FI68222C - Foerfarande foer 0-metylering av hydroxiaporfiner - Google Patents
Foerfarande foer 0-metylering av hydroxiaporfiner Download PDFInfo
- Publication number
- FI68222C FI68222C FI783951A FI783951A FI68222C FI 68222 C FI68222 C FI 68222C FI 783951 A FI783951 A FI 783951A FI 783951 A FI783951 A FI 783951A FI 68222 C FI68222 C FI 68222C
- Authority
- FI
- Finland
- Prior art keywords
- process according
- methylation
- solvent
- mixture
- methylated
- Prior art date
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 238000007069 methylation reaction Methods 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- -1 methylol hydroxyl group Chemical group 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 239000012022 methylating agents Substances 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 230000011987 methylation Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 7
- HADKRTWCOYPCPH-UHFFFAOYSA-M trimethylphenylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C1=CC=CC=C1 HADKRTWCOYPCPH-UHFFFAOYSA-M 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 5
- 150000008441 aporphines Chemical class 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- BZKUYNBAFQJRDM-UHFFFAOYSA-N aporphine Chemical group C12=CC=CC=C2CC2N(C)CCC3=CC=CC1=C32 BZKUYNBAFQJRDM-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KRXUKJMUOTUYOP-UHFFFAOYSA-N COC(C=C1)(C(OC)=C(C=C2)NC2=CC(C=C2)=NC2=C2)N=C1C=C(C=C1OC)NC21OC Chemical compound COC(C=C1)(C(OC)=C(C=C2)NC2=CC(C=C2)=NC2=C2)N=C1C=C(C=C1OC)NC21OC KRXUKJMUOTUYOP-UHFFFAOYSA-N 0.000 description 3
- PESVOXGFJDYKMD-UHFFFAOYSA-N OC=1C2(NC(C=1)=CC=1C=CC(N=1)(C(=C1C=CC(N1)=CC=1C=CC(N=1)=C2)OC)O)OC Chemical compound OC=1C2(NC(C=1)=CC=1C=CC(N=1)(C(=C1C=CC(N1)=CC=1C=CC(N=1)=C2)OC)O)OC PESVOXGFJDYKMD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- ZFLRVRLYWHNAEC-AWEZNQCLSA-N (6as)-1,2,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-9-ol Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(O)=C1 ZFLRVRLYWHNAEC-AWEZNQCLSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LZJRNLRASBVRRX-ZDUSSCGKSA-N Boldine Chemical compound CN1CCC2=CC(O)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(O)=C1 LZJRNLRASBVRRX-ZDUSSCGKSA-N 0.000 description 2
- KQSYENIABPWUEJ-UHFFFAOYSA-N COC(C=C1)(C(OC)=C(C=C2)NC2=CC(C=C2)=NC2=C2)N=C1C=C(C=C1O)NC21OC Chemical compound COC(C=C1)(C(OC)=C(C=C2)NC2=CC(C=C2)=NC2=C2)N=C1C=C(C=C1O)NC21OC KQSYENIABPWUEJ-UHFFFAOYSA-N 0.000 description 2
- HLUNBGMOGGEWFX-UHFFFAOYSA-N Hernandaline Natural products C1=C(OC)C(OC)=CC(OC=2C(=CC=3C=4C(OC)=C(OC)C=C5CCN(C)C(C=45)CC=3C=2)OC)=C1C=O HLUNBGMOGGEWFX-UHFFFAOYSA-N 0.000 description 2
- LINHZVMHXABQLB-ZDUSSCGKSA-N Isoboldine Chemical compound CN1CCC2=CC(OC)=C(O)C3=C2[C@@H]1CC1=C3C=C(OC)C(O)=C1 LINHZVMHXABQLB-ZDUSSCGKSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- IHQMYKRBWNYBLD-UHFFFAOYSA-N OC(C(C=C1)(NC1=CC(C=C1)=NC1=C1)O)C(C=C2)=NC2=CC2=CC=C1N2 Chemical compound OC(C(C=C1)(NC1=CC(C=C1)=NC1=C1)O)C(C=C2)=NC2=CC2=CC=C1N2 IHQMYKRBWNYBLD-UHFFFAOYSA-N 0.000 description 2
- DTUQSVQYZYBKFX-UHFFFAOYSA-N OC12C=CC(C=C3C=C(C(N3)(C=C3C=CC(C=C4C=CC(=C2OC)N4)=N3)OC)OC)=N1 Chemical compound OC12C=CC(C=C3C=C(C(N3)(C=C3C=CC(C=C4C=CC(=C2OC)N4)=N3)OC)OC)=N1 DTUQSVQYZYBKFX-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WNGGWVAYNUANOX-UHFFFAOYSA-N [N]1C2=CC=C1C=C(N1)C=C(O)C1=CC([N]1)=CC=C1C=C(N1)C=CC1=C2 Chemical class [N]1C2=CC=C1C=C(N1)C=C(O)C1=CC([N]1)=CC=C1C=C(N1)C=CC1=C2 WNGGWVAYNUANOX-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
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- 230000001035 methylating effect Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
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- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- DYAAXURJUVSJEZ-AWEZNQCLSA-N (+)-Mecambroline Chemical compound C12=C3C4=CC(O)=CC=C4C[C@@H]1N(C)CCC2=CC1=C3OCO1 DYAAXURJUVSJEZ-AWEZNQCLSA-N 0.000 description 1
- KYVJVURXKAZJRK-UHFFFAOYSA-N (+)-laurolitsine Natural products N1CCC2=CC(O)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 KYVJVURXKAZJRK-UHFFFAOYSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- YRYCIFUZSUMAAY-UHFFFAOYSA-N (RS)-1-benzyl-1,2,3,4-tetrahydroisoquinoline Chemical compound N1CCC2=CC=CC=C2C1CC1=CC=CC=C1 YRYCIFUZSUMAAY-UHFFFAOYSA-N 0.000 description 1
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- ISQZUTSKBGVRCP-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6-methoxy-7-phenylmethoxy-2-propyl-3,4-dihydro-1h-isoquinoline Chemical compound C1=C2C(CC=3C=C(OC)C(OC)=CC=3)N(CCC)CCC2=CC(OC)=C1OCC1=CC=CC=C1 ISQZUTSKBGVRCP-UHFFFAOYSA-N 0.000 description 1
- PLEOQAHCVRVCDL-UHFFFAOYSA-N 2,9-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-1,10-diol Natural products CN1CCC2=CC(OC)=C(O)C3=C2C1CC1=C3C=C(O)C(OC)=C1 PLEOQAHCVRVCDL-UHFFFAOYSA-N 0.000 description 1
- DLKMKVONCILRDQ-UHFFFAOYSA-N 2-methoxy-21,23-dihydro-2H-porphyrin-1-ol Chemical compound OC12C(C=C(N1)C=C1C=CC(C=C3C=CC(=CC=4C=CC(=C2)N=4)N3)=N1)OC DLKMKVONCILRDQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- IVDPYSFXHBPIHY-UHFFFAOYSA-N OC12C(=CC(N1)=CC=1C=CC(N1)=CC1(C=CC(N1)=CC=1C=CC(N1)=C2)OC)OC Chemical compound OC12C(=CC(N1)=CC=1C=CC(N1)=CC1(C=CC(N1)=CC=1C=CC(N1)=C2)OC)OC IVDPYSFXHBPIHY-UHFFFAOYSA-N 0.000 description 1
- NNIUMSOWYUGTAK-UHFFFAOYSA-N OC12C(=CC(N1)=CC=1C=CC(N=1)(C(=C1C=CC(N1)=CC=1C=CC(N=1)=C2)O)OC)OC Chemical compound OC12C(=CC(N1)=CC=1C=CC(N=1)(C(=C1C=CC(N1)=CC=1C=CC(N=1)=C2)O)OC)OC NNIUMSOWYUGTAK-UHFFFAOYSA-N 0.000 description 1
- OUSFLDYOMOPDGU-UHFFFAOYSA-N OC1C=2C=CC(=CC3=CC=C(N3)C=C3C=CC(C=C4C=CC1(N4)O)=N3)N2.COC2C=3C=CC(=CC4=CC=C(N4)C=C4C=CC(C=C1C=CC2(N1)OC)=N4)N3 Chemical compound OC1C=2C=CC(=CC3=CC=C(N3)C=C3C=CC(C=C4C=CC1(N4)O)=N3)N2.COC2C=3C=CC(=CC4=CC=C(N4)C=C4C=CC(C=C1C=CC2(N1)OC)=N4)N3 OUSFLDYOMOPDGU-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- MHVCSDLBQKSFQV-HNNXBMFYSA-N boldine Natural products COc1cc2c(C[C@@H]3N(C)CCc4cc(C)c(OC)c2c34)cc1O MHVCSDLBQKSFQV-HNNXBMFYSA-N 0.000 description 1
- LZJRNLRASBVRRX-UHFFFAOYSA-N boldine trifluoroacetic acid salt Natural products CN1CCC2=CC(O)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 LZJRNLRASBVRRX-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
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical group ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- HORZNQYQXBFWNZ-UHFFFAOYSA-N dl-Norisoboldin Natural products N1CCC2=CC(OC)=C(O)C3=C2C1CC1=C3C=C(OC)C(O)=C1 HORZNQYQXBFWNZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- CRSMCADHSFQBLA-UHFFFAOYSA-N isoboldine Natural products COc1cc-2c(CC3N(C)CCc4cccc-2c34)cc1O CRSMCADHSFQBLA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229930013053 morphinan alkaloid Natural products 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Inorganic materials [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2757335 | 1977-12-22 | ||
| DE2757335A DE2757335C3 (de) | 1977-12-22 | 1977-12-22 | Verfahren zur O-Methylierung von Hydroxyaporphinen |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI783951A7 FI783951A7 (fi) | 1979-06-23 |
| FI68222B FI68222B (fi) | 1985-04-30 |
| FI68222C true FI68222C (fi) | 1985-08-12 |
Family
ID=6026924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI783951A FI68222C (fi) | 1977-12-22 | 1978-12-21 | Foerfarande foer 0-metylering av hydroxiaporfiner |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4309542A (cs) |
| JP (1) | JPS54119474A (cs) |
| AT (1) | AT362535B (cs) |
| BE (1) | BE872843A (cs) |
| CH (1) | CH645629A5 (cs) |
| CS (1) | CS238601B2 (cs) |
| DD (1) | DD141830A5 (cs) |
| DE (1) | DE2757335C3 (cs) |
| FI (1) | FI68222C (cs) |
| FR (1) | FR2430942A1 (cs) |
| GB (1) | GB2010841B (cs) |
| HU (1) | HU177060B (cs) |
| NL (1) | NL7812394A (cs) |
| SU (1) | SU925249A3 (cs) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3118521A1 (de) * | 1981-05-09 | 1982-12-02 | Gödecke AG, 1000 Berlin | Dibenzo(de,g)chinolin-derivate, verfahren zu deren herstellung und deren verwendung bei der bekaempfung von erkaeltungskrankheiten und allergien |
| US4795759A (en) * | 1985-07-27 | 1989-01-03 | Sandoz Ltd. | Use of dibenz(CD,F)indoles |
| US6210680B1 (en) | 1999-06-11 | 2001-04-03 | Univera Pharmaceuticals, Inc. | Method for the prevention and treatment of chronic venous insufficiency |
| TWI225397B (en) * | 2000-05-04 | 2004-12-21 | Nat Science Council | Uses of thaliporphine or its derivatives in treatment of cardiac diseases and preparation of the same |
| PT1311486E (pt) * | 2000-08-23 | 2006-09-29 | Lotus Pharmaceutical Co Ltd | Uso de taliporfina ou dos seus derivados no tratamento de doencas cardiacas e preparacao da mesma |
| WO2004110449A1 (fr) * | 2003-06-19 | 2004-12-23 | Lotus Pharmaceutical Co., Ltd. | Aporphine et oxoaporphine et leur utilisation a des fins medicales |
| CN1884265A (zh) * | 2005-06-20 | 2006-12-27 | 美时化学制药股份有限公司 | 治疗糖尿病的阿朴芬及次阿朴芬化合物 |
| WO2007134485A1 (en) * | 2006-05-22 | 2007-11-29 | Lotus Pharmaceutical Co., Ltd. | Aporphine and oxoaporphine compounds and pharmaceutical use thereof |
| TWI531369B (zh) * | 2014-05-30 | 2016-05-01 | 資元堂生物科技股份有限公司 | 阿朴啡生物鹼衍生物用於製備促進ａｍｐｋ活性的藥物之用途 |
| CN111196801B (zh) * | 2020-01-14 | 2022-10-14 | 中国药科大学 | 阿朴菲类生物碱衍生物及其制备方法与用途 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1100998A (en) * | 1912-05-06 | 1914-06-23 | Firm Of Mckesson & Robbins | Process of manufacuring alkyl-ethers of morphin. |
| GB1364318A (en) * | 1971-03-15 | 1974-08-21 | Bellon Labor Sa Roger | Laurotetanine derivatives |
| DE2337507A1 (de) * | 1973-07-24 | 1975-02-13 | Research Corp | Verfahren zur herstellung von aporphinen ueber neue zwischenprodukte |
| DE2625116C2 (de) * | 1976-06-04 | 1984-01-26 | Gödecke AG, 1000 Berlin | Verfahren zur Herstellung von 4-Hydroxy-aporphin-Derivaten |
-
1977
- 1977-12-22 DE DE2757335A patent/DE2757335C3/de not_active Expired
-
1978
- 1978-12-14 FR FR7835193A patent/FR2430942A1/fr active Granted
- 1978-12-18 BE BE192382A patent/BE872843A/xx not_active IP Right Cessation
- 1978-12-19 US US05/971,143 patent/US4309542A/en not_active Expired - Lifetime
- 1978-12-19 GB GB7849004A patent/GB2010841B/en not_active Expired
- 1978-12-20 DD DD78209943A patent/DD141830A5/de unknown
- 1978-12-21 AT AT913578A patent/AT362535B/de not_active IP Right Cessation
- 1978-12-21 SU SU782700555A patent/SU925249A3/ru active
- 1978-12-21 JP JP15695578A patent/JPS54119474A/ja active Pending
- 1978-12-21 FI FI783951A patent/FI68222C/fi not_active IP Right Cessation
- 1978-12-21 CH CH1305678A patent/CH645629A5/de not_active IP Right Cessation
- 1978-12-21 NL NL7812394A patent/NL7812394A/xx not_active Application Discontinuation
- 1978-12-21 HU HU78WA355A patent/HU177060B/hu unknown
- 1978-12-22 CS CS788857A patent/CS238601B2/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US4309542A (en) | 1982-01-05 |
| CS238601B2 (en) | 1985-12-16 |
| FI68222B (fi) | 1985-04-30 |
| AT362535B (de) | 1981-05-25 |
| NL7812394A (nl) | 1979-06-26 |
| CH645629A5 (de) | 1984-10-15 |
| DE2757335A1 (de) | 1979-06-28 |
| FI783951A7 (fi) | 1979-06-23 |
| ATA913578A (de) | 1980-10-15 |
| HU177060B (hu) | 1981-06-28 |
| DD141830A5 (de) | 1980-05-21 |
| SU925249A3 (ru) | 1982-04-30 |
| GB2010841B (en) | 1982-08-18 |
| BE872843A (fr) | 1979-04-17 |
| GB2010841A (en) | 1979-07-04 |
| DE2757335B2 (de) | 1981-05-27 |
| DE2757335C3 (de) | 1982-03-25 |
| JPS54119474A (en) | 1979-09-17 |
| FR2430942B1 (cs) | 1985-02-22 |
| FR2430942A1 (fr) | 1980-02-08 |
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