CN1235607A - 由毒扁豆醚制备毒扁豆碱氨基甲酸酯衍生物的方法 - Google Patents
由毒扁豆醚制备毒扁豆碱氨基甲酸酯衍生物的方法 Download PDFInfo
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- CN1235607A CN1235607A CN97199271A CN97199271A CN1235607A CN 1235607 A CN1235607 A CN 1235607A CN 97199271 A CN97199271 A CN 97199271A CN 97199271 A CN97199271 A CN 97199271A CN 1235607 A CN1235607 A CN 1235607A
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- Prior art keywords
- hydrogen
- formula
- compound
- cis
- carbamate
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- -1 physostigmine carbamate derivatives Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 16
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 title description 3
- 229960001697 physostigmine Drugs 0.000 title description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 98
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000011541 reaction mixture Substances 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 8
- 239000012948 isocyanate Substances 0.000 claims abstract description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 34
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- HKGWQUVGHPDEBZ-OLZOCXBDSA-N eseroline Chemical compound C1=C(O)C=C2[C@]3(C)CCN(C)[C@@H]3N(C)C2=C1 HKGWQUVGHPDEBZ-OLZOCXBDSA-N 0.000 claims description 9
- 238000005728 strengthening Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 4
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- CZWAZSRVYNBYOB-UHFFFAOYSA-N ClC=1C(CC(C(=O)O)=CC1)(C(=O)O)C Chemical compound ClC=1C(CC(C(=O)O)=CC1)(C(=O)O)C CZWAZSRVYNBYOB-UHFFFAOYSA-N 0.000 claims description 2
- UJDOBHZZPQOQBV-UHFFFAOYSA-N OC1=CC=C(CC1(C(=O)O)C)C(=O)O Chemical compound OC1=CC=C(CC1(C(=O)O)C)C(=O)O UJDOBHZZPQOQBV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- KQWOEHQIZVGMMT-CABCVRRESA-N (3ar,8bs)-7-ethoxy-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indole Chemical compound C12=CC(OCC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C KQWOEHQIZVGMMT-CABCVRRESA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 150000002513 isocyanates Chemical class 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 26
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229940043232 butyl acetate Drugs 0.000 description 15
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 230000020335 dealkylation Effects 0.000 description 14
- 238000006900 dealkylation reaction Methods 0.000 description 14
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 13
- 241000418088 Physostigma Species 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 235000014347 soups Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SHXGGYLLZCCNAX-UHFFFAOYSA-N (3-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=CC(Cl)=C1 SHXGGYLLZCCNAX-UHFFFAOYSA-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
- HHIRBXHEYVDUAM-UHFFFAOYSA-N 1-chloro-3-isocyanatobenzene Chemical compound ClC1=CC=CC(N=C=O)=C1 HHIRBXHEYVDUAM-UHFFFAOYSA-N 0.000 description 2
- QPAISQJRPIWMNN-WLHGVMLRSA-N C(\C=C\C(=O)O)(=O)O.ClC=1C=C(C=CC1)NC(O)=O Chemical compound C(\C=C\C(=O)O)(=O)O.ClC=1C=C(C=CC1)NC(O)=O QPAISQJRPIWMNN-WLHGVMLRSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 241000418087 Physostigma venenosum Species 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- AUELWJRRASQDKI-UHFFFAOYSA-N cyclohexyl carbamate Chemical compound NC(=O)OC1CCCCC1 AUELWJRRASQDKI-UHFFFAOYSA-N 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 238000000039 preparative column chromatography Methods 0.000 description 2
- 230000002787 reinforcement Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000000207 volumetry Methods 0.000 description 2
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PKRSYEPBQPFNRB-UHFFFAOYSA-N 2-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC=C1 PKRSYEPBQPFNRB-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CDSUEGXTPYWXAB-UHFFFAOYSA-N acetic acid ethyl acetate Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CCOC(C)=O CDSUEGXTPYWXAB-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- ZYCMDWDFIQDPLP-UHFFFAOYSA-N hbr bromine Chemical compound Br.Br ZYCMDWDFIQDPLP-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 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
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 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
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent 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
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明涉及一种制备式(Ⅰ)化合物或其药学上可接受的盐的方法,其中R为低级烷基;R1为氢,低级烷基,低级环烷基,低级环烷基低级烷基,低级二环烷基,芳基或芳基低级烷基;R2为低级烷基,低级环烷基,低级环烷基低级烷基,低级二环烷基,芳基或芳基低级烷基;或R1和R2以及与其连接的氮原子一起形成式(Ⅰa)基团,其中Y为氢或低级烷基,Z为氢,低级烷基,卤素,低级烷氧基或羟基;X为低级烷基,低级烷氧基,卤素或三氟甲基;以及m为0,1或2;该方法包括(a)使定义如上的式(Ⅱ)化合物与强化的溴化氢反应得到定义如上的式(Ⅲ)化合物;(b)使含有式(Ⅲ)化合物的反应混合物(1)与式R1NCO异氰酸酯反应,分离其中R2为氢的式(Ⅰ)产物;或(2)与定义如上的式(Ⅳ)化合物反应得到定义如上的式(Ⅴ)化合物;(c)在式R5COOH羧酸的存在下,使含式(Ⅴ)化合物的反应混合物与式R1R2NH胺反应,分离,得到式(Ⅰ)产物。
Description
烷基,芳基或芳基低级烷基;R2为低级烷基,低级环烷基,低级环烷基低级烷基,低级二环烷
基,芳基或芳基低级烷基;或R1和R2以及与其连接的氮原子一起形成式(Ⅰa)基团
其中Y为氢或低级烷基,Z为氢,低级烷基,卤素,低级烷氧基
或羟基;
X为低级烷基,低级烷氧基,卤素或三氟甲基;以及
m为0,1或2;该方法包括(a)使式(Ⅱ)化合物其中R,X和m定义如上而R3为低级烷基,与强化的溴化氢反应得到式(Ⅲ)化合物其中R,X和m定义如上;(b)使含有式(Ⅲ)化合物的反应混合物(1)与式R1NCO异氰酸酯反应,分离其中R2为氢的式(Ⅰ)产物;或(2)与式(Ⅳ)化合物反应其中R4为氢或低级烷基,得到式(Ⅴ)化合物其中R,R4,X和m定义如上;(c)在其中R5为低级烷基的羧酸R5COOH存在下使含在步骤(b)中得到的式(Ⅴ)化合物的反应混合物与其中R1和R2定义如上的化合物R1R2NH反应,分离,得到式(Ⅰ)产物。
本申请还提供了一种制备式(Ⅲ)化合物或其药学上可接受的盐的新方法其中R为低级烷基;X为低级烷基,低级烷氧基,卤素或三氟甲基;以及m为0,1或2;该方法包括使式(Ⅱ)化合物其中R,X和m定义如上而R3为低级烷基,与强化的溴化氢反应得到式(Ⅲ)化合物。
如公开于1988年12月13日的美国专利4,791,107;公开于1993年2月19日的美国专利5,187,165;公开于1996年7月30日的美国专利5,541,216;和公开于1996年8月20日的美国专利5,547,977所述,式(Ⅰ)化合物用作记忆增强剂和止痛剂。如公开于1996年7月30日的美国专利5,541,216;公开于1982年12月14日的加拿大专利1,137,489所述,式(Ⅲ)化合物用作记忆增强剂和止痛剂;另外式(Ⅲ)化合物也可用作制备其他记忆增强剂和止痛剂的中间体。
除非另外说明或指出,术语低级烷基表示具有1到6个碳原子的直链或支链烷基。烷基的例子包括甲基,乙基,正丙基,异丁基,戊基,己基,等。
除非另外说明或指出,术语环烷基表示含3到7个碳原子的饱和环。环烷基的例子包括环丙基,环己基,环庚基,等。
除非另外说明或指出,术语双环烷基表示具有7到11个碳原子的基团。
除非另外说明或指出,术语卤素表示氟,氯,溴或碘。
除非另外说明或指出,术语芳基表示未取代的苯基或芳族杂环基;或由1,2或3个独立地选自低级烷基,低级烷氧基,卤素,羟基,三氟甲基,苯氧基或苄氧基的取代基取代的苯基或芳族杂环基。
术语“药学上可接受的盐”指酸加成盐。词组“药学上可接受的酸加成盐”表示式(Ⅰ)化合物的任何无毒的有机或无机酸加成盐。可形成合适的盐的典型的无机酸包括盐酸,氢溴酸,硫酸,和磷酸以及酸式金属盐如正磷酸一氢钠,和硫酸氢钾。可形成合适的盐的典型的有机酸包括单,二和三羧酸。这样的酸的例子有乙酸,羟基乙酸,乳酸,丙酮酸,丙二酸,丁二酸,戊二酸,富马酸,苹果酸,酒石酸,柠檬酸,抗坏血酸,马来酸,羟基马来酸,苯甲酸,羟基苯甲酸,苯乙酸,肉桂酸,水杨酸,2-苯氧基苯甲酸,和磺酸如对甲苯磺酸,甲磺酸和2-羟基乙磺酸。这些盐可以水合物或基本无水的形式存在。
其他一些制备毒扁豆碱氨基甲酸酯衍生物的方法是已知的。例如,参见Hamer et al.,U.S.Pat.No.3,791,107;Brufani et al.,U.S.Pat.No.4,831,15 5;Wong et al.,U.S.Pat.No.5,302,721;和Wong etal.,U.S.Pat.No.5,455,35 4。但是我们仍需要提供更高产率,使用生态学上可接受的试剂和/或以更经济的方式得到上述化合物的方法。
与已知方法相比,本发明方法具有下列主要优点:·强化氢溴酸既作为脱烷基化试剂也作为反应溶剂使用。该试剂比在先技术中使用的脱烷基化试剂如三溴化硼或三氯化铝便宜。·不使用卤化物溶剂。卤化物溶剂如二氯甲烷或二氯乙烷是生态学上不能接受的。·不需要使用制备柱层析进行提纯。制备柱层析昂贵,劳动强度大以及生产规模受限制。·更容易控制环境排放,因为氢溴酸可以循环使用。
使用下述合成步骤可制备本发明化合物。除非另外指出,在合成步骤的描述中取代基“X”,“m”,“R”,“R1”,“R2”,“R3”,“R4”和“R5”分别如上定义。
在本发明化合物结构式中,从1,2,3,3a,8,8a-六氢吡咯并[2,3-b]吲哚环体系的3a-碳和8a-碳伸出的实线
表示两个取代基在三环体系平面的上方,而虚线
表示两个取代基在三环体系平面的下方,波浪线
表示两个取代基可在上述平面的上方或下方。由于构象限制,3a-和8a-位的两个取代基一定同在上述平面的上方或下方。因此,式(Ⅰ)中3a-和8a-位的两个取代基为顺式,因为它们都在三环体系的同一侧。当上述取代基同在三环体系平面的上方时,其构象为3aS-cis,当上述取代基同在三环平面的下方时,其构象为3aR-cis。这两种构象形式如下所示。
上述两种顺式异构体,也就是,3aS-cis异构体和3aR-cis异构体各由化合物名称或上述含波浪线的结构式表示。另外,也可表示包括外消旋混合物(1∶1的3aS-cis∶3aR-cis)的所有3aS-cis和3aR-cis的混合物。流程 流程(续)
步骤a中,式(Ⅱ)化合物与强化溴化氢在室温下混合。然后在1到5小时,优选3到4小时内,将反应物加热至80℃-100℃,优选90-95℃。将反应物冷却,用水洗涤并用合适的碱,例如,20%氢氧化钾中和。然后用有机溶剂如乙酸丁酯或乙酸乙酯提取式(Ⅲ)化合物,并用干燥剂如碳酸钾或分子筛干燥所得溶液。
本申请中,术语“强化氢溴酸”指溴化氢的浓度为约55%到约62%。优选地,溴化氢的浓度范围为约57%到60%。使用本领域普通技术人员已知的技术和方法,由48%氢溴酸得到强化氢溴酸。此外,还可以从市场上购得62%氢溴酸。
在步骤b1中,式(Ⅲ)化合物与异氰酸烷基酯或取代的异氰酸烷基酯反应,得到上述结构式(Ⅰb)表示的其中R2为氢的式(Ⅰ)化合物。该反应的温度一般为约0℃到约25℃,优选约5℃到约10℃。检测反应,通过加入碱例如叔丁醇钾或酸例如乙酸使pH保持在约9到10之间。
在步骤b2中,式(Ⅲ)化合物与式(Ⅳ)羰基二咪唑化合物反应,得到结构式(Ⅴ)表示的咪唑氨基甲酸酯。该加成反应的温度为约0℃到约25℃,优选约20℃。
在步骤c中,该反应一般通过依次向以上获得的溶液中添加羧酸如乙酸和胺如四氢异喹啉来进行。在与适当的胺接触之前,该酸性溶液的pH值可视具体情况而定借助酸如乙酸被酸化至约4.5~6。胺的添加过程一般在约-15~25℃,优选约-10~20℃下进行。
使用本发明方法制备的化合物的例子包括下列化合物以及它们的3aR-cis异构体和包括外消旋体混合物的3aS-cis异构体和3aR-cis异构体的混合物:(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-乙基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-丙基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-丁基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-氯-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-氯-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-氯-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-氯-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-羟基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-羟基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-羟基-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-羟基-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,环己基氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,3-氯苯基氨基甲酸酯富马酸盐;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,3-氯苯基氨基甲酸酯;和(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,1-(苯基)乙基氨基甲酸酯。
下列实施例是为了说明本发明的,它不以任何方式限制本发明的范围。
实施例1
使用48%HBr作为脱烷基化试剂制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯(HP-290)
在室温及氮气氛下,将20.0g(81mmol)毒扁豆醚溶于80mL HBr(48%)。将反应物在90-95℃加热3.5小时。将反应混合物倒入250mL冰水中,用50mL水洗涤。将该溶液用20%KOH中和,然后用乙酸丁酯(2×100mL)萃取。在室温及氮气氛下,将合并的乙酸丁酯溶液用40g碳酸钾进行短暂干燥。过滤干燥剂。在乙酸丁酯滤液中先加入1,1-羰基二咪唑(CDI),再加入14.8mL乙酸和12.02g(90mmol)1,2,3,4-四氢异喹啉。在室温及氮气氛下,搅拌该混合物过夜。通过外标HPLC测得粗品反应混合物中含有3.90g(12.72%)HP290。用40mL水洗涤反应混合物,并用乙酸丁酯(2×40mL)萃取水溶液。用稀盐酸萃取合并的有机层。将含水溶液用氢氧化钠中和,并用环己烷(2×125mL)萃取。将合并的环己烷用碳酸钾干燥,并与25g氧化铝搅拌。过滤吸收剂,用环己烷洗涤滤饼。将该溶液浓缩,得到含2.66g(8.67%)HP290的浆状物。试图用环己烷使该浆状物结晶以得到HP290结晶产物,但是未成功。
实施例2
使用62%HBr作为脱烷基化试剂制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯(HP-290)a)强化氢溴酸(60-62%)的制备
在0℃到室温下在市售的1.0L HBr(48%)水溶液中充入溴化氢气体直到由滴定法测的HBr浓度达到60-62%为止。80mL该溶液用于下列步骤。b)(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯的制备
在室温及氮气氛下,将20.00g(81mmol)毒扁豆醚溶于80mL HBr(62%)。将反应物在90-95℃加热3.5小时。将反应混合物倒入250mL冰水中,用50mL水洗涤。将该溶液用20%KOH中和,然后用乙酸丁酯(2×100mL)萃取。在室温及氮气氛下,将合并的乙酸丁酯溶液用40g碳酸钾进行短暂干燥。过滤干燥剂。在乙酸丁酯溶液中先加入1,1-羰基二咪唑(CDI),再加入14.8mL乙酸和12.02g(90mmol)1,2,3,4-四氢异喹啉。通过外标HPLC测得混合物中含有26.23g(85.58%)HP290。用40mL水洗涤反应混合物,并用乙酸丁酯(2×40mL)萃取水溶液。用稀盐酸萃取合并的有机层。将水溶液用氢氧化钠中和,并用环己烷(2×125mL)萃取。将合并的环己烷用碳酸钾干燥,并与25g氧化铝搅拌。过滤吸收剂,用环己烷洗涤滤饼。将该溶液浓缩,得到含27.07g(75.27%)HP290的浆状物。用环己烷使该浆状物结晶,得到22.07(72.01%)白色结晶状HP290。
实施例3
制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,环己基氨基甲酸酯
在(-)毒扁豆酚碱溶液(2.2g,来自实施例2的“乙酸丁酯溶液”)中加入含异氰酸环己基酯(1.2g)的苯(50mL),将该混合物在25℃搅拌3小时。通过用水(200mL),氢氧化钠溶液(100mL,0.5N)和水(100mL)连续萃取乙酸丁酯溶液分离产物。将残留物用无水硫酸钠干燥,减压浓缩乙酸丁酯溶液,得到标题化合物。
实施例4
制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,3-氯苯基氨基甲酸酯富马酸盐
在5℃在1小时内,在(-)毒扁豆酚碱溶液(2.2g,来自实施例2的“乙酸丁酯溶液”)中加入异氰酸3-氯苯基酯(1.5g),将该混合物在25℃搅拌3小时。通过用水洗涤,减压浓缩,硅胶柱层析纯化,以及用富马酸(1当量)酸化纯化的游离碱,分离呈富马酸盐形式的产物。
实施例5
制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,3-氯苯基氨基甲酸酯
在-5℃在5分钟内,在(-)毒扁豆酚碱溶液(2.2g,来自实施例2的“乙酸丁酯溶液”)中加入异氰酸3-氯苯基酯(1.6g)。搅拌0.25小时后,基本上按照实施例2的方法分离标题化合物。
实施例6
制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,1-(苯基)乙基氨基甲酸酯
在10℃在1.5小时内,在(-)毒扁豆酚碱溶液(2.2g,来自实施例2的“乙酸丁酯溶液”)中加入(S)-(-)-α-甲基苯甲基异氰酸酯(1.5g)。基本上按实施例2的方法分离标题化合物。
实施例7
使用57%HBr作为脱烷基化试剂制备(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯(HP-290)a)强化氢溴酸(57%)的制备
在0℃到室温下在市售的700ml HBr(48%)水溶液中充入溴化氢气体,直到由滴定法测的HBr浓度达到57%为止。b)(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯的制备
在室温及氮气氛下,将100g(0.41mol)毒扁豆醚加入实施例7步骤a的溶液中。将该混合物在氮气氛下加热搅拌5-6小时。蒸发混合物,除去过量HBr(循环使用),将残留物溶于1.0L水中。将五分之一该溶液用50%氢氧化钠水(16.5g)溶液碱化,并用乙酸乙酯萃取。将含毒扁豆酚碱的萃取液用碳酸钾干燥,用15.1g(94mmol)1,1-羰基二咪唑(CDI),14.8mL乙酸和12.0g(90mmol)1,2,3,4-四氢异喹啉进行短暂处理。在室温下,将该混合物搅拌过夜。将红色反应混合物用水洗涤。再用乙酸乙酯反萃取含水溶液。将乙酸乙酯萃取液依次用稀氢氧化钠和水萃取,用碳酸钾干燥。真空除去溶剂,得到浆状物,将其溶于200mL环己烷,与25g氧化铝形成淤浆30分钟,过滤。用环己烷洗涤滤饼,浓缩滤液,用环己烷结晶残留物,得到21.43(70%)白色结晶状固体产物。表1.用48%HBr和62%HBr使毒扁豆醚脱烷基化的反应过程
*通过HPLC测定反应混合物中毒扁豆醚向毒扁豆酚碱的转化(相对比例)表2.用48%HBr和62%HBr得到的HP290的产率的比较
通过外标HPLC定量测定HP290和毒扁豆醚与48%HBr相比,62%HBr的优点在于:·48%HBr脱烷基化速度太慢,不能作为实用的毒扁豆醚脱烷基化方法。62%HBr脱烷基化速度快,为方便的和实用的毒扁豆醚脱烷基化方法。·用48%HBr进行毒扁豆醚脱烷基化仅能得到产率约为13%的粗品HP290,而在完全相同的条件下用62%HBr进行毒扁豆醚脱烷基化可得到产率约为86%的粗品HP290。·使用48%HBr进行脱烷基化得到的粗品HP290含杂质太多,以至于不能用环己烷有效地结晶HP290,而用环己烷结晶采用62%HBr进行脱烷基化得到的粗品HP290,可得到72%的HP290结晶。
时间 | 48%HBr* | 62%HBr* | ||
0:301:001:303:452:303:003:30 | 毒扁豆酚碱(%)1.582.734.115.456.568.709.91 | 毒扁豆醚(%)98.4296.8295.3593.9292.4889.9388.76 | 毒扁豆酚碱(%)51.7360.1376.1184.1488.0990.9291.80 | 毒扁豆醚(%)48.2238.1121.4612.707.422.661.05 |
样品 | 48%HBr | 62%HBr |
HP290产率(%) 毒扁豆醚产率(%) | HP290产率(%) 毒扁豆醚产率(%) | |
粗反应混合物*结晶产物 | 12.72 75.710 - | 85.58 072 - |
Claims (17)
1.一种制备式(Ⅰ)化合物或其药学上可接受的盐的方法其中R为低级烷基;R1为氢,低级烷基,低级环烷基,低级环烷基低级烷基,低级二环
烷基,芳基或芳基低级烷基;R2为低级烷基,低级环烷基,低级环烷基低级烷基,低级二环烷
基,芳基或芳基低级烷基;或R1和R2以及与其连接的氮原子一起形成式(Ⅰa)基团
其中Y为氢或低级烷基,Z为氢,低级烷基,卤素,低级烷氧基
或羟基;
X为低级烷基,低级烷氧基,卤素或三氟甲基;以及
2.权利要求1的方法,其中强化氢溴酸中溴化氢的浓度为约60%到约62%。
3.权利要求1的方法,其中强化氢溴酸中溴化氢的浓度为约57%到约60%。
4.权利要求1的方法,其中R和R3为低级烷基,X为氢。
5.权利要求4的方法,其中R为甲基,R3为乙基。
6.权利要求5的方法,其中式(Ⅱ)化合物为(-)-毒扁豆醚(eserethole)。
7.权利要求1的方法,其中R为低级烷基,X为氢,R1和R2与其连接的氮原子一起形成1,2,3,4-四氢异喹啉基或1-甲基-1,2,3,4-四氢异喹啉基。
8.权利要求7的方法,其中R为甲基。
9.权利要求1的方法,其中式(Ⅰ)化合物选自(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-乙基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-丙基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1-丁基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-氯-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-氯-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-氯-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-氯-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-羟基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-羟基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(6-羟基-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯;(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(7-羟基-1-甲基-1,2,3,4-四氢异喹啉基)氨基甲酸酯。
10.权利要求1的方法,其中式(Ⅰ)化合物为(3aS-cis)-1,2,3,3a,8,8a-六氢-1,3a,8-三甲基吡咯并[2,3-b]吲哚-5-醇,(1,2,3,4-四氢异喹啉基)氨基甲酸酯。
12.权利要求11的方法,其中强化氢溴酸中溴化氢的浓度为约60%到约62%。
13.权利要求11的方法,其中强化氢溴酸中溴化氢的浓度为约57%到约60%。
14.权利要求11的方法,其中R和R3为低级烷基,X为氢。
15.权利要求14的方法,其中R为甲基,R3为乙基。
16.权利要求15的方法,其中式(Ⅱ)化合物为(-)-毒扁豆醚。
17.权利要求11的方法,其中式(Ⅲ)化合物为(-)-毒扁豆酚碱。
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US08/739,402 US5665880A (en) | 1996-10-31 | 1996-10-31 | Method of preparation of physostigmine carbamate derivatives from eseretholes |
US08/739,402 | 1996-10-31 |
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US (2) | US5665880A (zh) |
EP (1) | EP0937080A1 (zh) |
JP (1) | JP2001503049A (zh) |
KR (1) | KR20000052891A (zh) |
CN (1) | CN1235607A (zh) |
AR (1) | AR009300A1 (zh) |
AU (1) | AU712493B2 (zh) |
BR (1) | BR9712719A (zh) |
CA (1) | CA2268150A1 (zh) |
HU (1) | HUP9904284A3 (zh) |
IL (1) | IL129661A0 (zh) |
NO (1) | NO992058L (zh) |
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-
1996
- 1996-10-31 US US08/739,402 patent/US5665880A/en not_active Expired - Fee Related
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1997
- 1997-05-20 US US08/858,987 patent/US5734062A/en not_active Expired - Fee Related
- 1997-07-21 IL IL12966197A patent/IL129661A0/xx unknown
- 1997-07-21 CA CA002268150A patent/CA2268150A1/en not_active Abandoned
- 1997-07-21 WO PCT/US1997/012370 patent/WO1998018799A1/en not_active Application Discontinuation
- 1997-07-21 EP EP97934964A patent/EP0937080A1/en not_active Withdrawn
- 1997-07-21 AU AU38010/97A patent/AU712493B2/en not_active Ceased
- 1997-07-21 BR BR9712719-1A patent/BR9712719A/pt not_active Application Discontinuation
- 1997-07-21 JP JP10520434A patent/JP2001503049A/ja active Pending
- 1997-07-21 KR KR1019990703755A patent/KR20000052891A/ko not_active Application Discontinuation
- 1997-07-21 HU HU9904284A patent/HUP9904284A3/hu unknown
- 1997-07-21 CN CN97199271A patent/CN1235607A/zh active Pending
- 1997-07-28 ZA ZA9706712A patent/ZA976712B/xx unknown
- 1997-08-22 AR ARP970103813A patent/AR009300A1/es unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101121717B (zh) * | 2007-05-17 | 2010-07-28 | 四川大学 | 抗老年痴呆疾病的天然药物毒扁豆碱及其衍生物苯胺基甲酸酯毒扁豆酚碱的合成 |
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AR009300A1 (es) | 2000-04-12 |
NO992058D0 (no) | 1999-04-29 |
WO1998018799A1 (en) | 1998-05-07 |
HUP9904284A3 (en) | 2000-09-28 |
ZA976712B (en) | 1998-04-30 |
KR20000052891A (ko) | 2000-08-25 |
HUP9904284A2 (hu) | 2000-05-28 |
EP0937080A1 (en) | 1999-08-25 |
IL129661A0 (en) | 2000-02-29 |
NO992058L (no) | 1999-04-29 |
JP2001503049A (ja) | 2001-03-06 |
BR9712719A (pt) | 1999-10-26 |
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CA2268150A1 (en) | 1998-05-07 |
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