JP2001518444A5 - - Google Patents
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- JP2001518444A5 JP2001518444A5 JP2000502051A JP2000502051A JP2001518444A5 JP 2001518444 A5 JP2001518444 A5 JP 2001518444A5 JP 2000502051 A JP2000502051 A JP 2000502051A JP 2000502051 A JP2000502051 A JP 2000502051A JP 2001518444 A5 JP2001518444 A5 JP 2001518444A5
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- Japan
- Prior art keywords
- mmol
- benzyl
- give
- yield
- sharp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 74
- NFDFQCUYFHCNBW-SCGPFSFSSA-N dienestrol Chemical compound C=1C=C(O)C=CC=1\C(=C/C)\C(=C\C)\C1=CC=C(O)C=C1 NFDFQCUYFHCNBW-SCGPFSFSSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 59
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 47
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 238000004519 manufacturing process Methods 0.000 description 41
- 229960005181 morphine Drugs 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000000034 method Methods 0.000 description 37
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- XYYVYLMBEZUESM-CMKMFDCUSA-N codeinone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=CC(=O)[C@@H]1OC1=C2C3=CC=C1OC XYYVYLMBEZUESM-CMKMFDCUSA-N 0.000 description 32
- 235000019253 formic acid Nutrition 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
- 239000000284 extract Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 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 28
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 28
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 28
- JJGRKZBXASWTLH-JFJMRBLZSA-N (4R,4aR,7aR,12bS)-9-benzyl-9-hydroxy-3-methyl-2,4,4a,7a,10,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound C(C1=CC=CC=C1)C1(CC=C2C[C@@H]3[C@@H]4C=CC([C@H]5[C@@]4(C2=C1O5)CCN3C)=O)O JJGRKZBXASWTLH-JFJMRBLZSA-N 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 27
- 229960002085 oxycodone Drugs 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 26
- YYCRAERBSFHMPL-XFKAJCMBSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)C=C[C@@]3(O)[C@]4([H])N(C)CC[C@]13C1=C2C(OC)=CC=C1C4 YYCRAERBSFHMPL-XFKAJCMBSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- 229960004126 codeine Drugs 0.000 description 25
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 25
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 23
- 229960005118 oxymorphone Drugs 0.000 description 23
- 239000011734 sodium Substances 0.000 description 23
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 22
- YYCRAERBSFHMPL-UHFFFAOYSA-N 14beta-Hydroxycodeinone Natural products O1C2C(=O)C=CC3(O)C4CC5=CC=C(OC)C1=C5C23CCN4C YYCRAERBSFHMPL-UHFFFAOYSA-N 0.000 description 21
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- 229960003086 naltrexone Drugs 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 19
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 238000002329 infrared spectrum Methods 0.000 description 16
- 239000013074 reference sample Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- MLVMHYBEWQXNNS-OEUJKCCCSA-N (4R,4aR,7aR,12bS)-9-acetyl-9-hydroxy-3-methyl-2,4,4a,7a,10,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound C(C)(=O)C1(CC=C2C[C@@H]3[C@@H]4C=CC([C@H]5[C@@]4(C2=C1O5)CCN3C)=O)O MLVMHYBEWQXNNS-OEUJKCCCSA-N 0.000 description 14
- 239000007800 oxidant agent Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- WNWMXBNVDZYCKT-WQARDWCWSA-N 1-[(4r,4ar,7s,7ar,12bs)-9-benzyl-7,9-dihydroxy-3-methyl-2,4,4a,7a,10,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-yl]ethanone Chemical compound C([C@]1(N(CC[C@@]23C4=C5O[C@H]3[C@@](O)(C=C[C@@H]12)C(C)=O)C)[H])C4=CCC5(O)CC1=CC=CC=C1 WNWMXBNVDZYCKT-WQARDWCWSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- ORXWIMVTSMUFKA-XJCQYFIJSA-N (4R,4aS,7aR,12bS)-9-benzyl-4a,9-dihydroxy-3-methyl-1,2,4,7a,10,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound C(C1=CC=CC=C1)C1(CC=C2C[C@@H]3[C@@]4(C=CC([C@H]5[C@@]4(C2=C1O5)CCN3C)=O)O)O ORXWIMVTSMUFKA-XJCQYFIJSA-N 0.000 description 11
- WJZVCRUPHQAKSZ-IPOQPSJVSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-1,2,3,4,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 WJZVCRUPHQAKSZ-IPOQPSJVSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- -1 acyl anhydride Chemical class 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 229960002921 methylnaltrexone Drugs 0.000 description 10
- 238000007254 oxidation reaction Methods 0.000 description 10
- 230000001590 oxidative effect Effects 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- WLAZIEAWWALKKX-MUMHOZHSSA-N (4r,4ar,7s,7ar,12bs)-9-benzyl-3-methyl-1,2,4,4a,7,7a,10,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound C([C@]1(N(CC[C@@]23C4=C5O[C@H]3[C@@H](O)C=C[C@@H]12)C)[H])C4=CCC5(O)CC1=CC=CC=C1 WLAZIEAWWALKKX-MUMHOZHSSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000004663 dialkyl amino group Chemical group 0.000 description 8
- 239000012156 elution solvent Substances 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- 235000006408 oxalic acid Nutrition 0.000 description 7
- BEYOTYCQJXUUHC-OJRLVACOSA-N (4R,4aS,7aR,12bS)-9-acetyl-4a,9-dihydroxy-3-methyl-1,2,4,7a,10,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound C(C)(=O)C1(CC=C2C[C@@H]3[C@@]4(C=CC([C@H]5[C@@]4(C2=C1O5)CCN3C)=O)O)O BEYOTYCQJXUUHC-OJRLVACOSA-N 0.000 description 6
- GMLREHXYJDLZOU-LEPYJNQMSA-N 3-Acetylmorphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GMLREHXYJDLZOU-LEPYJNQMSA-N 0.000 description 6
- DMGAPZQHWZFIRE-GRGSLBFTSA-N 3-acetyloxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O DMGAPZQHWZFIRE-GRGSLBFTSA-N 0.000 description 6
- MFXFQKMUCYHPFQ-BKRJIHRRSA-N 6-monoacetylcodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](OC(C)=O)[C@@H]1OC1=C2C3=CC=C1OC MFXFQKMUCYHPFQ-BKRJIHRRSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000004965 peroxy acids Chemical class 0.000 description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000006859 Swern oxidation reaction Methods 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 5
- 229960000805 nalbuphine Drugs 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 4
- 239000008896 Opium Substances 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 4
- 229960005297 nalmefene Drugs 0.000 description 4
- HKOIXWVRNLGFOR-KOFBORESSA-N norcodeine Chemical compound O[C@H]([C@@H]1O2)C=C[C@H]3[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 HKOIXWVRNLGFOR-KOFBORESSA-N 0.000 description 4
- 229950004392 norcodeine Drugs 0.000 description 4
- HKOIXWVRNLGFOR-UHFFFAOYSA-N norcodeine Natural products O1C2C(O)C=CC3C4CC5=CC=C(OC)C1=C5C23CCN4 HKOIXWVRNLGFOR-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 229960001027 opium Drugs 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 229930003945 thebaine Natural products 0.000 description 4
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 4
- PNRHAWADPSUWEX-GBWBWFAWSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-1,2,3,4,4a,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrochloride Chemical compound Cl.O[C@H]([C@@H]1O2)C=C[C@H]3[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 PNRHAWADPSUWEX-GBWBWFAWSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001335 demethylating effect Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 229960004127 naloxone Drugs 0.000 description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 3
- 229950006134 normorphine Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- 229910004373 HOAc Inorganic materials 0.000 description 2
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| PCT/US1998/013592 WO1999002529A1 (en) | 1997-07-11 | 1998-07-10 | Preparation of oxymorphone, oxycodone and derivatives |
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1997
- 1997-07-11 US US08/893,464 patent/US5869669A/en not_active Expired - Fee Related
-
1998
- 1998-07-10 AT AT98934213T patent/ATE291023T1/de not_active IP Right Cessation
- 1998-07-10 KR KR20007000252A patent/KR100363486B1/ko not_active Expired - Fee Related
- 1998-07-10 JP JP2000502051A patent/JP2001518444A/ja active Pending
- 1998-07-10 WO PCT/US1998/013592 patent/WO1999002529A1/en not_active Ceased
- 1998-07-10 DE DE69829379T patent/DE69829379D1/de not_active Expired - Lifetime
- 1998-07-10 IL IL13379298A patent/IL133792A0/xx unknown
- 1998-07-10 CA CA002296035A patent/CA2296035C/en not_active Expired - Fee Related
- 1998-07-10 TR TR2000/00033T patent/TR200000033T2/xx unknown
- 1998-07-10 RU RU2000100062/04A patent/RU2183636C2/ru not_active IP Right Cessation
- 1998-07-10 EP EP98934213A patent/EP1000065B1/en not_active Revoked
- 1998-07-10 CN CNB988088169A patent/CN1152880C/zh not_active Expired - Fee Related
- 1998-07-10 SK SK10-2000A patent/SK102000A3/sk unknown
- 1998-07-10 HU HU0003918A patent/HUP0003918A3/hu unknown
- 1998-07-10 AU AU83791/98A patent/AU740822B2/en not_active Ceased
- 1998-07-10 ZA ZA986144A patent/ZA986144B/xx unknown
- 1998-07-16 US US09/116,284 patent/US5922876A/en not_active Expired - Fee Related
- 1998-07-16 US US09/116,283 patent/US6008355A/en not_active Expired - Fee Related
- 1998-07-16 US US09/116,282 patent/US6013796A/en not_active Expired - Fee Related
- 1998-07-16 US US09/116,285 patent/US6008354A/en not_active Expired - Fee Related
- 1998-07-16 US US09/116,286 patent/US5952495A/en not_active Expired - Fee Related
- 1998-07-17 US US09/118,577 patent/US5948788A/en not_active Expired - Fee Related
- 1998-08-21 IN IN1500KO1998 patent/IN1998KO01500A/en unknown
- 1998-09-29 TW TW087116132A patent/TW505648B/zh not_active IP Right Cessation
-
2000
- 2000-01-10 NO NO20000111A patent/NO20000111L/no not_active Application Discontinuation
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