CN102108082A - Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia - Google Patents
Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia Download PDFInfo
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- CN102108082A CN102108082A CN2009102141215A CN200910214121A CN102108082A CN 102108082 A CN102108082 A CN 102108082A CN 2009102141215 A CN2009102141215 A CN 2009102141215A CN 200910214121 A CN200910214121 A CN 200910214121A CN 102108082 A CN102108082 A CN 102108082A
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- Prior art keywords
- vincamine
- acid
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- 229960002726 vincamine Drugs 0.000 title claims abstract description 42
- 201000006474 Brain Ischemia Diseases 0.000 title description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 title description 3
- 206010008118 cerebral infarction Diseases 0.000 title description 3
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 claims abstract description 78
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 22
- FNGGIPWAZSFKCN-ACRUOGEOSA-N tabersonine Chemical class N1C2=CC=CC=C2[C@]2([C@H]34)C1=C(C(=O)OC)C[C@]3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-ACRUOGEOSA-N 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- JSLDLCGKZDUQSH-RTBUJCADSA-N 19-epivindolinine Natural products O=C(OC)[C@H]1[C@@]23[C@H](C)[C@]4([C@@H]5N(CC=C4)CC[C@]25c2c(N3)cccc2)C1 JSLDLCGKZDUQSH-RTBUJCADSA-N 0.000 claims description 13
- KILNDJCLJBOWAN-UHFFFAOYSA-N Tabersonine Natural products CCC12CC(=C3N(C)c4cc(OC)ccc4C35CCN(CC=C1)C25)C(=O)OC KILNDJCLJBOWAN-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- FNGGIPWAZSFKCN-UHFFFAOYSA-N xi-tabersonine Natural products N1C2=CC=CC=C2C2(C34)C1=C(C(=O)OC)CC3(CC)C=CCN4CC2 FNGGIPWAZSFKCN-UHFFFAOYSA-N 0.000 claims description 13
- GIGFIWJRTMBSRP-ACRUOGEOSA-N (-)-vincadifformine Chemical compound C1C(C(=O)OC)=C2NC3=CC=CC=C3[C@@]22CCN3CCC[C@]1(CC)[C@@H]23 GIGFIWJRTMBSRP-ACRUOGEOSA-N 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- GIGFIWJRTMBSRP-UHFFFAOYSA-N DL-Vincadifformin Natural products C1C(C(=O)OC)=C2NC3=CC=CC=C3C22CCN3CCCC1(CC)C23 GIGFIWJRTMBSRP-UHFFFAOYSA-N 0.000 claims description 6
- NAMSIRMSFVGAKD-UHFFFAOYSA-N vincadifformine Natural products CCC12CCCN3CCC4(C13)C(Nc1cc(OC)ccc41)=C(C2)C(=O)OC NAMSIRMSFVGAKD-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000004965 peroxy acids Chemical class 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- -1 ethanol tabersonine salt Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- YKTNISGZEGZHIS-UHFFFAOYSA-N 2-$l^{1}-oxidanyloxy-2-methylpropane Chemical group CC(C)(C)O[O] YKTNISGZEGZHIS-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- OMASBWAHGBPSHI-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)OO.[Br] Chemical compound C(C1=CC=CC=C1)(=O)OO.[Br] OMASBWAHGBPSHI-UHFFFAOYSA-N 0.000 claims description 2
- FMMULDHNCJCPTA-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)OO.[F] Chemical compound C(C1=CC=CC=C1)(=O)OO.[F] FMMULDHNCJCPTA-UHFFFAOYSA-N 0.000 claims description 2
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000002638 heterogeneous catalyst Substances 0.000 claims description 2
- 239000002815 homogeneous catalyst Substances 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims 3
- 238000004090 dissolution Methods 0.000 claims 2
- DWCNNQOORRREID-UHFFFAOYSA-N 1,2-dichloroethane;methanol Chemical compound OC.ClCCCl DWCNNQOORRREID-UHFFFAOYSA-N 0.000 claims 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 150000001243 acetic acids Chemical class 0.000 claims 1
- 150000005826 halohydrocarbons Chemical class 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 238000005502 peroxidation Methods 0.000 abstract description 6
- 230000008707 rearrangement Effects 0.000 abstract description 6
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 241000863480 Vinca Species 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 241001246889 Voacanga Species 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 241000208327 Apocynaceae Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229930005303 indole alkaloid Natural products 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- FDNDLNFGITWTOZ-LJQANCHMSA-N (-)-Quebrachamine Chemical group C([C@@](C1)(CC2)CC)CCN1CCC1=C2NC2=CC=CC=C12 FDNDLNFGITWTOZ-LJQANCHMSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- UBTOWVZIZOJGLD-VTEIZNGOSA-N COC(=O)C1=C2Nc3ccccc3C22CCN3C\C(=C/C)[C@@H]1C(O)[C@@H]23 Chemical compound COC(=O)C1=C2Nc3ccccc3C22CCN3C\C(=C/C)[C@@H]1C(O)[C@@H]23 UBTOWVZIZOJGLD-VTEIZNGOSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- WYJAPUKIYAZSEM-MOPGFXCFSA-N Eburnamonine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)CC(=O)N5C2=C1 WYJAPUKIYAZSEM-MOPGFXCFSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- UBTOWVZIZOJGLD-UHFFFAOYSA-N Mossambine Natural products C1CN(C2C3O)CC(=CC)C3C(C(=O)OC)=C3C12C1=CC=CC=C1N3 UBTOWVZIZOJGLD-UHFFFAOYSA-N 0.000 description 1
- 241000863486 Vinca minor Species 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- PBKVEOSEPXMKDN-LZHUFOCISA-N chembl2311030 Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)CC)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 PBKVEOSEPXMKDN-LZHUFOCISA-N 0.000 description 1
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- 239000012141 concentrate Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- OQLYVMALDCKIQD-UHFFFAOYSA-N oxo-3 vincadifformine Natural products C1C(C(=O)OC)=C2NC3=CC=CC=C3C22CCN3C(=O)CCC1(CC)C23 OQLYVMALDCKIQD-UHFFFAOYSA-N 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- VLQAFTDOIRUYSZ-LJQANCHMSA-N rhazinilam Chemical class C12=CC=CC=C2NC(=O)CC[C@]2(CC)C3=C1C=CN3CCC2 VLQAFTDOIRUYSZ-LJQANCHMSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- 229960000744 vinpocetine Drugs 0.000 description 1
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a semisynthesis process route which takes tabersonine salt as raw material for producing vincamine. Catalytic hydrogenation, peroxidation, rearrangement, crystallization and recrystallization are sequentially performed on the tabersonine salt for getting the high-purity vincamine, and the content is greater than 99.0%. Calculated according to the tabersonine salt, the overall yield of the vincamine is 55.3%. The method has the characteristics of low cost, high yield, short time, and simplicity and safety in operation, and is completely applicable to industrialized large-scale production.
Description
Technical field
The present invention relates to the synthetic of a kind of treatment cardiovascular medicament vincamine (vincamine), purifying, the intermediate Changchun Buddhist bright (vincadifformine) that is specifically related to semi-synthetic raw material tabersonine synthesizes, Buddhist bright oxynitride in intermediate Changchun is synthetic, the synthetic and industrially scalable purifying process of vincamine.
Background technology
Vincamine belongs to single indole alkaloids, has very strong physiologically active.Early stage external its hypotensive activity of research of concentrating, owing to penetrating hemato encephalic barrier, the back finds aspect vasodilation, the cerebral blood flow increasing amount good effect is being arranged, and heart, blood vessel and blood pressure etc. are not had influence.Be treatment cerebral ischemia one line medicine at present, clinical indication is applicable to cerebrovascular disorder, cerebral embolism, cerebral thrombosis and hemorrhage sequela etc.Curative effect to cerebral arteriosclerosis is stronger than hydergine and Papaverine.According to World Health Organization's statistics, the cardiovascular and cerebrovascular diseases of the recycle system is the elderly's common disease and a frequently-occurring disease, and wherein cerebral ischemia death accounts for about 80% of cerebrovascular disease death.So the research and development for the treatment of brain ischemia medicament both at home and abroad are one of focuses always.The producer that vincamine, Vinpocetine oral tablet and injection are produced in the domestic registration of China reaches more than 30 families.But, because the domestic manufacturer that does not have vincamine, vinpocetin raw material of China, so all raw material relies on import.In the international market, the big manufacturer of vincamine, vinpocetin is Spain CONVEX company and Switzerland medicine company SIWSS PHARM. company.The annual production of this two family is about 50 tons, and gross sales (GS) reaches 300,000,000 dollars.
Vincamine at present mainly from apocynaceae plant periwinkle (Vinca minor) extraction separation obtain, but the content of vincamine only is 0.7 ‰ in the periwinkle, and main resource distribution is in Europe, (Wang Yongjian. the extraction separation purifying and the qualitative and quantitative analysis of vincamine in the periwinkle. Northwest University's master thesis, 200621079. it is yellow kind fixed, Huang Liying, Zhou Yunli. alkaloidal separation and evaluation in the periwinkle. herbal medicine, 29 (10): 658-659. what beautiful one, Zhou Jinyun, side's departure. vincamine Determination on content method research in the periwinkle. Acta Pharmaceutica Sinica, 1983,18 (12): 926-928), this method production cost is very high.And from the fifties in last century so far, Europe and many scientists of the U.S. are devoted to study synthesizing of vincamine, main route has 3:
(1) first synthetic intermediate tabersonine, again by reduction, peroxidation, rearrangement obtains vincamine (Janos Eles, Gyorgy Kalaus, IstvanGreiner, et al., ASynthesis of Vinca Alkaloids and Related Compounds.100.Stereoselective Oxidation Reactionsof Compounds with the idospermane and Quebrachamine Ring System.First Synthesis of Some AlkaloidsContaining the Epoxy Ring.J.Org.Chem.2002,67:7255-7260.Christophe Dupont, Daniel Guenard, LubaTchertanov, et al., D-Ring Substituted Rhazinilam Analogues:Semisynthesis and Evaluation of AntitubulinActivity.Bioorganic﹠amp; Medicinal Chemistry, 1999,7:2961-2969.Martin E.Kuehne, Upul K.Bandarage, Abdelhakim Hammach, et al., Application of Ferrocenylalkyl Chiral Auxiliaries to Syntheses of IndolenineAlkaloids:Enantioselective Syntheses of Vincadifformine, α-and 20-epi-α-Vincadifformines, Tabersonine, Ibophyllidine, and Mossambine.J.Org.Chem.1998,63,2172-2183.et al.).
(2) first synthetic intermediate Changchun Buddhist is bright, both got vincamine (Martin E.Kuehne through peroxidation and rearrangement again, Tiansheng Wang, andPamela J.Seaton.Total Syntheses of Vincadifformine, 3-Oxovincadifformine, Pseudo-and20-epi-Pseudovincadifformine, Tabersonine, and 18-Tabersonine through Radical Reactions and Heck Reactions.J.Org.Chem., 1996,61 (17), 6001-6008.James P.Kutney, Ka Kong.Chan, Amedeo.Failli, et al., Total synthesisof some monomeric Vinca alkaloids:dl-vincadine, dl-vincaminoreine, dl-vincaminorine, dl-vincadifformine, dl-minovine, and dl-vincaminoridine.J.Am.Chem.Soc., 1968,90 (14), 3891-3893.Martin E.Kuehne, BurlintonVt.Vincadifformine synthesis progcess.USP.4220774.et al.).
(3) be the complete synthesis (J.L.Herrmann of raw material directly with indoles parent nucleus derivative, R.J.Cregge, J.E.Richman, Total synthesis ofthe indole alkaloids dl-eburnamonine and dl-vincamine.J.Am.Chem.Soc., 1979,101 (6), 1540-1544.Martin E.Kuehne, The Total Synthesis of Vincamine.J.Am.Chem.Soc., 1964,86 (14), 2946-2946.Guy Rossey, AlexanderWick, Ernest Wenkert.Synthesis of vincamine.J.Org.Chem., 1982,47 (24), 4745-4749.Mauri Lounasmaa, ArtoTolvanen.A new synthesis of (.+-.)-vincamine via Oppolzer ' s aldehyde.J.Org.Chem., 1990,55 (13), 4044-4047.et al.).
About vincamine synthetic document utilization CA search, nearly more than 200 pieces, not following 10 of wherein complete synthesis route, the domestic report that does not have new synthetic method.And the overall yield of these methods all is no more than 10%, and cost is too high, can not realize suitability for industrialized production.In sum, the method for producing at present both at home and abroad vincamine exists following problems: chemical Atom economy is low, and overall yield is less than 10%, the chemical waste that produces will cause very big burden to environment; Productive rate is not high, will cause cost higher, and it is big that manufacturing enterprise bears operational risk; All synthetic routes are all above 10 steps, and all to production unit requirement height, making manufacturing enterprise drop into fixed cost increases.
The different characteristics part of the present invention and aforesaid method is: (1) is raw material with tabersonine salt directly, this raw material extracts from African apocynaceae plant seed Voacanga (Voacanga africana seed) and obtains, the Voacanga aboundresources in Africa, connect this seed every year one, can keep biological Sustainable development.And the content of tabersonine is about about 2%, so the tabersonine cost controllability that obtains is strong in the Voacanga.(2) from tabersonine with new reduction, peroxidation and rearrangement, obtain the vincamine of high yield 50% (in tabersonine).(3) it is simple respectively to go on foot conversion unit, and controllability is strong, chemical reagent utilization ratio height, and organic solvent can all be recycled.(4) crucial purification step is succinct, and big production unit is simple to operate, and industrialization production feasibility is strong.More than be the route of good suitability for industrialized production from economy, environment and Occupational health angle.
Summary of the invention
The key problem that the present invention need solve is the shortcoming that overcomes existing vincamine synthetic technology, sets up environmental friendliness, low cost, the succinct industrialization process route from the semi-synthetic vincamine of tabersonine.And the vincamine of large-scale commercial production reaches the requirement of Europe, the U.S., Japan and Chinese Pharmacopoeia.
Purpose of the present invention is achieved through the following technical solutions (synthetic route is seen Fig. 1):
The semi-synthetic route of Fig. 1 vincamine
The semi-synthesizing technology route of vincamine (structural formula 1) is to be raw material with tabersonine salt (structural formula 2), through catalytic hydrogenation, peroxidation, rearrangement and crystallization recrystallization.Concrete steps are as follows:
1, with 40%-100% methyl alcohol or 50%-95% dissolve with ethanol raw material tabersonine salt, at heterogeneous catalyst Raney nickel, PdCO
3, Pd-CaCO
3Or homogeneous catalyst chlorine three (triphenyl phosphine) closes rhodium, chlorine three (triphenyl phosphine) and closes rubidium etc. and be catalyzer, under 1-3atm, and the hydrogenation room temperature reaction.And detect with thin layer and to track to the raw material tabersonine and react completely, about 4h obtains Changchun Buddhist bright (structural formula 3).
2, the Buddhist bright anhydrous organic solvent that is dissolved in Changchun is comprised 1,3-dioxane, 1,4-dioxane, chloroform, methylene dichloride, ethylene dichloride etc.Temperature control keeps 0～10 ℃ to add peroxy acid again, comprises tert-butyl peroxy acid, Peracetic Acid, trifluoro Peracetic Acid, peroxyformic acid, metachloroperbenzoic acid, a fluorine benzoyl hydroperoxide, a bromine benzoyl hydroperoxide etc.In room temperature reaction 16-24h, add 5% weak caustic solution such as Na
2CO
3, NaHCO
3, K
2CO
3Deng the acid of removing the sharp generation of unnecessary peroxy acid.Tell organic phase, again with organic solvent extraction twice, merge organic phase, spend the night with anhydrous sodium sulphate or dried over mgso, concentrating under reduced pressure gets 1, the 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-bright oxynitride of Changchun Buddhist (structural formula 4).
3,1, the bright oxynitride of 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-Changchun Buddhist adds organic acid (comprise in glacial acetic acid, formic acid, propionic acid or halo glacial acetic acid, the halopropanoic acid a kind of), and temperature control-5～0 ℃ adds triphenyl phosphorus again, slowly is warming up to backflow.Behind the backflow 2h, be chilled to room temperature, add the frozen water of equivalent, with ethylene dichloride flush away triphenyl phosphorus oxide compound.Water is transferred pH to 8-9 with 1%NaOH again, with the dichloromethane extraction secondary, merges organic phase and is concentrated into certain volume, adds decolorizing with activated carbon, filters.Mother liquor adds a certain amount of methanol crystallization, gets vincamine (structural formula 1) crude product.Crude product gets the vincamine elaboration again with ethylene dichloride and methanol system recrystallization, and purity is greater than 99.0%.
The invention provides the high efficiency method of semi-synthetic vincamine, obtain semi-synthetic raw material, obtain vincamine through reduction, peroxidation and rearrangement again with natural renewable resources extraction separation.Present method has atom economy type, simple, the production sequence environmental protection of equipment, and very large economic and social benefit is arranged.
Embodiment:
Further illustrate the present invention in the following embodiments, this does not limit the scope of the invention.
Synthesizing of embodiment 1 Changchun Buddhist bright (3)
Take by weighing hydrochloric acid tabersonine (2) 5.0kg in the 100L stainless steel cauldron, add 75% ethanol 50L, the stirring at room dissolving.Add 250gRaney nickel then, feed hydrogen immediately, stir behind the 0.5h, and control hydrogen pressure 1.1atm, reaction 8h.Reaction is finished, and feeds nitrogen 10min, removes by filter catalyzer, concentrate the bright thick product of Changchun Buddhist, get purity greater than 99.0% the bright 4.8kg of hydrochloric acid Changchun Buddhist, productive rate 96% with the ethyl acetate-ethanol crystallization.
Embodiment 21,2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-bright oxynitride of Changchun Buddhist (4) synthetic
Get the hydrochloric acid Changchun bright 5.0kg of Buddhist and place the 100L stainless steel cauldron, add 1,3-dioxane 50L, stirring at room dissolving.Charge into nitrogen protection, the about 16h of lucifuge room temperature reaction.TLC detection reaction process disappears to intermediate (3) is basic, generates intermediate (4).In reaction solution, add 5%NaHCO
3Solution does not produce to there being bubble, removes the acid of unnecessary peroxy acid and generation.Tell organic phase, so that 20L ethylene dichloride extracting twice to be arranged, merge organic phase again, with anhydrous sodium sulphate 500g dried overnight, concentrating under reduced pressure gets 1, and the 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-bright oxynitride of Changchun Buddhist (structural formula 4) crude product is oily mater.Obtain intermediate (4) 4.0kg, productive rate 80% with methylene dichloride-acetone crystallization again.
Synthesizing of embodiment 3 vincamines (1)
Get 1,2-dehydrogenation-16-methoxycarbonyl-bright oxynitride 5.0kg of 16-hydroxyl-Changchun Buddhist places the 100L stainless steel cauldron, adds trichoroacetic acid(TCA) 60L, and the about 0 ℃ of stirring and dissolving of temperature control adds triphenyl phosphorus 3.0kg, the about 3h of back flow reaction again.TLC detection reaction process disappears to intermediate (4) is basic.Cool off reaction solution, add the frozen water of equivalent again, with ethylene dichloride flush away triphenyl phosphorus oxide compound.Water is transferred pH to 8-9 with 1%NaOH again, with the dichloromethane extraction secondary, merges organic phase and is concentrated into the 20L volume, adds decolorizing with activated carbon 30min.Filter organic phase, with anhydrous sodium sulphate 500g dried overnight, mother liquor adds a certain amount of methanol crystallization, vincamine (structural formula 1) crude product.Crude product gets the pure product 3.6kg of vincamine again with ethylene dichloride and methanol system recrystallization, productive rate 72%, and purity is greater than 99.0%.
Claims (12)
1. one kind prepares vincamine intermediate-bright method of Changchun Buddhist, and it is characterized by tabersonine hydrochloride or vitriol is raw material.
2. require described method according to right 1, it is characterized by with 40%-100% methyl alcohol or 10-20 times of mass volume ratio dissolving raw material of 50%-95% ethanol tabersonine salt.
3. require described method according to right 1, it is characterized in that heterogeneous catalyst Raney nickel, diatomite nickel, nickel borides, PdCO
3, Pd-CaCO
3, Pd-C or homogeneous catalyst chlorine three (triphenyl phosphine) closes rhodium, chlorine three (triphenyl phosphine) closes hydrogenating reductions such as rubidium, consumption is the 1/10-1/100 of tabersonine quality.
4. one kind prepares vincamine intermediate-1, the method of 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-bright oxynitride of Changchun Buddhist, it is characterized by in 1,3-dioxane, 1, oxygen heterocyclic ring such as 4-dioxane, chloroform, methylene dichloride, ethylene dichloride or halohydrocarbon are that dissolution with solvents Changchun Buddhist is bright, and consumption is a 10-30 times of mass volume ratio.
5. require described method according to right 4, it is characterized in that adding peroxy acid, comprise tert-butyl peroxy acid, Peracetic Acid, trifluoro Peracetic Acid, peroxyformic acid, metachloroperbenzoic acid, a fluorine benzoyl hydroperoxide, a bromine benzoyl hydroperoxide etc., consumption is 3-5 a times of vincadifformine quality.
6. require described method according to right 5, its feature is when adding peroxy acid, and system temperature is controlled in below 0～10 ℃.
7. method for preparing vincamine, it is characterized in that with organic acid, comprise that glacial acetic acid, formic acid, propionic acid or halogenated acetic acids, halopropanoic acid etc. are dissolution with solvents 1, the 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-bright oxynitride of Changchun Buddhist, consumption is a 10-30 times of mass volume ratio.
8. require described method according to right 7, its feature is with the triphenyl phosphorus reaction promoter, and consumption is 1, the 50%-90% of 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-vincadifformine nitrogen oxide mass.
9. require described method according to right 7, it is characterized in that the temperature that adds triphenyl phosphorus should be controlled in below-5～0 ℃, then the about 3h of back flow reaction.
10. require described method according to right 1, it is characterized in that with the ethyl acetate-ethanol system being solvent crystallization purifying vincadifformine.
11. require described method, it is characterized in that with methylene dichloride-acetone-inso be solvent crystallization purifying 1, the 2-dehydrogenation-16-methoxycarbonyl-16-hydroxyl-bright oxynitride of Changchun Buddhist according to right 4.
12. require described method according to right 7, it is characterized in that ethylene dichloride-methanol system is a solvent crystallization purifying vincamine.
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| CN103232452A (en) * | 2013-05-14 | 2013-08-07 | 彭学东 | Industrialized semi-synthesis process of vincamine |
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| CN102276599A (en) * | 2011-08-18 | 2011-12-14 | 张家口市格瑞高新技术有限公司 | Process for preparing vincamine by semisynthetic method |
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| CN103664941A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Preparation method of vinpocetine analogue |
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| CN112679493B (en) * | 2020-12-29 | 2021-12-14 | 张家港威胜生物医药有限公司 | Preparation method of vincamine |
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