NO326771B1 - Fremgangsmate for fremstilling av optisk aktivt tropinonmonokarboksylsyreesterderivat - Google Patents
Fremgangsmate for fremstilling av optisk aktivt tropinonmonokarboksylsyreesterderivat Download PDFInfo
- Publication number
- NO326771B1 NO326771B1 NO20011601A NO20011601A NO326771B1 NO 326771 B1 NO326771 B1 NO 326771B1 NO 20011601 A NO20011601 A NO 20011601A NO 20011601 A NO20011601 A NO 20011601A NO 326771 B1 NO326771 B1 NO 326771B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- acid ester
- ester derivative
- optically active
- carbon atoms
- Prior art date
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- -1 tropinone monocarboxylic acid ester Chemical class 0.000 title claims abstract description 137
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 title claims description 67
- QQXLDOJGLXJCSE-KNVOCYPGSA-N Tropinone Natural products C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 title claims description 60
- 238000000034 method Methods 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title description 2
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001412 amines Chemical class 0.000 claims abstract description 12
- 238000005933 dealkoxycarbonylation reaction Methods 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 108090000790 Enzymes Proteins 0.000 claims description 14
- 102000004190 Enzymes Human genes 0.000 claims description 14
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 claims description 10
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 claims description 10
- 125000001931 aliphatic group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 10
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 108090000371 Esterases Proteins 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 7
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 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 claims description 7
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 7
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 abstract description 55
- 230000003287 optical effect Effects 0.000 abstract description 40
- 230000015572 biosynthetic process Effects 0.000 abstract description 39
- 238000003786 synthesis reaction Methods 0.000 abstract description 39
- MPSNEAHFGOEKBI-VXNVDRBHSA-N Anhydroecgonine methyl ester Chemical compound COC(=O)C1=CC[C@@H]2CC[C@H]1N2C MPSNEAHFGOEKBI-VXNVDRBHSA-N 0.000 abstract description 15
- 229960003920 cocaine Drugs 0.000 abstract description 15
- MPSNEAHFGOEKBI-UHFFFAOYSA-N anhydroecogonine methyl ester Natural products COC(=O)C1=CCC2CCC1N2C MPSNEAHFGOEKBI-UHFFFAOYSA-N 0.000 abstract description 13
- 230000018044 dehydration Effects 0.000 abstract description 11
- 238000006297 dehydration reaction Methods 0.000 abstract description 11
- 150000002148 esters Chemical class 0.000 abstract description 8
- 238000001953 recrystallisation Methods 0.000 abstract description 5
- 150000003813 tropane derivatives Chemical class 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 88
- 239000000243 solution Substances 0.000 description 77
- 238000006243 chemical reaction Methods 0.000 description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- 239000000203 mixture Substances 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 30
- 239000000284 extract Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 21
- 239000011734 sodium Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 19
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 12
- 108090001060 Lipase Proteins 0.000 description 12
- 102000004882 Lipase Human genes 0.000 description 12
- 239000004367 Lipase Substances 0.000 description 12
- 229940040461 lipase Drugs 0.000 description 12
- 235000019421 lipase Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 239000008363 phosphate buffer Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- RNJOKCPFLQMDEC-UHFFFAOYSA-N 4(R),8-dimethyl-trans-2-nonenoyl-CoA Chemical compound COC(=O)CC(=O)CC(=O)OC RNJOKCPFLQMDEC-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- XNWMGKAGYXRTAI-IKCIUXDWSA-N methyl (1s,5r)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound N1([C@]2([H])CC[C@]1(CC(=O)C2C(=O)OC)[H])CC1=CC=CC=C1 XNWMGKAGYXRTAI-IKCIUXDWSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 6
- AAIZGPHLWXEORL-UHFFFAOYSA-N dimethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound COC(=O)C1C(=O)C(C(=O)OC)C2CCC1N2CC1=CC=CC=C1 AAIZGPHLWXEORL-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- KEKHRISJFVUHMZ-MWLCHTKSSA-N 8-o-tert-butyl 4-o-methyl (1s,5r)-8-azabicyclo[3.2.1]oct-3-ene-4,8-dicarboxylate Chemical compound CC(C)(C)OC(=O)N1[C@]2([H])CC[C@@]1([H])CC=C2C(=O)OC KEKHRISJFVUHMZ-MWLCHTKSSA-N 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YSEQNZOXHCKLOG-UHFFFAOYSA-N 2-methyl-octanoic acid Chemical compound CCCCCCC(C)C(O)=O YSEQNZOXHCKLOG-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 235000019445 benzyl alcohol Nutrition 0.000 description 4
- 239000002026 chloroform extract Substances 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical group C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- BWOKYTYRQZLBKO-SWQDIRLTSA-N butyl (1s,5r)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound N1([C@]2([H])CC[C@]1(CC(=O)C2C(=O)OCCCC)[H])CC1=CC=CC=C1 BWOKYTYRQZLBKO-SWQDIRLTSA-N 0.000 description 3
- JLDZUJHGEJECNI-UHFFFAOYSA-N dibutyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound CCCCOC(=O)C1C(=O)C(C(=O)OCCCC)C2CCC1N2CC1=CC=CC=C1 JLDZUJHGEJECNI-UHFFFAOYSA-N 0.000 description 3
- XODOFSOXQUCRGH-UHFFFAOYSA-N diethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound CCOC(=O)C1C(=O)C(C(=O)OCC)C2CCC1N2CC1=CC=CC=C1 XODOFSOXQUCRGH-UHFFFAOYSA-N 0.000 description 3
- GFZRMTCBJHINDD-UHFFFAOYSA-N dimethyl 8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound COC(=O)C1C(=O)C(C(=O)OC)C2CCC1N2C GFZRMTCBJHINDD-UHFFFAOYSA-N 0.000 description 3
- GORZSELSICQVNE-UHFFFAOYSA-N dipropan-2-yl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound CC(C)OC(=O)C1C(=O)C(C(=O)OC(C)C)C2CCC1N2CC1=CC=CC=C1 GORZSELSICQVNE-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- AOTYYXWUGXMHPQ-NNKZFNQJSA-N ethyl (1s,5r)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound N1([C@]2([H])CC[C@]1(CC(=O)C2C(=O)OCC)[H])CC1=CC=CC=C1 AOTYYXWUGXMHPQ-NNKZFNQJSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 210000000653 nervous system Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IIYDOMZZEODIBL-UHFFFAOYSA-N 8-o-benzyl 2-o,4-o-diethyl 3-oxo-8-azabicyclo[3.2.1]octane-2,4,8-tricarboxylate Chemical compound CCOC(=O)C1C(=O)C(C(=O)OCC)C2CCC1N2C(=O)OCC1=CC=CC=C1 IIYDOMZZEODIBL-UHFFFAOYSA-N 0.000 description 2
- KLRZSGVNONCIIT-VUHGHZMFSA-N 8-o-tert-butyl 4-o-methyl (1s,5r)-3-oxo-8-azabicyclo[3.2.1]octane-4,8-dicarboxylate Chemical compound C1C(=O)C(C(=O)OC)[C@@]2([H])CC[C@]1([H])N2C(=O)OC(C)(C)C KLRZSGVNONCIIT-VUHGHZMFSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 108050004812 Dopamine receptor Proteins 0.000 description 2
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 101710098556 Lipase A Proteins 0.000 description 2
- 101710099648 Lysosomal acid lipase/cholesteryl ester hydrolase Proteins 0.000 description 2
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 2
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 2
- 108050006759 Pancreatic lipases Proteins 0.000 description 2
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- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 238000006707 demethoxycarbonylation reaction Methods 0.000 description 2
- HWQSGLBUQREXCM-UHFFFAOYSA-N dibenzyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound C=1C=CC=CC=1CN1C2CCC1C(C(=O)OCC=1C=CC=CC=1)C(=O)C2C(=O)OCC1=CC=CC=C1 HWQSGLBUQREXCM-UHFFFAOYSA-N 0.000 description 2
- NTSQPQGVJKLWME-UHFFFAOYSA-N dimethyl 3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate Chemical compound COC(=O)C1C(=O)C(C(=O)OC)C2CCC1N2 NTSQPQGVJKLWME-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
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- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 229940116369 pancreatic lipase Drugs 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 229930004668 tropane alkaloid Natural products 0.000 description 2
- PXLVPMMLLRSAJQ-UHFFFAOYSA-N (+)-Ferruginine Natural products CCOC1=CCC2CCC1N2C PXLVPMMLLRSAJQ-UHFFFAOYSA-N 0.000 description 1
- KQIRSQYBYQBMIG-WPRPVWTQSA-N 1-[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-en-2-yl]ethanone Chemical compound C1C=C(C(C)=O)[C@@H]2CC[C@H]1N2C KQIRSQYBYQBMIG-WPRPVWTQSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PAOWIXJMMCDIPE-UHFFFAOYSA-N 2-butyl-4-methylpentanedioic acid Chemical compound CCCCC(C(O)=O)CC(C)C(O)=O PAOWIXJMMCDIPE-UHFFFAOYSA-N 0.000 description 1
- OXTNCQMOKLOUAM-UHFFFAOYSA-N 3-Oxoglutaric acid Chemical compound OC(=O)CC(=O)CC(O)=O OXTNCQMOKLOUAM-UHFFFAOYSA-N 0.000 description 1
- AJYIGJXFGZQYHI-UHFFFAOYSA-N 3-diazoprop-1-ene Chemical compound C=CC=[N+]=[N-] AJYIGJXFGZQYHI-UHFFFAOYSA-N 0.000 description 1
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 description 1
- SJGALKWNWUNYKD-NNKZFNQJSA-N 8-o-benzyl 4-o-ethyl (1s,5r)-3-oxo-8-azabicyclo[3.2.1]octane-4,8-dicarboxylate Chemical compound N1([C@]2([H])CC[C@]1(CC(=O)C2C(=O)OCC)[H])C(=O)OCC1=CC=CC=C1 SJGALKWNWUNYKD-NNKZFNQJSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010001541 Akinesia Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000274626 Darlingia darlingiana Species 0.000 description 1
- 240000006890 Erythroxylum coca Species 0.000 description 1
- 239000007995 HEPES buffer Substances 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
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 229910019032 PtCl2 Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- JOWCHADLUAORPW-KTVLMBSMSA-N benzyl (1s,5r)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1([C@]2(CC[C@@](CC1=O)(N2CC=1C=CC=CC=1)[H])[H])C(=O)OCC1=CC=CC=C1 JOWCHADLUAORPW-KTVLMBSMSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000008957 cocaer Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- ZSANYRMTSBBUCA-UHFFFAOYSA-N diethyl 3-oxopentanedioate Chemical compound CCOC(=O)CC(=O)CC(=O)OCC ZSANYRMTSBBUCA-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- AASUFOVSZUIILF-UHFFFAOYSA-N diphenylmethanone;sodium Chemical compound [Na].C=1C=CC=CC=1C(=O)C1=CC=CC=C1 AASUFOVSZUIILF-UHFFFAOYSA-N 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930193761 ferruginin Natural products 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 208000018883 loss of balance Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- ZPUCINDJVBIVPJ-GBJTYRQASA-N methyl (1s,3r,4r,5r)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound O([C@@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-GBJTYRQASA-N 0.000 description 1
- ZPUCINDJVBIVPJ-YJNKXOJESA-N methyl (1s,3r,4s,5r)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound O([C@@H]1C[C@@H]2CC[C@@H](N2C)[C@@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-YJNKXOJESA-N 0.000 description 1
- KZMKYPJLCLFAGP-FWHJPCMOSA-N methyl (1s,5r)-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound N1[C@]2([H])CC[C@@]1([H])CC(=O)C2C(=O)OC KZMKYPJLCLFAGP-FWHJPCMOSA-N 0.000 description 1
- WXEMSGQRTGSYOG-PMDVUHRTSA-N methyl (1s,5r)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1C(=O)C(C(=O)OC)[C@@]2([H])CC[C@]1([H])N2C WXEMSGQRTGSYOG-PMDVUHRTSA-N 0.000 description 1
- XNWMGKAGYXRTAI-UHFFFAOYSA-N methyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1C(=O)C(C(=O)OC)C2CCC1N2CC1=CC=CC=C1 XNWMGKAGYXRTAI-UHFFFAOYSA-N 0.000 description 1
- WXEMSGQRTGSYOG-UHFFFAOYSA-N methyl 8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1C(=O)C(C(=O)OC)C2CCC1N2C WXEMSGQRTGSYOG-UHFFFAOYSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 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
- 239000004081 narcotic agent Substances 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- NQHJWFYVHSKTLX-UHFFFAOYSA-N phosphoric acid;toluene Chemical compound OP(O)(O)=O.CC1=CC=CC=C1 NQHJWFYVHSKTLX-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- JHQFDLFDOINLNH-BTPDTDQASA-N propan-2-yl (1s,5r)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound N1([C@]2([H])CC[C@]1(CC(=O)C2C(=O)OC(C)C)[H])CC1=CC=CC=C1 JHQFDLFDOINLNH-BTPDTDQASA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 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
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27786898 | 1998-09-30 | ||
| PCT/JP1999/003754 WO2000018946A1 (fr) | 1998-09-30 | 1999-07-12 | Procede de production d'un derive d'acide tropinone-monocarboxylique optiquement actif |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20011601D0 NO20011601D0 (no) | 2001-03-29 |
| NO20011601L NO20011601L (no) | 2001-03-29 |
| NO326771B1 true NO326771B1 (no) | 2009-02-16 |
Family
ID=17589413
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20011601A NO326771B1 (no) | 1998-09-30 | 2001-03-29 | Fremgangsmate for fremstilling av optisk aktivt tropinonmonokarboksylsyreesterderivat |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US6486323B1 (de) |
| EP (1) | EP1118674B1 (de) |
| JP (1) | JP4386399B2 (de) |
| KR (1) | KR100615867B1 (de) |
| AT (1) | ATE494385T1 (de) |
| CA (1) | CA2340218C (de) |
| DE (1) | DE69943110D1 (de) |
| ES (1) | ES2356225T3 (de) |
| NO (1) | NO326771B1 (de) |
| WO (1) | WO2000018946A1 (de) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100847415B1 (ko) * | 2007-03-20 | 2008-07-18 | 이도훈 | 항경련제 |
| DE102007046887A1 (de) * | 2007-09-28 | 2009-04-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung von (1R,5S)-Anhydroecgoninestersalzen |
| CN112480107B (zh) * | 2020-11-30 | 2022-08-16 | 上海海雁医药科技有限公司 | 取代的氮杂双环辛烷化合物及其中间体和制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE352981C (de) * | 1920-06-16 | 1922-05-10 | Horst Maeder Dr | Verfahren zur Darstellung von Tropinonmonocarbonsaeureestern |
| DE354950C (de) * | 1920-06-28 | 1922-06-17 | Horst Maeder Dr | Verfahren zur Herstellung von Tropinondicarbonsaeureestern |
| WO1994004146A1 (en) * | 1992-08-24 | 1994-03-03 | President And Fellows Of Harvard College | Cocaine analogues and their use as cocaine drug therapies and therapeutic and imaging agents for neurodegenerative disorders |
| EP0831941B1 (de) * | 1995-06-06 | 2012-04-04 | GE Healthcare Limited | Iodierte neurosonden zum kartieren von monoamin-reabsorptionsstellen |
| DE69705608T2 (de) * | 1996-02-22 | 2002-05-16 | Neurosearch A/S, Ballerup | Tropanderivate, deren herstellung und verwendung |
-
1999
- 1999-07-12 ES ES99929794T patent/ES2356225T3/es not_active Expired - Lifetime
- 1999-07-12 US US09/806,592 patent/US6486323B1/en not_active Expired - Lifetime
- 1999-07-12 EP EP99929794A patent/EP1118674B1/de not_active Expired - Lifetime
- 1999-07-12 DE DE69943110T patent/DE69943110D1/de not_active Expired - Lifetime
- 1999-07-12 AT AT99929794T patent/ATE494385T1/de not_active IP Right Cessation
- 1999-07-12 JP JP2000572393A patent/JP4386399B2/ja not_active Expired - Fee Related
- 1999-07-12 CA CA002340218A patent/CA2340218C/en not_active Expired - Fee Related
- 1999-07-12 WO PCT/JP1999/003754 patent/WO2000018946A1/ja active Application Filing
- 1999-07-12 KR KR1020017003824A patent/KR100615867B1/ko not_active IP Right Cessation
-
2001
- 2001-03-29 NO NO20011601A patent/NO326771B1/no not_active IP Right Cessation
-
2002
- 2002-09-26 US US10/255,053 patent/US20030065183A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| NO20011601D0 (no) | 2001-03-29 |
| CA2340218C (en) | 2008-10-14 |
| JP4386399B2 (ja) | 2009-12-16 |
| US6486323B1 (en) | 2002-11-26 |
| WO2000018946A1 (fr) | 2000-04-06 |
| DE69943110D1 (de) | 2011-02-17 |
| EP1118674A4 (de) | 2005-05-25 |
| EP1118674B1 (de) | 2011-01-05 |
| CA2340218A1 (en) | 2000-04-06 |
| US20030065183A1 (en) | 2003-04-03 |
| ATE494385T1 (de) | 2011-01-15 |
| KR100615867B1 (ko) | 2006-08-25 |
| NO20011601L (no) | 2001-03-29 |
| KR20010075363A (ko) | 2001-08-09 |
| EP1118674A1 (de) | 2001-07-25 |
| ES2356225T3 (es) | 2011-04-06 |
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