ
ｈ）。After the reaction was completed, the same treatment as in Example 1 was carried out to obtain compound + Ill.
It weighed 3.6 g. (Yield 61.0%) Example 5 Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene glucoside + I11 Compound +1) (R
= -CoCH2C1) 8.2 g methanol 15
0 ml, add 1 Q ml of pyridine and 5.0 g of ammonium acetate, and reflux for 1 hour. After methanol was distilled off under reduced pressure, the residue was treated in the same manner as in Example 1 to obtain 4.5 g of compound +Ill. (Yield 76.3%) Example 6 Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylide/glucoside (II) Compound (It (R
= -COCH2Cl) 8.2 g to 1 chloroform
50#/ and methanol 50mt, triethylamine LOmt and ammonium chloride 3.5
g and stirred at room temperature for 4 hours. Example 1 after completion of reaction
The mixture was treated in the same manner as above to obtain 4.9 g of the compound. (Yield 83
．． 1%) Example 7゜4'-demethyl-epipodophyllotoxin-β-〇-ethylidene glucoside (compound 11 in Example 6 of Preparation of Ill) (R= -COCH,CI) instead of 4'
-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D -2,3-dyl-0-bromoacetyl-
4,6-0-ethylidene glucoside (1) (R= −
When the reaction was carried out in the same manner as in Example 6 using 9.5 g of COCH2Br, compound (11) 4.8
I got g. (Yield 81.8) Example A 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin-β-D-2.3-di-0-chloroacetyl-4,6-0-ethylidene glucoside (11(R=-e
Ocl-1, Cl production method fa) 4'-chloroacetyl-4'-demeter-epipod 740toki'/71J
Sil (R= -COCH,CI) -Production method 4'-temethyl-epibodophyllotoxinfffl)4
0.0 g was suspended in 750 ml of anhydrous ethylene chloride, and 11.9 g of anhydrous pyridine was added thereto, followed by cooling to -2000. Add 15.4 g of 95% chloroacetyl chloride to this solution.
Add dropwise at 5 o'clock and stir for additional 0.5 hour. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to obtain compound qν) (R= -COC
43.4 g of H2Cl) were obtained. (Yield 91.1%)
m, p, 238-240°C Br Irt ν 3550.1783.1765 (S
h).
１ηａｘ
１４８３．１２３０，１１３０Ｃｍ
（１１１４，６−０−エチリデン−１−０−ベンジルオ
キシカルボニル−２，３−ジー０−クロロアセチル−β
−Ｄ−グルコビラノース（Ｖｌ（Ｒ＝−ＣＯＣＨ２Ｃ１
）の製法
４．６−０−エチリデン−１−０−ベンジルオキシカル
ボニル−β−Ｄ−グルコビラノース（ｖＤ５１．Ｏｇを
無水りｏ ｏ ホにム５００ＭＩＫ懸濁させ、無水ピリ
ジン３５．６ｇを加えて０℃に冷却する。この液に９５
％塩化クロロアセチル４２．８ｇを１時間を要して滴下
した後、室温で０．５時間攪拌する。反応終了後反応液
を水洗し有機層を無水硫酸ナトリウムで乾燥する。溶媒
を減圧下留去して得られた粗生成物をイソプロピルエー
テルから再結晶して化合物＠ＣＲ＝−（？ＯＣＨ，ＣＩ
） ６６．６ｇを碍た。1ηax 1483.1230,1130Cm (1114,6-0-ethylidene-1-0-benzyloxycarbonyl-2,3-di-0-chloroacetyl-β
-D-glucobylanose (Vl(R=-COCH2C1
4. Suspend 51.0 g of 6-0-ethylidene-1-0-benzyloxycarbonyl-β-D-glucobylanose (vD) in 500 MIK of anhydrous water and add 35.6 g of anhydrous pyridine. and cool to 0℃.
% chloroacetyl chloride was added dropwise over a period of 1 hour, and the mixture was stirred at room temperature for 0.5 hour. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from isopropyl ether to form the compound @CR=-(?OCH,CI
) 66.6g was consumed.
（収率９０．１％）
ｍ、Ｉ）、１３０〜１３１°Ｃ
Ｂｒ
ＩＲＩ／ｍａＸ１７６５，１２５５．．１０９８．７０
０ｃｍ’ｌｃｌ ４，６−０−ｘチリデ／−２，３−
ジー０−クロロアセチル−β−Ｄ−グルコビラノース凹
☆−Ｃｏ（？Ｈｔ（？ｌ ）の製法
化合物（Ｖｌｌ （Ｒ＝ −ＣＯＣＨ，ＣＩ ） ４９
、３ ｇを乾燥アセトン５００ゴに溶解し、１０％ノ
くラジウム−炭素１０．ｇを加えて一１０〜１５°Ｃで
常圧で水素添加を行う。反応終了後触媒をｆ別し乾燥ア
セトンＩＱＱｍ／で洗浄した後、溶媒な浴温３００Ｃで
減圧濃縮し、残渣を高真空下３０℃で乾燥して化合物Ｍ
（Ｉｔ ＝−ＣＯＣＨ２Ｃ１）３５．６ｇを白い泡状
物として得た。（収率９９．２％）
ＩＲｖＣＨＣ” ３６００，１７６５，１２８２゜ａ
ｘ
１１３０．１０９５ｃｍ−’
（ｄ） ４’−クロロアセチル−４′−デメチルーエ
ヒ。(Yield 90.1%) m, I), 130-131°C Br IRI/maX1765, 1255. ．． 1098.70
0cm'lcl 4,6-0-x Chilide/-2,3-
Process for producing di-0-chloroacetyl-β-D-glucobylanose concave☆-Co (?Ht(?l) Compound (Vll (R= -COCH,CI) 49
, 3 g in 500 g of dry acetone and 10% radium-carbon. g and hydrogenation is carried out at -10 to 15°C under normal pressure. After the reaction, the catalyst was separated and washed with dry acetone IQQm/, concentrated under reduced pressure at a solvent bath temperature of 300C, and the residue was dried at 30C under high vacuum to obtain compound M.
35.6 g of (It = -COCH2C1) were obtained as a white foam. (Yield 99.2%) IRvCHC” 3600, 1765, 1282°a
x 1130.1095 cm-' (d) 4'-chloroacetyl-4'-demethyl-ech.
ポドフィロトキシン−β−Ｄ −２，３−ジ・−〇−ク
ロロアセチルー４．５−ｏ−エチリテノグル：Ｉ ７）
”（１） （Ｆｔ ＝ −ＣＯＣＨｔＣｌ ） ノ製法
化合物ｆｌＶ） （Ｒ＝ −ＣＯＣＨ２（？ｌ ） ｌ
１ 、９ ｇを無水塩化エチレン１５０５Ｉｌに溶解
し、次いで化合物（Ｖ） （Ｒ＝ −ＣＯＣＨ，ＣＩ
） ９．９ ｇを加えて一２０℃に冷却する。三弗化硼
素エチルニーテラー） ５，３ ｇを滴下した後−２０
℃で０．５時間攪拌する。反応終了後ピリジン４．０ｇ
を滴下し、反応液を水洗後有機層を無水硫酸ナトリウム
で乾燥する。溶媒を減圧下留去して得られた粗生成物を
メタノールから再結晶して化合物１ｉｔ（Ｒ＝−ＣＯＣ
Ｈ，ＣＩ） １ｓ、ｓｇを得た。Podophyllotoxin-β-D-2,3-di-〇-chloroacetyl-4,5-o-ethyritenoglu: I 7)
”(1) (Ft = -COCHtCl) No manufacturing process compound flV) (R= -COCH2(?l) l
1.9 g was dissolved in 1505 Il of anhydrous ethylene chloride, and then compound (V) (R= -COCH, CI
) Add 9.9 g and cool to -20°C. After dropping 5.3 g of boron trifluoride (ethyl niteller) -20
Stir for 0.5 hour at <0>C. After the reaction, 4.0g of pyridine
was added dropwise, the reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to give compound 1it (R=-COC
H, CI) 1s, sg were obtained.
（収率８０．３％）
ｍ、ｌ）、 ２４４〜２４６°Ｃ
Ｂｒ
ＩＲν １７７５，１６０１，１４８３゜ ａ
ｘ
１２３２ 、１１２６ ｃｍ−’
実施例Ｂ
４′−フロモアセチル−４′−デメチル−エピポドフィ
ロトキシン−β−Ｄ −２，３−ジーＯ−フ。(Yield 80.3%) m, l), 244-246°C Br IRν 1775, 1601, 1483° a
x 1232, 1126 cm-' Example B 4'-furomoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-diO-f.
ロモアセチルー４．６−０−エチリデングルコシド（１
） （Ｒ＝ −ＣＯＣＨ，Ｂｒ ）の製法（ａ） ４
’−ブロモアセチル−４′−デメチル−エピポドフィロ
トキシン（ＩＶ） （Ｒ＝ Ｃ０ＣＨｔＢｒ ）の製
法
実施例Ａ−（ａｌにおいて塩化クロロアセチルの代りに
９８％塩化ブロモアセチル２０．９ｇを用いて得られた
粗生成物をベンゼンから再結晶して化合物（ＩＶ） （
Ｒ＝ −Ｃ’０ＣＩ（２Ｂｒ ） ４７ 、 Ｏｇを得
た。（収率９０．２チ）
ｍ、Ｉ）、２２０〜２２２°Ｃ
Ｂｒ
ＩＲν ３５４０．１７８２．１７６５゜ａ ｘ
１６０１．１４ｇ３，１２３２゜
１１２４ｃｍ−’
Ｔｂｌ ４．６−０−エチリデン−１−０−ベンジル
オキシカルボニル−２，３−ジー０−ブロモアセテルー
β−Ｄ−グルコビラノース（Ｗｅ（Ｒ＝−ＣＯＣＨｚＢ
ｒ ）の製法
実施例Ａ−（ｂ）において塩化クロロアセチルの代りに
９８％塩化ブロモアセチル５３．０ｇを用いて化合物（
Ｖｌｌ （Ｒ＝（？０（？Ｈ２Ｂｒ ） ７６ 、２ｇ
を得た。（収率８７．３％）
ｍ、ｌ）、１４０５１４２℃
Ｂｒ
ＩＲν １７７０，１７６０．１２４３，１１２２Ｃ
ｍ１１ａｘ
ｆｃｌ ４，６−０−エチリデン−２，３−ジー０−
ブロモアセチル−β−Ｄ−グルコビラノース閏（Ｒ＝
Ｃ０ＣＨｔＢｒ ）の製法
実施例Ａ−（Ｃ）ニオイテ化合物（Ｖｌｌ（Ｒ＝ −Ｃ
０ＣＨ２Ｃ１）の代りに化合物（Ｓ’ｌｌ （Ｒ＝
Ｃ０ＣＨ２Ｂｒ）５８．２ｇを用いて化合物（Ｖｌ （
Ｒ＝ Ｃ０ＣＨ，Ｂｒ）４４．４ｇを用い泡状物とし
て得た。（収率９８．９％）
ＩＲν””’ ３５７５．１７５８，１２７５゜ａｘ
１１２５ 、１０９５ ｃｍ−’
（中 ４′−ブロモアセチル−４′−デメチル−エピポ
ドフィロトキシン−β−Ｄ −２，３−ジー０−ブロモ
アセチル−４，６−０−エチリデングルコシド（１）
（Ｒ＝ Ｃ０ＣＨｔＢｒ ）の製法実施例Ａ −ｔｄ
Ｈｃオイ”ｉｃ化合物（ＩＶＩ （Ｒ＝ −Ｃ０ＣＨ２
ＣＩ ）の代りに化合物（ＩＶ） （Ｒ＝ Ｃ０ＣＨ
Ｊｒ）１３．０ｇを用い、化合物（Ｖ） （Ｒ＝ −Ｃ
ＯＣＨ，（？ｌ）の代りに化合物（Ｖ） （Ｒ、＝
Ｃ０ＣＨｔＢｒ ） １２ 、４ｇを用いて化合物（１
） （Ｒ＝ −ｃｏｃＨ２Ｂｒ） １８．８ｇを寿た。lomoacetyl-4.6-0-ethylidene glucoside (1
) (R= -COCH,Br) production method (a) 4
Preparation of '-Bromoacetyl-4'-demethyl-epipodophyllotoxin (IV) (R=C0CHtBr) Example A-(obtained using 20.9 g of 98% bromoacetyl chloride in place of chloroacetyl chloride in al) The obtained crude product was recrystallized from benzene to obtain compound (IV) (
R=-C'0CI(2Br)47, Og was obtained. (Yield 90.2cm) m, I), 220-222°C Br IRν 3540.1782.1765°a x 1601.14g3,1232°1124cm-' Tbl 4.6-0-ethylidene-1-0- Benzyloxycarbonyl-2,3-di-0-bromoaceter-β-D-glucobylanose (We(R=-COCHzB
In Example A-(b), 53.0 g of 98% bromoacetyl chloride was used instead of chloroacetyl chloride to prepare the compound (
Vll (R=(?0(?H2Br) 76, 2g
I got it. (Yield 87.3%) m, l), 1405142°C Br IRν 1770, 1760.1243, 1122C
m11ax fcl 4,6-0-ethylidene-2,3-di0-
Bromoacetyl-β-D-glucobylanose (R=
Example A-(C) Nioite compound (Vll(R= -C
0CH2C1) instead of the compound (S'll (R=
Using 58.2 g of C0CH2Br), the compound (Vl (
A foam was obtained using 44.4 g of R=C0CH,Br). (Yield 98.9%) IRν""' 3575.1758, 1275°ax 1125, 1095 cm-' (in 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2, 3-di-0-bromoacetyl-4,6-0-ethylidene glucoside (1)
(R=C0CHtBr) Production Example A-td
Hc oi”ic compound (IVI (R= -C0CH2
CI ) instead of compound (IV) (R= C0CH
Jr), 13.0 g of compound (V) (R= -C
Compound (V) (R,=
Using 4 g of C0CHtBr ) 12 , compound (1
) (R=-cocH2Br) 18.8g was consumed.
（収率７９．１チ）
ｍ、ｐ、 ２０１〜２０３°Ｃ
Ｂｒ
ＩＲν １７７０，１７６３（Ｓｈ）、 １６
０３゜ａ ｘ
１４８３．１２３２，１１２０Ｃｍ’
（発明の効果）
本発明の化合物（１）を用いることにより、化合物（ム
）を高収率で容易に得ることができる。(Yield 79.1cm) m, p, 201-203°C Br IRν 1770, 1763 (Sh), 16
03°a x 1483.1232,1120Cm' (Effects of the Invention) By using the compound (1) of the present invention, the compound (M) can be easily obtained in high yield.
Claims (1)
示す）で表わされるハロゲノアセチル基を示す〕で表わ
される４′−ハロゲノアセチル−４′−デメチル−エピ
ポドフィロトキシン−β−Ｄ−２，３−ジ−Ｏ−ハロゲ
ノアセチル−４，６−Ｏ−エチリデングルコシド。[Claims] 1. 4 represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. '-halogenoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-O-halogenoacetyl-4,6-O-ethylidene glucoside.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31768789A JPH02191294A (en) | 1989-12-08 | 1989-12-08 | Acyl derivative of 4'-dimethyl-epipodophyllotoxin-beta-d-ethylidene glucoside |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31768789A JPH02191294A (en) | 1989-12-08 | 1989-12-08 | Acyl derivative of 4'-dimethyl-epipodophyllotoxin-beta-d-ethylidene glucoside |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20618882A Division JPS5998098A (en) | 1982-11-26 | 1982-11-26 | Novel method for preparing 4'-demethyl- epipodophyllotoxin-beta-d-ethylidene glucoside and acyl derivative thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02191294A true JPH02191294A (en) | 1990-07-27 |
| JPH032875B2 JPH032875B2 (en) | 1991-01-17 |
Family
ID=18090905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP31768789A Granted JPH02191294A (en) | 1989-12-08 | 1989-12-08 | Acyl derivative of 4'-dimethyl-epipodophyllotoxin-beta-d-ethylidene glucoside |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02191294A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002514223A (en) * | 1997-06-02 | 2002-05-14 | ブリストルーマイヤーズ スクイブ カンパニー | Method for producing etoposide |
-
1989
- 1989-12-08 JP JP31768789A patent/JPH02191294A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002514223A (en) * | 1997-06-02 | 2002-05-14 | ブリストルーマイヤーズ スクイブ カンパニー | Method for producing etoposide |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH032875B2 (en) | 1991-01-17 |
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