CN1070647A - Preparation has the method for optically active false bufotoxin amidoalcohol - Google Patents
Preparation has the method for optically active false bufotoxin amidoalcohol Download PDFInfo
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- CN1070647A CN1070647A CN 92108585 CN92108585A CN1070647A CN 1070647 A CN1070647 A CN 1070647A CN 92108585 CN92108585 CN 92108585 CN 92108585 A CN92108585 A CN 92108585A CN 1070647 A CN1070647 A CN 1070647A
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- bufotoxin
- amidoalcohol
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- HDTHCLKLBSPBIS-JBXNKDOXSA-N (2s)-2-[[8-[[(3s,5r,8r,9s,10s,13r,14s,16s,17r)-16-acetyloxy-14-hydroxy-10,13-dimethyl-17-(6-oxopyran-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-8-oxooctanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C=1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@@H](C[C@H]5CC[C@H]4[C@@]3(O)C[C@@H]2OC(=O)C)OC(=O)CCCCCCC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C=CC(=O)OC=1 HDTHCLKLBSPBIS-JBXNKDOXSA-N 0.000 title claims abstract description 35
- HDTHCLKLBSPBIS-UHFFFAOYSA-N Bufotoxin Natural products CC(=O)OC1CC2(O)C3CCC4CC(OC(=O)CCCCCCC(=O)NC(CCCN=C(N)N)C(O)=O)CCC4(C)C3CCC2(C)C1C=1C=CC(=O)OC=1 HDTHCLKLBSPBIS-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 230000002829 reductive effect Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000013375 chromatographic separation Methods 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- -1 bromomethyl crotonate Chemical compound 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical compound NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- FCQRLHQHKFKTQE-HCTDMSSWSA-N (4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-acetyloxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C([C@H]1CC2)[C@H](OC(C)=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 FCQRLHQHKFKTQE-HCTDMSSWSA-N 0.000 claims 1
- 239000002168 alkylating agent Substances 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- BTFSVBAFIHSVBO-UHFFFAOYSA-N dichloromethane;1,4-dioxane Chemical compound ClCCl.C1COCCO1 BTFSVBAFIHSVBO-UHFFFAOYSA-N 0.000 claims 1
- 229950010911 orazamide Drugs 0.000 claims 1
- 239000013067 intermediate product Substances 0.000 abstract description 3
- ORPXSJHNYUTKGM-UHFFFAOYSA-N Pseudophrynaminol Natural products CN1CCC2(CC=C(/C)CO)C1N(C)c3ccccc23 ORPXSJHNYUTKGM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007787 solid Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
- UIERETOOQGIECD-ARJAWSKDSA-M 2-Methyl-2-butenoic acid Natural products C\C=C(\C)C([O-])=O UIERETOOQGIECD-ARJAWSKDSA-M 0.000 description 3
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 3
- 101150065749 Churc1 gene Proteins 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 3
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 3
- 238000006257 total synthesis reaction Methods 0.000 description 3
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 241000269476 Crinia georgiana Species 0.000 description 2
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 2
- 229960001697 physostigmine Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- APLHEOBEIBHCHW-YQEJDHNASA-N Selagine Natural products O=C1NC2=C([C@]3(N)/C(=C/C)/[C@@H](CC(C)=C3)C2)C=C1 APLHEOBEIBHCHW-YQEJDHNASA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- ZRJBHWIHUMBLCN-UHFFFAOYSA-N Shuangyiping Natural products N1C(=O)C=CC2=C1CC1C(=CC)C2(N)CC(C)=C1 ZRJBHWIHUMBLCN-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- NWEKXBVHVALDOL-UHFFFAOYSA-N butylazanium;hydroxide Chemical compound [OH-].CCCC[NH3+] NWEKXBVHVALDOL-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- ZRJBHWIHUMBLCN-YQEJDHNASA-N huperzine A Chemical compound N1C(=O)C=CC2=C1C[C@H]1\C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-YQEJDHNASA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- ZRJBHWIHUMBLCN-BMIGLBTASA-N rac-huperzine A Natural products N1C(=O)C=CC2=C1C[C@@H]1C(=CC)[C@@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-BMIGLBTASA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to prepare first method with optically active false bufotoxin amidoalcohol (pseudophry-naminol).It is characterized in that on the 2-oxyindole that replaces, introducing multi-functional group (multi-rolegroup earlier, MRG), carry out selectively alkylated reaction of solid then, obtain having optically active intermediate product, again it is reduced, made and have optically active false bufotoxin amidoalcohol.Adopt method of the present invention can make left-handed and dextral false bufotoxin amidoalcohol and analogue or derivative respectively.Have the reaction conditions gentleness, reaction path is short, advantage such as is easy to synthesize.
Description
The present invention relates to the preparation method of false bufotoxin amidoalcohol (pseudophrynaminol), particularly relate to total synthesis method with optically active false bufotoxin amidoalcohol.
False bufotoxin amidoalcohol is a kind of new alkaloid with following molecular formula, and it can be separated from Australian frog skin (Pseudpohryne coriacea):
Though this alkaloidal biological activity is not clear fully as yet, it should be noted that its absolute configuration is consistent with Physostigmine.Show with computer molecular image simulation comparative studies, false bufotoxin amidoalcohol and vagusstoff selagine, Physostigmine etc. have good friendship lid property, thereby have the effect of potential anti-acetylcholinesterase, be expected to become the new drug of treatment senile dementia and myasthenia gravis and memory.Because this alkaloidal purposes is extensive day by day, so isolated natural false bufotoxin amidoalcohol far can not satisfy the needs of research and development, clinical trial from Australian frog skin.In recent years, American-European, each state of Japan is all in the total synthesis method of being engaged in this Alkaloid of development research and clinical application thereof, Miguel O.Mitchell etc. disclose the total synthesis method of false bufotoxin amidoalcohol first on Tetrahedron Letters the 31st No. 19 2681-2684 page or leaf of volume (1990), Pier Giorgio Cozzi etc. are at No. 39 5661-5664(1990 of Telrahedron Letters the 31st volume) set forth the another kind of synthetic method of false bufotoxin amidoalcohol on the page or leaf, but adopt the prepared false bufotoxin amidoalcohol of these methods to be racemic form, and synthetic route is long, investigators have found that, many materials are different in the biological activity of levo form and dextrorotatory form, so the false bufotoxin amidoalcohol with the racemic form that is synthesized (mixture of dextrorotatory form and dextrorotatory form) is studied, can not make definite definition to its biological activity veritably, also be unfavorable for application clinically in future.So be badly in need of providing method that a kind of preparation has optically active false bufotoxin amidoalcohol to satisfy the demand of research and development, this preparation method also should have route of synthesis and lacks simultaneously, is easy to the synthetic advantage.
An object of the present invention is to provide the short preparation of a kind of route of synthesis and have the method for optically active false bufotoxin amidoalcohol.
Through long-term concentrated research, the present inventor has been developed a kind of new asymmetric synthesis technology, promptly introduces in synthetic
Be called " multi-functional " group (multi-role group MRG), as
, make alkylated reaction then have selectivity, to reach the purpose of asymmetric synthesis; Can be used as blocking group protection NH in addition, also can increase the solvability of intermediate product in solvent and the stability of intermediate product; This multi-functional group has the indication group that also can be used as definite diastereomer ratio in optically active false bufotoxin amidoalcohol simultaneously synthetic, and as the fractionation group that splits enantiomer.
The cis false bufotoxin amidoalcohol has following two kinds of left-handed and dextral optical isomers.
Approach according to reaction process I of the present invention can easily make two kinds of above-mentioned false toadpoison amine
The reaction process I
In the formula: the solid line (-) of usefulness is meant the substituting group that is positioned at the paper plane top, dotted line (...) be meant the substituting group that is positioned at low degree below;
R
1Be C
1-C
10Alkyl
-R
*Can be optional chiral carbon group, comparatively preferably
R can be alkyl, benzyl, alkene benzyl or formula
The group of expression;
X represents chlorine, bromine, iodine.
According to method provided by the present invention, the 2-oxyindole that compound 3(is replaced) and N-(S) (-) thereby-reagent 4 of the Orazamide class that 1-replaces reacts in the presence of alkali reagent or when not having alkali reagent and makes carbamide compounds 5.
Preferred alkali reagent can be LiOH, NaOH, KOH, Na
2CO
3, NaHCO
3, K
2CO
3, sodium methylate, EtONa, sodium hydride, lithium, sodium, potassium hydride KH, n-Butyl Lithium, LDA, lithium hydride, wherein sodium hydride is particularly preferred.
This reaction can-40 ℃ to the solvent refluxing temperature in such as normal hexane, anhydrous diethyl ether, hexanaphthene, dehydrated alcohol, anhydrous methanol, methylene dichloride, carried out in the organic solvent of tetracol phenixin tetrahydrofuran (THF) or dioxane about five minutes to 48 hours.
Then, the alkylating reagent with RX makes carbamide compounds 5 carry out alkylated reaction.
This alkylated reaction can be in room temperature--under 78 ℃ the temperature, in the presence of the phase-transfer catalyst of routine or aforementioned bases reagent, stirred 10 minutes to 48 hours or they mixture and make optionally that alkylated reaction is complete, have optically active compound 6 and 7 thereby made.
At last, in the presence of organic solvent, make compound 6 and 7 reduction.The reductive agent that is adopted can be Lithium Aluminium Hydride, H
2/ catalyzer, (H)/palladium-carbon, Platinic chloride/H
2
Described organic solvent can be solvent commonly used, even more preferably ether, tetrahydrofuran (THF) or dioxane.
This reduction reaction was carried out 3-6 hour.
When needing, come separating compound 6 and 7 to reach (+) and (-) false bufotoxin amidoalcohol with quick silica gel column chromatography.
For with quick silica gel column chromatography separating compound 6 and 7, adoptable elutriant is the elutriant of dichloromethane/ethyl acetate, methylene dichloride/ether and so on, and its ratio is about 98: 2-80: 20, and also available n-hexane/ethyl acetate about 70: 30-30: 70.
For with quick silica gel column chromatography chromatographic separation (+) and (-)-false bufotoxin amidoalcohol, can select for use methylene chloride as elutriant, its methylene dichloride: the ratio of methyl alcohol can be 1: 1-9: 1, also can at random add triethylamine.
Below, we will do further detailed elaboration to method of the present invention in conjunction with most preferred embodiment.
Preparation embodiment 1
The 2-oxyindole (compound 3) that preparation replaces
Under 0 ℃ to tryptamines (commercially available, 30g, 0.1875mol) and NaOH solution (3M, 187ml, 0.561mol) at the 200ml acetonitrile (through P
2O
5Drying) adds methyl-chloroformate (ethyl ester, propyl ester, butyl ester gradually in the solution in ... nonyl, decyl) (28.8ml, 0.3762 mole) solution in acetonitrile (174ml).Allow solution stirring 40 minutes, be added dropwise to hydrochloric acid (50% 110ml) and isolate the acetonitrile phase, use CH
2Cl
2Anhydrous Na is used in extraction
2SO
4Drying boils off solvent, uses ethanol: methylene dichloride: hexane=recrystallization obtained in 2: 1: 1
Under 0 ℃ and agitation condition, under 0 ℃ to ⅰ) add concentrated hydrochloric acid (93ml, 10 equivalents) in the solution of product (12 grams, 1 equivalent) in methyl-sulphoxide (40ml, 10 equivalents) that makes in the step.After reinforced the finishing, mixture stirred 20 minutes at ambient temperature.Also (8 * 200ml) extractions merge organic phase to the mixture dilute with water, and Na is used in water and salt water washing with ethyl acetate
2SO
4Drying is removed the title compound 3 that desolvates and obtain oily matter.
1HNMR（200MHz，CDCl
3）ppm
8.30（s，1H），7.20-7.40（m，2M），7.10（t，1H），6.90（d，1M），5.25（1b，1H），3.68（s，3H），3.30-3.60（m，3H），2.00-2.33（m，2M）。
Total yield 80%
Preparation embodiment 2
Preparation N-S-(-)-1-styroyl imidazoles-1-methane amide
With 1 equivalent 1,1 '-the diimidazole ketone is dissolved in the tetrahydrofuran (THF), add 1 equivalent S-(-)-the 1-phenylethylamine, at room temperature stirred 20 minutes, extract 4 times with methylene dichloride (50ml * 4), use anhydrous sodium sulfate drying again, boil off solvent, (elutriant is an ethyl acetate to residue: the title compound that methylene dichloride 95: 5) obtains colourless oily matter through the rapid column chromatography wash-out.
Yield: 95%
Preparation embodiment 3
Preparation bromomethyl crotonate
ⅰ) tiglic acid (tiglic acid) methylates
Make tiglic acid solution (60g, 0.6mol), methyl alcohol (85ml, excessive) and the vitriol oil (12ml) refluxed 7 hours, with the ether extraction several times, is washed till pH=10 with saturated sodium bicarbonate, uses anhydrous Na
2SO
4Drying, removing desolvates obtains 50.5g
Product.
Yield: 80%
(E) bromination of 2-methyl but-2-ene acid methyl esters
Make step ⅰ) product (50.5g, 0.443mol) and NBS(90g) solution in tetracol phenixin (300ml) refluxed 4 hours, then as in the refrigerator, the elimination precipitation, solvent in the pressure reducing and steaming filtrate makes the oily residue distill the title product (60g) that obtains light yellow liquid under 110-112 ℃ of (16mmHg) condition.
Yield 76%
Embodiment 1
The compound 3 2-oxyindoles (compound 3) (1 equivalent) of getting the replacement of 298 milligrams of preparation embodiment 1 synthetic are dissolved in the 8ml anhydrous tetrahydro furan, 60% sodium hydride (1.1 equivalent) that adds 56 milligrams, tetrahydrofuran (THF) (5ml) solution that adds 293 milligrams of preparation embodiment 2 synthetic compounds (1.07 equivalent) again, after 10 minutes, add water, extract four times (50 * 4ml) with anhydrous methylene chloride, use anhydrous sodium sulfate drying, boil off solvent, obtain title compound with rapid column chromatography purification (elutriant is dichloromethane/ethyl acetate 9: 1).
Yield 96%
1HNMR(CDCl
3, 200MHz) spectrum
ppm 1.60（d，3H，CHCH
a），2.02-2.41（m，2H，CH
2CH
2N），3.27-3.54（m，2H，CH
2N），3.61（s，1H），3.69（s，3H，OCH
3），4.83（b，1H，NH）CO
2CH
3），5.08-5.24（m，1H，NCHCH
3），7.13-7.40（m，7H），8.25（d，1H），9.01（d，1H）.
Synthetic
The 1 equivalent compound that above-mentioned a) step makes is put into flask, add 100ml toluene, make solution reach 0.1 volumetric molar concentration, add the 40%1.5 normal 4-n-butyl ammonium hydroxide aqueous solution in room temperature, stir after 10 minutes, add the compound (bromomethyl crotonate) that 2 equivalents preparation embodiment 3 makes, behind the stirring reaction 2 hours, thin layer chromatography analysis shows to react to be finished, add the washing of neutral buffered solution, use dichloromethane extraction four times, use anhydrous magnesium sulfate drying then, boil off solvent, obtain the title compound of colorless oil.Separating the title compound that title compound that (with 9: 1 wash-outs of dichloromethane/ethyl acetate) obtain (-) respectively reaches (+) with quick silica gel column chromatography, is 100% in total product, levorotatory form account for 53%, dextrorotatory form accounts for 47%, yield 98%.
The specific optical rotation of (-)-compound (α)
26 D=-20.8(C=0.91, chloroform)
1HNMR(CDCl
3, 200MHz) spectrum
ppm 1.61（d，3H，CHCH
3），1.73（s，3H，C＝CCH
3），2.04-2.45（m，2H，CH
2CH
2N），2.68（d，2H，CH
2CH＝C），2.72-3.05（m，2H，CH
2N），3.61（s，3H，CO
2CH
3），3.65（s，3H，NCO
2CH
2），4.50（tb，1H，NHCO
2CH
3），5.12（m，1H，NCHCH
3），6.44（t，1H，HC＝C），7.13-7.42（m，7H），8.25（d，1H），9.0（d，1H），
The specific optical rotation of (+)-compound (α)
26 D=+28.1(C=0.97 chloroform)
1HNMR(CDCl
3, 200MHz) spectrum
ppm 1.61（d，3H，CHCH
3），1.77（s，3H，C＝CCH
3），2.02-2.44（m，2H，CH
2CH
2N），2.70（d，2H，CH
2CH＝C），2.75-3.06（m，2H，CH
2N），3.46（s，3H，CO
2CH
3），3.70（s，3H，NCO
2CH
3），4.43（tb，1H，NHCO
2CH
3），5.13（m，1H，NCHCH
3），6.50（t，1H，HC＝C），7.19-7.43（m，7H），8.25（d，1H），9.0（d，1H）.
C) false bufotoxin amidoalcohol of preparation (-) and (+)
ⅰ) with b) 1mol(-that makes of step)-add in the dioxane solution in the compound, add the 5mol Lithium Aluminium Hydride then, reflux 4 hours, add water, remove by filter insolubles except that desolvating, obtain (-)-false bufotoxin amidoalcohol, the little yellow solid of color through quick silica gel column chromatography purification (elutriant is methylene chloride 2: 1).
Yield: 76%
Specific optical rotation (α)
29 D=-82.8(C=0.98CHCl
3)
Spectroscopic data is consistent with the natural product of (-).
ⅱ) except using b) 1mol-(+ that makes of step)-compound replaces (-)-compound in the step (ⅰ), and the operation of other repeating step (ⅰ) obtains (+)-false bufotoxin amidoalcohol.
Yield: 76%
Specific optical rotation (α)
29 D=+82.1(C=1.23, chloroform)
Other spectroscopic data is consistent with natural (+)-false bufotoxin amidoalcohol.
Embodiment 2
A) to 4ml replace-oxyindole compound 3(199mg, 1 equivalent) dioxane solution in add 43mg60% potassium hydride KH (1 equivalent).And add the dioxane solution of 5ml preparation embodiment 2 synthetic compounds (196mg, 1.07 equivalents), after 10 minutes, add water, with dichloromethane extraction four times (30 * 4ml), use anhydrous MgSO
4Drying boils off solvent and obtains embodiment 1(a) the prepared compound of step.
B) with 1 normal above-mentioned steps a) prepared compound be dissolved in an amount of sodium methylate (1.1 equivalent)/methanol solution, make concentration reach 0.1M, mixture is placed ice bath, add 2 equivalents preparation embodiment, 3 prepared 2 equivalent bromomethyl crotonates when being chilled to zero degree, reacted 40 minutes down at 0 ℃, obtain embodiment 1b) title product, use embodiment 1b) described quick silica gel column chromatography chromatographic separation obtains 75.5% left-handed product and 24.5% dextrorotation product.
Yield: 54%
C) except replacing embodiment 1(c as reductive agent with (Platinic chloride (H)) under the room temperature) in Lithium Aluminium Hydride, other and method c) thus consistent (+)-false bufotoxin amidoalcohol and (-)-false bufotoxin amidoalcohol of having obtained.
Embodiment 3
A) except replacing embodiment 1a as alkaline reagents with lithium hydride) in the used sodium hydride, other all with embodiment 1a) step identical, thereby made embodiment 1a) title compound.
B) aqueous sodium hydroxide solution with 5 normal a) gained compounds places ethanol to add the dry ice bath, add 0.1 equivalent N-(4-trifluoromethyl benzyl) cinchonine bromide (N-(4-trifluoromethylbenzyl) bromide)-40 ℃ of reactions 40 minutes down, again through embodiment 1(b) described in quick silica gel column chromatography chromatographic separation, obtain b) levorotatory form of title compound and dextrorotatory form respectively be 50% product.
Yield: 90%
C) step repetition embodiment 1c), thus made (+)-false bufotoxin amidoalcohol and (-)-false bufotoxin amidoalcohol.
The present invention has adopted and the synthetic distinct route of synthesis of false bufotoxin amidoalcohol of prior art, has optically active this class material thereby synthesized first; Outstanding features such as in addition, preparation method of the present invention also has the reaction conditions gentleness, and route of synthesis is short.
Method of the present invention has optically active false bufotoxin amidoalcohol except preparing, and also can be used to prepare its analogue, derivative.
Claims (10)
1, a kind ofly prepare following method with optical false bufotoxin amidoalcohol:
It is characterized in that this method comprises:
A) Orazamide of the 2-oxyindole of formula 3 replacements and the N-S-(-) of formula 4-1-replacement is reacted:
R wherein
1Be C
1-C
10Alkyl, R
*Be the chiral carbon group, reaction can obtain the product of formula 5;
B) make formula 5 compounds and alkylating reagent RX (wherein R represent alkyl, benzyl and or
The group of representative, X represents chlorine, bromine, iodine) reaction, make following formula 6 and 7 compounds:
C) make the reduction of formula 6 and formula 7 compounds can make (-)-false bufotoxin amidoalcohol and (+)-false bufotoxin amidoalcohol respectively.
2, method according to claim 1 is characterized in that wherein step (a) is carried out in the presence of alkali reagent, alkali reagent is sodium hydride, metallic lithium, sodium Metal 99.5, potassium hydride KH, lithium hydride, LOA, n-Butyl Lithium, LiOH, NaOH, KOH, Na
2CO
3, K
2CO
3, sodium methylate, EtONa.
3, according to the method for claim 2, it is characterized in that step a) is reflected in the organic solvent carries out.
4, method according to claim 1 is characterized in that wherein step (b) is carried out in the presence of solvent and phase-transfer catalyst or alkali reagent.
5, method according to claim 4, it is characterized in that in the step (b) temperature of reaction further for-78 ℃ to room temperature.
6, method according to claim 1, the reduction reaction that it is characterized in that step (c) is under the organic solvent reflux temperature, with reductive agent reducing compound 6 and 7.
7, method according to claim 6 is characterized in that described solvent is a tetrahydrofuran (THF), ether, dioxane methylene dichloride, benzene or toluene.
8,, it is characterized in that wherein said reductive agent is a Lithium Aluminium Hydride according to claim 6 or 7 described methods.
9, method according to claim 1 is characterized in that further comprising in this method:
B ') makes compound 6 and 7 after the silica gel column chromatography chromatographic separation, restore, obtain respectively (-)-false bufotoxin amidoalcohol and (+)-false bufotoxin amidoalcohol.
10, method according to claim 1 is characterized in that the alkylating agent in the step (b) wherein is the bromomethyl crotonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92108585 CN1070647A (en) | 1992-09-30 | 1992-09-30 | Preparation has the method for optically active false bufotoxin amidoalcohol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92108585 CN1070647A (en) | 1992-09-30 | 1992-09-30 | Preparation has the method for optically active false bufotoxin amidoalcohol |
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| Publication Number | Publication Date |
|---|---|
| CN1070647A true CN1070647A (en) | 1993-04-07 |
Family
ID=4943680
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|---|---|---|---|
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| Country | Link |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278866A (en) * | 2016-07-21 | 2017-01-04 | 邯郸学院 | A kind of 2 alkyl replace .beta.-methylacrylic acid and the synthetic method of ester thereof |
| CN110698384A (en) * | 2019-11-05 | 2020-01-17 | 上海健康医学院 | 3-substituted 3-aryl (alkyl) group-3- (1-phenyl vinyl) indolone and preparation method thereof |
| CN113717092A (en) * | 2021-10-11 | 2021-11-30 | 美罗药业股份有限公司 | Preparation method of trifluoromethyl-containing 3-substituted-2-indolinone compound |
-
1992
- 1992-09-30 CN CN 92108585 patent/CN1070647A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106278866A (en) * | 2016-07-21 | 2017-01-04 | 邯郸学院 | A kind of 2 alkyl replace .beta.-methylacrylic acid and the synthetic method of ester thereof |
| CN110698384A (en) * | 2019-11-05 | 2020-01-17 | 上海健康医学院 | 3-substituted 3-aryl (alkyl) group-3- (1-phenyl vinyl) indolone and preparation method thereof |
| CN113717092A (en) * | 2021-10-11 | 2021-11-30 | 美罗药业股份有限公司 | Preparation method of trifluoromethyl-containing 3-substituted-2-indolinone compound |
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