CN85103648A - Production 4 '-demethyl epipodophyllotoxin-9-4, the novel method of 6-0-ethidine β-D pyranoglucose - Google Patents
Production 4 '-demethyl epipodophyllotoxin-9-4, the novel method of 6-0-ethidine β-D pyranoglucose Download PDFInfo
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- CN85103648A CN85103648A CN85103648.1A CN85103648A CN85103648A CN 85103648 A CN85103648 A CN 85103648A CN 85103648 A CN85103648 A CN 85103648A CN 85103648 A CN85103648 A CN 85103648A
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- China
- Prior art keywords
- fontanel
- alcohol
- acetyl
- amine
- salt
- Prior art date
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- Expired - Lifetime
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 30
- 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 claims abstract description 21
- 229960005420 etoposide Drugs 0.000 claims abstract description 21
- 150000001412 amines Chemical class 0.000 claims abstract description 17
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 15
- 229930182470 glycoside Natural products 0.000 claims abstract 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 15
- -1 alkali metal salt Chemical class 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 150000003863 ammonium salts Chemical class 0.000 claims description 6
- 150000007942 carboxylates Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 150000001414 amino alcohols Chemical class 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003729 cation exchange resin Substances 0.000 claims 1
- 150000001261 hydroxy acids Chemical group 0.000 claims 1
- 150000004671 saturated fatty acids Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract 3
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 30
- 239000002904 solvent Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 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 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical class ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229930182478 glucoside Natural products 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- SCBJZDPIRGXHFV-JAJWTYFOSA-N 1-[(2S,3R,4S,5S,6R)-2,3,4,5-tetrahydroxy-6-(hydroxymethyl)oxan-2-yl]ethanone Chemical compound C(C)(=O)[C@]1(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO SCBJZDPIRGXHFV-JAJWTYFOSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 2
- 239000011654 magnesium acetate Substances 0.000 description 2
- 235000011285 magnesium acetate Nutrition 0.000 description 2
- 229940069446 magnesium acetate Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 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 1
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- KWIPUXXIFQQMKN-UHFFFAOYSA-N 2-azaniumyl-3-(4-cyanophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C#N)C=C1 KWIPUXXIFQQMKN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IVAIKLPWWORRPT-AWEZNQCLSA-N COc1cc2C[C@@H]3N(CCc4ccc(OC)c(O)c34)Cc2cc1O Chemical class COc1cc2C[C@@H]3N(CCc4ccc(OC)c(O)c34)Cc2cc1O IVAIKLPWWORRPT-AWEZNQCLSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical class CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940090948 ammonium benzoate Drugs 0.000 description 1
- NHJPVZLSLOHJDM-UHFFFAOYSA-N azane;butanedioic acid Chemical compound [NH4+].[NH4+].[O-]C(=O)CCC([O-])=O NHJPVZLSLOHJDM-UHFFFAOYSA-N 0.000 description 1
- ZRAOWOQXOMXTQN-UHFFFAOYSA-N azanium;2-aminobenzoate Chemical compound [NH4+].NC1=CC=CC=C1C([O-])=O ZRAOWOQXOMXTQN-UHFFFAOYSA-N 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- NGBDVHCLWGVLEN-UHFFFAOYSA-N caseamine Natural products COc1cc2CN3CCc4ccc(OC)c(O)c4C3Cc2cc1O NGBDVHCLWGVLEN-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 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
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000003053 piperidines Chemical class 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
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention is the method for producing etoposide, this method be with 4 shown in the general formula '-halogen ethanoyl-4 ＇-demethyl epipodophyllotoxin-β-D-2,3-2-O-halogen ethanoyl-4,6-O-ethylidene glycoside,
R wherein
1And R
2Can be identical, also can be different, each represents one-COCHX
2Or-COCX
3, wherein X represents a halogen atom, and with alcohol, amine and/or ammonia react are to remove the halogen Acetyl Groups.
Description
With the etoposide shown in following step (1) and (2) production molecular formula
(4 '-demethyl epipodophyllotoxin-9-4,6-0-ethidine β-D pyranoglucose)
Be known (seeing Canadian Patent 95639)
Wherein A represents formyl radical or ethanoyl, and B represents carbobenzoxy.
Yet, aforesaid method has narrowed down to two of necessity and has gone on foot, promptly a step is to remove A, a step subsequently is to remove B, owing to the step of removing A very time-consuming (for example still intact do not become after 20～30 hours reaction) has increased by product, resemble foxed product,, yield poorly so that the etoposide that is generated is of poor quality.
As the repeatedly result of study of producing the etoposide novel method, inventor of the present invention found with the compound shown in the molecule formula III (this compound with two-or three-fontanel be that raw material makes for the acetyl fontanel)
R wherein
1And R
2Can be identical also can be different, each represents a COCHX
2Or COCX
3
Wherein X represents the plain atom of a fontanel,
This compound and alcohol, amine and/or ammonia react
Can remove R simultaneously
1And R
2Obtain etoposide, prepared etoposide foreign matter content is low, is easy to purify.
Be found to be basic the present invention and be accomplished with above-mentioned.
Below just the present invention be further introduced.
In the present invention, its R when the compound with the molecular formula III is raw material
1And R
2In X can be fluorine, chlorine, bromine, iodine, preferentially use chlorine and bromine.And R
1And R
2Can be dichloro-acetyl, dichloro-acetyl, two bromo acetyl, two iodo acetyl, three fluoro acetyl, three chloro acetyl, three bromo acetyl and three iodo acetyl.
The alcohol that uses among the present invention has: the lower alcohol (C with 1-3 hydroxyl
1-C
4), on nitrogen-atoms, have the lower alcohol (C of 1-3 hydroxyl
1-C
4), on nitrogen-atoms, have the rudimentary amino alcohol of 1-3 low-carbon (LC) hydroxyalkyl group, more properly say, low-grade monobasic alcohol, as methyl alcohol, ethanol, propyl alcohol and butanols, lower polyol, as ethylene glycol and glycerine, rudimentary amino alcohol (C
1-C
4), as monoethanolamine, two carbinolamine and tripropanol amine, wherein preferably use low-grade monobasic alcohol such as methyl alcohol and ethanol.
Then the amount that participates in the alcohol of reaction should be taken into account when needing with these alcohol in the present invention as solvent.In this case, the consumption with compound (III) is identical at least for Chun consumption.
Used amine can be C among the present invention
1～C
6The aliphatics primary amine, as methylamine, ethamine, just-propylamine, just-butylamine, C
1～C
6The aliphatics secondary amine, as dimethylamine, diethylamine, two-Tri N-Propyl Amine, two-n-Butyl Amine 99 and two-normal hexyl Amine; The C that can contain Sauerstoffatom
4～C
5Cyclammonium, as tetramethyleneimine, piperidines and morpholine, with aliphatie diamine,, in above-mentioned amine, preferentially select the alkyl firsts and seconds amine of low carbon atom for use, as methylamine and diethylamine as quadrol.When using these amine and/or ammonia, they itself can be used as solvent, but generally also need use other solvent.
Its amount equivalent general and compound (III) is suitable in this case, or preferably the normal 1-3 of compound (III) times.
Certainly amine or ammonia are added in the reactive system, also can be in the presence of alkali with the acetate or the hydrochloride of amine and/or ammonia, can produce unhindered amina to the reactive system and/or ammonia effectively reacts as pyridine or triethylamine.
Said in the present invention alcohol, amine, or ammonia can use separately, also can two or morely at least mix mutually and use.When using, need with alcohol as solvent with form of mixtures.The used in this case amine or the amount of ammonia are the normal 1-10 of compound (III) times, and the amount of preferentially selecting for use is 1-3 times.
Except alcohols, also available other compound is as solvent outside amine and the ammonia, and they can not produce detrimentally affect to reaction, and the example of these compounds is chloroforms, ether, 1,2-ethylene dichloride, dimethyl formamide, and pyridine.
When adding rudimentary three grades of alkanamines such as Trimethylamine 99 or triethylamine, pyridine or low alkyl group substituted pyridines, or organic carboxylate is during as catalysts, and the reaction among the present invention is particularly carried out very wellly with the reaction of alcohol.
As organic carboxylic salt ammonium salt that can be (1) metal-salt or monobasic aliphatic carboxylic acid, for example, sodium acetate, potassium acetate, magnesium acetate, Sodium Propionate, Succinic acid ammonium salt, acetate alkylammonium, the ammonium salt of (2) metal-salt (an alkali metal salt or salt earth metal salt) or aromatic carboxylic acid, Sodium Benzoate for example, the iso-nicotinic acid ammonium, ammonium benzoate, anthranilic acid ammonium, phenylformic acid alkyl ammonium and (3) and can carboxylic group the ammonium salt or metal-salt basic metal or the alkaline earth salt that generate from exchange resin of the slightly acidic sun of group in return).Can use C in the ammonium salt
1～C
3The saturated fatty acid ammonium salt is preferentially selected ammonium acetate and ammonium formiate for use, and the consumption of these compounds is 5-100%(w/w), the amount of preferentially selecting for use is the 30-50%(w/w), in the compound of logical formula III.
Temperature among the present invention changes with solvent for use and catalyzer, but generally is-10～100 ℃, preferentially selects 0-90 ℃ for use, and particularly 20～70 ℃, the time of finishing the reaction times is 0.1～7 hour.
Compound as the molecule formula III of raw material among the present invention is the novel substance that was not disclosed in the literature, and can known 4-demethyl epipodophyllotoxin (IV) (seeing United States Patent (USP) 3524844) makes raw material and synthesizes by following reaction scheme down:
R wherein
1And R
2As defined above.
That is, in inert solvent with 4 '-demethyl epipodophyllotoxin (IV) and two fontanels generation one or three fontanels are for Acetyl Chloride 98Min. (R
2Cl) reaction be lower than in inert solvent then that condensation obtains in the presence of 0 ℃ and the boron trifluoride ethyl ether complex 4 '-fontanel for acetyl-4 '-demethyl-epipodophyllotoxin (V) and 4,6-O-ethylidene-2,3-two-O-fontanel makes compound (I) for acetyl-β-D-Glucopyranose (IV).The equivalent with general formula (V) is identical at least for the suitable consumption of Glucopyranose of logical formula IV.
The compound here (VI) is a new compound, and available known 4,6-O-ethylidene-1-O-benzyloxycarbonyl-β-D-Glucopyranose (XII) synthesizes with following reaction scheme for raw material, wherein R
1As defined above.
With 4,6-0-ethylidene-1-O-benzyloxycarbonyl-β-D-Glucopyranose (VII) reacts 4 of hydrogenolysis generation then with two fontanels-three fontanel for Acetyl Chloride 98Min. in inert solvent, 6-O-ethylidene-1-O-carbobenzoxy-(Cbz)-2, the 3-2-O-fontanel can obtain compound (VI) for acetyl-β-D-Glucopyranose (VIII).Although generate a spot of alpha-isomer in hydrogenolysis process is inevitably, owing to have only β-isomer selectively to go out from the reaction solution intercrystalline, so compound (VI) has the character that is easy to separate alpha-isomer from β-isomer.
In addition, the β-isomer of compound (VI) is stable, and reality is not converted into the α isomerization, therefore can store for a long time.
According to the present invention, can under general condition remove fontanel for acetyl group, for example, under 25 ℃ or room temperature condition, carry out the reaction of short period of time, by product such as dark product can generate the etoposide that can obtain high yield from compound (III) hardly.Therefore, the by product that the reaction after image is removed dark product and so on is easily, for example adds hydrophobic solvent such as chloroform in reaction soln, washes this solution with water, evaporate solvent, the recrystallization resistates can obtain pure etoposide from solvent.The inorganic content of the etoposide that obtains is extremely low, and ignition residue (residuum behind the calcination etoposide) content is 0.1%(weight) or lower.In addition, in the presence of the lower aliphatic acid ammonium salt, as ammonium acetate, three grades of ammoniums exist down and the alcohol reaction, or alcohol and amine or ammonia combined when using, then reaction is finished in the short period of time at ambient temperature, as long as concentration of reaction solution is recyclable etoposide, so it is operation and subsequent aftertreatment all are very easy to, very advanced as industrial process method of the present invention.Particularly under latter event, react and to finish at short notice.
Following embodiment will describe the present invention in detail.
Embodiment 1
With 1 the gram 4 '-two chloracetyls-4 '-demethyl epipodophyllotoxin-β-D-2,3-two-O-dichloro-acetyl-4,6-O-ethylidene glucose (III) (R
1, R
2=-COCHCl
2) and the ammonium acetate of 1 gram be dissolved in 20 ml methanol, stirred 1.5 hours at 25 ℃.After finishing reaction, methyl alcohol is concentrated into 10 milliliters, cooling gained solution obtains the etoposide of 0.55 gram (productive rate 86.1%).(silica gel, developping agent are chloroform to the thin-layer chromatography of gained material: R methyl alcohol 1: 1)
fValue, infrared, it is identical that nucleus magnetic resonance and optically-active and Canadian Patent 956939 described methods make material.
Fusing point: 259～260 ℃,
R
f＝0.44。
Embodiment 2-9
Under the condition shown in the following table, digest compound (III) (R with 1
1, R
2=-COCHCl
2) react, the method processing reaction solution with identical with embodiment 1 obtains etoposide.
Embodiment 10
With 1 the gram 4 '-dichloro-acetyl-4 '-demethyl epipodophyllotoxin-β-D-2,3-two-O-dichloro-acetyl-4,6-O-ethylidene glucose (III) (R
1, R
2=-COCHCl
2) and 1 the gram magnesium acetate in 20 ml methanol, refluxed 4 hours.Steam methyl alcohol after reaction is finished, add 30 milliliters of chloroforms then, wash resistates with water, use anhydrous magnesium sulfate drying.Vacuum boils off solvent, obtains 0.49 gram (productive rate 76.7%) etoposide crystallization with methyl alcohol for the solution weight crystalline residue.
Embodiment 11
Use the etoposide that makes 4.75 grams (productive rate 64.6%) similar in appearance to the reaction of embodiment 1; the going out of its difference only be with 4 '-two acetyl bromides-4 '-demethyl epipodophyllotoxin-β-D-2; 3-two-O-two acetyl bromides-4,6-O-ethylidene glucose (III) (R
1, R
2=-COCHBr
2) replace compound (the III) (R among the embodiment 1
1, R
2=-COCHCl
2).
Embodiment 12
Compound (III) (R with 1 gram
1, R
2=-COCHCl
2) be dissolved in 20 ml methanol, add the diethylamine of 0.64 gram then, stirred this solution 10 minutes at 25 ℃.Reaction is finished final vacuum and is steamed solvent.Add 20 milliliters of chloroforms, use in the hydrochloric acid of 2N and residuum, wash with water, use anhydrous magnesium sulfate drying.Under vacuum condition,, obtain 0.53 gram (productive rate: etoposide crystallization 83.1%) with solution concentration to 10 milliliter.
Embodiment 13
With 12 identical reactions obtain 0.51 gram (productive rate: etoposide crystallization 80.0%), its difference only are with the diethylamine among 0.88 gram two-just-propylamine replacement embodiment 12 with embodiment.
Embodiment 14
Compound (III) (R with 1 gram
1, R
2=-COCHCl
2) be added to 20 milliliters be dissolved with 0.15 the gram ammonia methyl alcohol in, stirred the mixture 30 minutes at 25 ℃.After reaction was finished, vacuum boiled off solvent.Add 10 milliliters of chloroform recrystallizations, obtain 0.54 gram (productive rate: etoposide crystallization 87.4%).
Embodiment 15
(productive rate: etoposide crystallization 62.7%), its difference only are to replace used methyl alcohol among the embodiment 12 with 20 milliliters of diethylamine with obtaining 0.40 gram with embodiment 12 identical methods.
In addition, reaction also can be carried out under the condition of 20 milliliters of pyridine instead of methanol.
Embodiment 16
4 '-demethyl epipodophyllotoxin-β-D-2 ,-3-two-O-two chloracetyls-4,6-O-ethylidene glucose (III) (R
1, R
2=COCHCl
2) preparation.
(a) 4 '-dichloro-acetyl-4 '-demethyl epipodophyllotoxin (V) (R
2=-COCHCl
2)
With 4 of 8 grams '-demethyl epipodophyllotoxin (IV) is dissolved in 160 milliliters of acetone, adds 3.2 gram pyridines, solution is cooled to-5～-10 ℃.Be added drop-wise in the solution with 1.5 hours two chloracetyls 4.1 grams, and again with this solution stirring 0.5 hour.Vacuum boils off acetone, and the gained solids is dissolved in 160 milliliter 1, in the 2-ethylene dichloride, washes with water.With anhydrous magnesium sulfate drying 1,2-dichloroethane solution, vacuum concentration obtain 9.5 gram (productive rates: compound (V) (R 93.4%)
2=-COCHCl
2).
Fusing point 207-208 ℃
IRν
KBr max3540，1775，1600，1481，1235，1130cm
-1。
(b) 4,6-O-ethylidene-1-O-carbobenzoxy-(Cbz)-2,3-two-O-dichloro-acetyl-β-D-pyranoglucose (VIII) (R
1=-COCHCl
2).
With 4 of 34.0 grams, 6-O-ethylidene-1-O-carbobenzoxy-(Cbz)-β-D-pyranoglucose (VIII) is suspended in 340 millis 1, in the 2-ethylene dichloride, adds 23.7 gram pyridines, and suspension is cooled to 0-5 ℃.Drip this suspension, restir 0.5 hour with about 1 hour dichloroacetyl chloride with 32.4 grams.Wash reaction solution with water, use the anhydrous magnesium sulfate drying organic layer, and vacuum concentration obtains compound (the VIII) (R of 51.0 grams (productive rate 90%)
1=-COCHCl
2).
Fusing point 150-151 ℃,
IRν
KBr max1770，1255，1100，820cm
-1。
(c) 4,6-0-ethylidene-2,3-two-0-two chloracetyls-β-D-pyranoglucose (VI) (R
1=-COCHCl
2)
The compound (VIII) of 10.0 grams (R=-COCHCL) is dissolved in 50 milliliters of acetone, adds 1.0 gram palladium blacks, hydrogenolysis under-5～10 ℃ of pressurized conditions.After reaction is finished, leach catalyzer, vacuum boils off solvent.Add 17 milliliters of isopropyl ethers to residuum, mixture is cooled to 0 ℃, suction strainer obtains 7.3 gram (productive rate 95.9%) compound (VI (R
1=-COCHCl
2).
Fusing point 133-135 ℃
IRν
KBr max3445，1775，1305，1165，1095，1005，815cm
-1。
(d) 4 '-dichloro-acetyl-4 '-demethyl epipodophyllotoxin-β-D-2,3-two-0-dichloro-acetyl-4 '-6-O-ethylidene glucose (III) (R
1, R
2=-COCHCl
2)
Digest compound (V) (R with 3.0
2=-COCHCl
2) be dissolved in 60 milliliters 1, in 2-two ethane, add compound (the VI) (R of 2.5 grams
1=-COCHCl
2), solution is cooled to-10 ℃.With about 1.5 hours 1.1 gram boron trifluoride ethyl ether complexs are added dropwise to solution, add the back and continue reaction 0.5 hour.Keep solution temperature at-5～-10 ℃, drip 0.8 gram pyridine, wash reaction mixture with water.Use the anhydrous magnesium sulfate drying organic phase, vacuum concentration with the residuum recrystallization, obtains compound (the III) (R of 4.4 grams (productive rate 81.4%) with methyl alcohol
1, R
2=-COCHCl
2).
Fusing point: 207～208,
IRν
KBr max1880，1610，1490，1240，1130，935，820cm
-1，
In addition, also available 1.5 compounds (VI) that digest compound (V) and 5.0 grams make compound (III) with above-mentioned reaction and processing mode.
Embodiment 17
4 '-two acetyl bromides-4 '-demethyl epipodophyllotoxin-β-D-2,3-two-0-two acetyl bromides-4,6-O-ethylidene glucose (III) (R
1, R
2=-COCHCl
2)
(a) 4 '-two acetyl bromides-4 '-demethyl epipodophyllotoxin (V) (R
2=-COCHBr
2)
With 4 of 5.0 grams '-demethyl table ghost toxin is dissolved in 150 milliliter 1, in the 2-ethylene dichloride.Add the pyridine of 1.5 grams, solution is cooled to-5～10 ℃.Be added dropwise to this solution with 1.5 hours two bromoacetyl chlorides, again mixed solution stirred 0.5 hour 3.8 grams.Wash reaction solution with water, use the anhydrous magnesium sulfate drying organic layer, vacuum concentration to 50 milliliter obtains containing compound (V) (R
2=-COCHBr
2) 1, the 2-dichloroethane solution.
(b) 4,6-O-ethylidene-1-O-carbobenzoxy-(Cbz)-2,3-two-O-two acetyl bromides-β-D-pyranoglucose (VIII) (R
2=-COCHBr
2)
With 4 of 5.1 grams, 6-O-ethylidene-1-O-carbobenzoxy-(Cbz)-β-D-pyranoglucose (VII) is suspended in 51 milliliter 1, in the 2-ethylene dichloride.Add 3.6 gram pyridines, suspension is cooled to 5 ℃.Be added dropwise to suspension with about 1 hour two bromoacetyl chlorides, further stirred this mixed solution 30 minutes 7.8 grams.Wash the reaction mixture organic phase then with water, use anhydrous magnesium sulfate drying, vacuum concentration obtains 25 milliliters of compounds (VIII) (R
1=-COCHBr
2) 1, the 2-dichloroethane solution.
(c) 4,6-O-ethylidene-2,3-two-O-two acetyl bromides-β-D-pyranoglucose (VI) (R
1=-COCHBr
2)
The palladium black of 0.4 gram is joined compound (the VIII) (R of 25 milliliters (b)
1=-COCHBr
2)
1, in the 2-dichloroethane solution, at-10～5 ℃, this solution of hydrogenation under the pressurized conditions.After reaction is finished, filter catalyzer, obtain compound (VI) (R
1=-COCHBr
2) 1, the 2-dichloroethane solution.
(d) 4 '-two acetyl bromides-4 '-the malicious mortar element-β of demethyl table ghost-D-2,3-two-O-two acetyl bromides-4,6-O-ethylidene glucose (III) (R
1, R
2=-COCHBr
2).
With 25 milliliters of compounds (V) (R
2=-COCHBr
2) 1,2-dichloroethane solution and 50 milliliters of compounds (VI) (R
1=-COCHBr
2) 1, the 2-dichloroethane solution mixes, and mixed solution is cooled to 10 ℃.Be added dropwise to mixed solution with about 1.5 hours boron trifluoride ethyl ether complexs with 2.8 grams.After adding, continued the stirring reaction mixed solution 30 minutes.Under-5～-10 ℃ of conditions, be added dropwise to the pyridine of 2.0 grams, wash reaction mixture with water.The vacuum concentration organic phase with the residuum recrystallization, obtains compound (III) (R with methyl alcohol
1, R
2=-COCHBr
2).
Embodiment 18
4 '-dichloro-acetyl-4 '-demethyl epipodophyllotoxin β-D-2,3-two-O-tribromo-acetyl base-4,6-O-ethylidene glucoside (III) (R
2=-COCl
2, R=-COCHCl
2)
(a) 4,6-O-ethylidene-1-O-O-carbobenzoxy-(Cbz)-2,3-two-O-tribromo-acetyl base-β-D-pyranoglucose glucoside (VIII) (R
1=COCCl
3)
With making 25 milliliters of compounds (VIII) (R with embodiment 17 identical methods
1=-COCCl
3) 1,2 dichloroethane solution, its difference is to substitute two bromoacetyl chlorides with trichoroacetic chloride.
(b) 4,6-O-ethylidene-2,3-two-O-tribromo-acetyl base-β-D-pyranoglucose (VI) (R
1=-COCCl
3)
With 25 milliliters of solution that obtain by step (a) with embodiment 17(c) identical method makes 25 milliliters of compounds (VI) (R
1=-COCCl
3) 1, the 2-dichloroethane solution.
(e) 4 '-two acetyl bromides-4 '-demethyl epipodophyllotoxin β-D-2,3-two-O-tribromo-acetyl base-4,6-O-ethylidene glucoside (III) (R
1=COCl
3, R=-COCHCl
2)
With with embodiment 16(d) 25 milliliters of identical method solution that step (b) is obtained with contain compound (V) (R
2=-COCHCL
2) 50 milliliter 1,2-ethylene dichloride reaction obtains compound (III) (R
1=-COCCl
3, R=-COCHCl
2).
Claims (11)
1, produce the method for etoposide shown in the molecule formula I, it is characterized in that this method comprises:
With 4 shown in the logical formula III '-fontanel acetyl-4 '-demethyl epipodophyllotoxin-β-D-2 ,-3-two-O-fontanel acetyl-4,6-O-ethylidene glycoside,
R wherein
1And R
2Can be identical, also can be different, each represents a COCHX
2Or COCX
3, wherein X represents a fontanelle atom, removes the fontanel Acetyl Groups with alcohol, amine and/or ammonia react.
2, according to the method for claim 1, it is characterized in that a compound and-C in the logical formula III
1～C
4The lower alcohol with 1～3 oh group, the rudimentary amino alcohol of the low carbon atom hydroxyalkyl group of 1-3 is arranged on nitrogen-atoms, single or two-(C
1～C
6Alkyl) amine, C
4～C
6Cyclammonium, morpholine and or ammonia react.
3, according to the method for claim 1, it is characterized in that the reaction with alcohol is at low-grade amine, pyridine or organic carboxylate exist and carry out down.
4, according to the method for claim 3, it is characterized in that this organic carboxylate is (1) an alkali metal salt, salt earth metal salt or C
1～C
4The aliphatic carboxylic acid ammonium salt, (2) metal-salt or aromatic carboxylic acid ammonium salt or (3) ammonium salt or have the metal-salt that forms as the weakly acidic cation-exchange resin of tradable hydroxy-acid group.
5, according to the method for claim four, it is characterized in that this organic carboxylate is C
1～C
3The ammonium salt of saturated fatty acid.
6, according to the method for claim 3, it is characterized in that this alcohol is methyl alcohol or ethanol.
7, according to the method for claim 1, it is characterized in that every normal compound (III) needs with the said alcohol of at least 1 equivalent or said amine of 1～3 equivalent or ammonia.
8, according to the method for claim 1, it is characterized in that said alkohol and amine or ammonia use together.
9, according to the method for claim 4, the amount that it is characterized in that said organic carboxylate is 5～100%(w/w), in the compound of logical formula III.
10, produce the method for etoposide, it is characterized in that this method comprise ammonium acetate or ammonium formiate exist down with 4 shown in the general formula '-fontanel ethanoyl-4 '-demethyl epipodophyllotoxin-β-D-2 ,-3-2-O-fontanel ethanoyl-4,6-O-ethylidene glycoside,
R wherein
1And R
2Can be the same or different each representative-COCHX
2Or COCX
3, wherein X represents a fontanelle atom, in the presence of ethanamide or ammonium formate with methyl alcohol or ethanol synthesis to remove the fontanel Acetyl Groups.
11,4 shown in the general formula '-fontanel ethanoyl-4 '-demethyl epipodophyllotoxin-β-D-2,3-I-O-fontanel ethanoyl-4,6-O-ethylidene glycoside,
R wherein
1And R
2Can be identical, also can be different, each representative-COCHX
2Or-COCX
3, wherein X represents the plain atom of a fontanel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85103648 CN1018457B (en) | 1984-10-24 | 1985-05-21 | Novel process for producing etoposide |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22339984A JPS61103883A (en) | 1984-10-24 | 1984-10-24 | Novel method for preparation of 4'-halogenoacetyl-4'-demethylepipodophyllotoxin |
| CN 85103648 CN1018457B (en) | 1984-10-24 | 1985-05-21 | Novel process for producing etoposide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85103648A true CN85103648A (en) | 1986-11-19 |
| CN1018457B CN1018457B (en) | 1992-09-30 |
Family
ID=25741640
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85103648 Expired CN1018457B (en) | 1984-10-24 | 1985-05-21 | Novel process for producing etoposide |
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| Country | Link |
|---|---|
| CN (1) | CN1018457B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570780A (en) * | 2013-10-21 | 2014-02-12 | 中国科学院昆明植物研究所 | Podophyllotoxin glycoside and acylated glycoside, and medicinal composition, preparation and application thereof |
| CN108129525A (en) * | 2017-12-28 | 2018-06-08 | 山东铂源药业有限公司 | A kind of preparation method of Etoposide intermediate |
| CN115141208A (en) * | 2022-08-05 | 2022-10-04 | 贵州大学 | Podophyllotoxin compound containing various ester group structures and preparation method and application thereof |
-
1985
- 1985-05-21 CN CN 85103648 patent/CN1018457B/en not_active Expired
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570780A (en) * | 2013-10-21 | 2014-02-12 | 中国科学院昆明植物研究所 | Podophyllotoxin glycoside and acylated glycoside, and medicinal composition, preparation and application thereof |
| CN108129525A (en) * | 2017-12-28 | 2018-06-08 | 山东铂源药业有限公司 | A kind of preparation method of Etoposide intermediate |
| CN108129525B (en) * | 2017-12-28 | 2019-11-22 | 山东铂源药业有限公司 | A kind of preparation method of Etoposide intermediate |
| CN115141208A (en) * | 2022-08-05 | 2022-10-04 | 贵州大学 | Podophyllotoxin compound containing various ester group structures and preparation method and application thereof |
| CN115141208B (en) * | 2022-08-05 | 2024-03-08 | 贵州大学 | Podophyllotoxin compound containing various ester structures and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1018457B (en) | 1992-09-30 |
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