CA2296035C - Preparation of oxymorphone, oxycodone and derivatives - Google Patents
Preparation of oxymorphone, oxycodone and derivatives Download PDFInfo
- Publication number
- CA2296035C CA2296035C CA002296035A CA2296035A CA2296035C CA 2296035 C CA2296035 C CA 2296035C CA 002296035 A CA002296035 A CA 002296035A CA 2296035 A CA2296035 A CA 2296035A CA 2296035 C CA2296035 C CA 2296035C
- Authority
- CA
- Canada
- Prior art keywords
- group
- formula
- benzyl
- acid
- lower alkyl
- 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.)
- Expired - Fee Related
Links
- 229960002085 oxycodone Drugs 0.000 title abstract description 25
- 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 title abstract 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 title abstract description 23
- 229960005118 oxymorphone Drugs 0.000 title abstract description 23
- 238000002360 preparation method Methods 0.000 title description 44
- 238000000034 method Methods 0.000 claims abstract description 35
- 230000008569 process Effects 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 59
- 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 claims description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 36
- 235000019253 formic acid Nutrition 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 23
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000000376 reactant Substances 0.000 claims description 10
- 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 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- -1 substituted-benzyl Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 5
- 239000003125 aqueous solvent Substances 0.000 claims 4
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims 1
- 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 abstract description 68
- 229960005181 morphine Drugs 0.000 abstract description 36
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 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 abstract description 15
- 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 abstract description 15
- 229960003086 naltrexone Drugs 0.000 abstract description 15
- 239000000543 intermediate Substances 0.000 abstract description 12
- 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 abstract description 7
- 229940035676 analgesics Drugs 0.000 abstract description 3
- 239000005557 antagonist Substances 0.000 abstract description 3
- 239000000730 antalgic agent Substances 0.000 abstract description 3
- 230000003533 narcotic effect Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 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 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
- 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 29
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 27
- 239000000047 product Substances 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- 239000000284 extract Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 21
- 101150041968 CDC13 gene Proteins 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 229960004126 codeine Drugs 0.000 description 18
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 18
- 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 17
- YYCRAERBSFHMPL-UHFFFAOYSA-N 14beta-Hydroxycodeinone Natural products O1C2C(=O)C=CC3(O)C4CC5=CC=C(OC)C1=C5C23CCN4C YYCRAERBSFHMPL-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000002329 infrared spectrum Methods 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 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 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 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 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 229960002921 methylnaltrexone Drugs 0.000 description 7
- 235000006408 oxalic acid Nutrition 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 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 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 229910017974 NH40H Inorganic materials 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000004965 peroxy acids Chemical class 0.000 description 6
- 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 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000006859 Swern oxidation reaction Methods 0.000 description 5
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 229930003945 thebaine Natural products 0.000 description 5
- 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 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-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
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229960000805 nalbuphine Drugs 0.000 description 4
- 229960005297 nalmefene Drugs 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
- 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 3
- 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
- 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 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 230000001590 oxidative effect Effects 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
- 238000001228 spectrum Methods 0.000 description 3
- 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 2
- VFNHLTBRAFJQER-ISWURRPUSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-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(O)=CC=C1C4 VFNHLTBRAFJQER-ISWURRPUSA-N 0.000 description 2
- 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 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010420 art technique Methods 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- PFBSOANQDDTNGJ-YNHQPCIGSA-N morphinone Chemical compound O([C@H]1C(C=C[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O PFBSOANQDDTNGJ-YNHQPCIGSA-N 0.000 description 2
- 229960004127 naloxone Drugs 0.000 description 2
- 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 2
- 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 2
- 229950004392 norcodeine Drugs 0.000 description 2
- HKOIXWVRNLGFOR-UHFFFAOYSA-N norcodeine Natural products O1C2C(O)C=CC3C4CC5=CC=C(OC)C1=C5C23CCN4 HKOIXWVRNLGFOR-UHFFFAOYSA-N 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YTLQUSFUTUNUQM-KFIKYVJASA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;(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)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C YTLQUSFUTUNUQM-KFIKYVJASA-N 0.000 description 1
- WYMBHLXUDPDGQJ-BRJGLHKUSA-N (4r,4as,7s,7ar,12bs)-3-methyl-1,2,4,7,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7,9-triol Chemical class O([C@H]1[C@H](C=C[C@]23O)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WYMBHLXUDPDGQJ-BRJGLHKUSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 description 1
- YNTJKQDWYXUTLZ-UHFFFAOYSA-N 2-(3-chlorophenoxy)propanoic acid Chemical compound OC(=O)C(C)OC1=CC=CC(Cl)=C1 YNTJKQDWYXUTLZ-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- FARFNWLIVJIUQC-CQUOIELDSA-N C1=CC(OC)=C2C=3[C@@]45[C@@H](O2)C(=O)C=C[C@H]4[C@@H](CC13)N(C)CC5.C5=CC(OC)=C1C=3[C@@]42[C@@H](O1)[C@@H](O)C=C[C@H]4[C@@H](CC53)N(C)CC2 Chemical compound C1=CC(OC)=C2C=3[C@@]45[C@@H](O2)C(=O)C=C[C@H]4[C@@H](CC13)N(C)CC5.C5=CC(OC)=C1C=3[C@@]42[C@@H](O1)[C@@H](O)C=C[C@H]4[C@@H](CC53)N(C)CC2 FARFNWLIVJIUQC-CQUOIELDSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-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
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- XQGSVNHIIVBMPX-UHFFFAOYSA-N Improsulfan tosylate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CS(=O)(=O)OCCC[NH2+]CCCOS(C)(=O)=O XQGSVNHIIVBMPX-UHFFFAOYSA-N 0.000 description 1
- 101100112104 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cnb-1 gene Proteins 0.000 description 1
- RIKMCJUNPCRFMW-ISWURRPUSA-N Noroxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 RIKMCJUNPCRFMW-ISWURRPUSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- KZTDCUYDEIJDGD-IPOQPSJVSA-N O[C@]([C@@H](C1)[I](CC2)P)([C@]22c3c1ccc(OP)c3O[C@H]21)C=CC1=O Chemical compound O[C@]([C@@H](C1)[I](CC2)P)([C@]22c3c1ccc(OP)c3O[C@H]21)C=CC1=O KZTDCUYDEIJDGD-IPOQPSJVSA-N 0.000 description 1
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 125000002820 allylidene group Chemical group [H]C(=[*])C([H])=C([H])[H] 0.000 description 1
- 238000013459 approach 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/893,464 US5869669A (en) | 1996-07-26 | 1997-07-11 | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
| US08/893,464 | 1997-07-11 | ||
| PCT/US1998/013592 WO1999002529A1 (en) | 1997-07-11 | 1998-07-10 | Preparation of oxymorphone, oxycodone and derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2296035A1 CA2296035A1 (en) | 1999-01-21 |
| CA2296035C true CA2296035C (en) | 2004-04-13 |
Family
ID=25401603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002296035A Expired - Fee Related CA2296035C (en) | 1997-07-11 | 1998-07-10 | Preparation of oxymorphone, oxycodone and derivatives |
Country Status (19)
| Country | Link |
|---|---|
| US (7) | US5869669A (en:Method) |
| EP (1) | EP1000065B1 (en:Method) |
| JP (1) | JP2001518444A (en:Method) |
| KR (1) | KR100363486B1 (en:Method) |
| CN (1) | CN1152880C (en:Method) |
| AT (1) | ATE291023T1 (en:Method) |
| AU (1) | AU740822B2 (en:Method) |
| CA (1) | CA2296035C (en:Method) |
| DE (1) | DE69829379D1 (en:Method) |
| HU (1) | HUP0003918A3 (en:Method) |
| IL (1) | IL133792A0 (en:Method) |
| IN (1) | IN1998KO01500A (en:Method) |
| NO (1) | NO20000111L (en:Method) |
| RU (1) | RU2183636C2 (en:Method) |
| SK (1) | SK102000A3 (en:Method) |
| TR (1) | TR200000033T2 (en:Method) |
| TW (1) | TW505648B (en:Method) |
| WO (1) | WO1999002529A1 (en:Method) |
| ZA (1) | ZA986144B (en:Method) |
Families Citing this family (93)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5912347A (en) * | 1996-09-30 | 1999-06-15 | Mallinckrodt Inc. | Process for preparing a morphinan derivative |
| WO2000066588A1 (en) * | 1999-05-05 | 2000-11-09 | The Government Of The United States Of America, Represented By The Secretary, Departmentof Health A Nd Human Services | Direct c-14 oxidation of opioids |
| US6177567B1 (en) | 1999-10-15 | 2001-01-23 | Boehringer Ingelheim Chemicals, Inc. | Method for preparing oxycodone |
| HUP0401600A3 (en) * | 2001-08-23 | 2008-05-28 | Organon Nv | Process for the preparation of 14-hydroxymorphine derivatives |
| JP3961796B2 (ja) * | 2001-08-27 | 2007-08-22 | ソニー株式会社 | 情報提供システム、情報処理装置および方法、情報提供装置および方法、記録媒体、並びにプログラム |
| DE10161963A1 (de) * | 2001-12-17 | 2003-07-03 | Johannes Schuetz | 6-Aminomorphinanderivate, Herstellungsverfahren dafür und deren Verwendung |
| US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
| US20040058946A1 (en) * | 2002-07-05 | 2004-03-25 | Buchwald Stephen L. | Abuse-resistant prodrugs of oxycodone and other pharmaceuticals |
| RU2236412C2 (ru) * | 2002-07-18 | 2004-09-20 | Власов Михаил Иванович | Способ получения производных морфинона, способ получения производных 14-гидроксиморфинона, и способ получения производных оксиморфона |
| RU2215741C1 (ru) * | 2002-11-05 | 2003-11-10 | Открытое Акционерное Общество "Международная Научно-Технологическая Корпорация" | Сложные эфиры n-замещенных 14-гидроксиморфинанов и способ их получения |
| RU2215742C1 (ru) * | 2002-11-05 | 2003-11-10 | Открытое Акционерное Общество "Международная Научно-Технологическая Корпорация" | Способ получения сложных эфиров n-замещенных 14-гидроксиморфинанов |
| EP1562953B1 (en) * | 2002-11-08 | 2009-09-30 | Mallinckrodt Inc. | Process for the preparation of quaternary n-alkyl morphinan alkaloid salts |
| CA2507522C (en) | 2002-12-13 | 2015-02-24 | Durect Corporation | Oral drug delivery system |
| US6864370B1 (en) * | 2003-06-05 | 2005-03-08 | Zhaiwei Lin | Process for manufacturing oxycodone |
| US6790959B1 (en) | 2003-06-05 | 2004-09-14 | Halsey Drug Company, Inc. | Process for manufacturing thebaine |
| US7875718B2 (en) * | 2003-09-22 | 2011-01-25 | Johnson Matthey Public Limited Company | Process for the synthesis of morphinane compounds and intermediates thereof |
| JP4879740B2 (ja) | 2003-09-22 | 2012-02-22 | ジョンソン、マッセイ、パブリック、リミテッド、カンパニー | モルヒナン化合物およびその中間体の合成法 |
| EP2194059A3 (en) | 2004-02-06 | 2010-09-22 | Euro-Celtique S.A. | Methods for making 3-O-protected morphinones and 3-O-protected morphinone dienol carboxylates |
| TWI365880B (en) | 2004-03-30 | 2012-06-11 | Euro Celtique Sa | Process for preparing oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone and oxycodone hydrochloride composition,pharmaceutical dosage form,sustained release oeal dosage form and pharmaceutically acceptable package having less than 25 pp |
| SK286047B6 (sk) * | 2004-04-13 | 2008-01-07 | Zentiva, A. S. | Spôsob prípravy derivátov 4,5alfa-epoxy-6-oxomorfínanu |
| US6946556B1 (en) * | 2004-05-21 | 2005-09-20 | Acura Pharmaceuticals, Inc. | Preparation of opioid analgesics by a one-pot process |
| EP1758908A1 (en) * | 2004-06-08 | 2007-03-07 | Mallinckrodt, Inc. | Extraction of alkaloids from opium |
| WO2005123039A1 (en) | 2004-06-12 | 2005-12-29 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
| EP2767292B1 (en) | 2004-09-17 | 2016-08-24 | Durect Corporation | Sustained Local Anesthetic Composition Containing SAIB |
| GB0421149D0 (en) * | 2004-09-23 | 2004-10-27 | Johnson Matthey Plc | Preparation of oxycodone |
| GB0421687D0 (en) * | 2004-09-30 | 2004-11-03 | Johnson Matthey Plc | Preparation of opiate analgesics |
| WO2006084389A1 (de) * | 2005-02-11 | 2006-08-17 | Cilag Ltd. | Verfahren zur reinigung von noroxymorphon-verbindungen |
| HRP20090387T1 (hr) * | 2005-03-04 | 2009-08-31 | Euro-Celtique S.A. | Postupak reduciranja alfa, beta nezasićenih ketona u opioidnim sastavima |
| EP1873158B1 (en) * | 2005-04-06 | 2016-04-06 | Toray Industries, Inc. | Crystals of morphinan derivative and process for producing the same |
| US8071768B2 (en) * | 2005-06-10 | 2011-12-06 | Janssen Pharmaceutica, N.V. | Alkylquinoline and alkylquinazoline kinase modulators |
| JP2008546688A (ja) * | 2005-06-16 | 2008-12-25 | マリンクロッド・インコーポレイテッド | １−ハロ−テバインまたは類似体を介する１４−ヒドロキシルオピエート類への合成経路 |
| US20070027105A1 (en) | 2005-07-26 | 2007-02-01 | Alza Corporation | Peroxide removal from drug delivery vehicle |
| US20070117826A1 (en) * | 2005-11-23 | 2007-05-24 | Forest Laboratories, Inc. | Pharmaceutical formulations comprising ibuprofen, oxycodone, and 14-hydroxycodeinone |
| DE602007003197D1 (de) | 2006-03-02 | 2009-12-24 | Mallinckrodt Inc | Verfahren zur herstellung von morphinan-6-on-produkten mit geringen konzentrationen von alpha-, beta-ungesättigten ketonverbindungen |
| SA07280459B1 (ar) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني |
| JP2010504325A (ja) * | 2006-09-20 | 2010-02-12 | マリンクロット インコーポレイテッド | 置換モルフィナン−６−オン、並びにその塩および中間体の調製 |
| EP2073636B1 (en) | 2006-10-17 | 2012-09-05 | Penick Corporation | Process for preparing oxymorphone |
| CA2674915C (en) * | 2006-10-17 | 2015-06-30 | Penick Corporation | Process for preparing oxymorphone |
| AU2012216358B2 (en) * | 2006-10-17 | 2014-11-20 | Penick Corporation | Process For Preparing Oxymorphone, Naltrexone and Buprenorphine |
| US20080125592A1 (en) * | 2006-10-17 | 2008-05-29 | Penick Corporation | Process for preparing oxymorphone, naltrexone, and buprenorphine |
| AU2007325918B2 (en) | 2006-11-03 | 2013-10-17 | Durect Corporation | Transdermal delivery systems comprising bupivacaine |
| CA2671518C (en) * | 2006-12-04 | 2016-06-07 | Noramco, Inc. | Process for preparing oxycodone having reduced levels of 14-hydroxycodeinone |
| ES2378710T3 (es) * | 2006-12-04 | 2012-04-17 | Noramco, Inc. | Procedimiento para reducir impurezas en la base de oxicodona |
| GB0624880D0 (en) * | 2006-12-14 | 2007-01-24 | Johnson Matthey Plc | Improved method for making analgesics |
| PL2137189T3 (pl) * | 2007-03-06 | 2015-12-31 | SpecGx LLC | Sposób wytwarzania czwartorzędowych N-alkilowych soli alkaloidu morfinanowego |
| US9040726B2 (en) * | 2007-03-06 | 2015-05-26 | Mallinckrodt Llc | Process for the preparation of quaternary N-alkyl morphinan alkaloid salts |
| JP2010522189A (ja) * | 2007-03-23 | 2010-07-01 | マリンクロッド・インコーポレイテッド | オリパビンからのオキシモルホンの改善された調製 |
| JP5373764B2 (ja) * | 2007-04-16 | 2013-12-18 | マリンクロッド エルエルシー | 触媒性水素転移反応を使用する新規なオピエート還元 |
| WO2008144320A2 (en) * | 2007-05-17 | 2008-11-27 | Endo Pharmaceuticals, Inc. | Opioid and methods of making and using the same |
| EP2219622A1 (en) | 2007-12-06 | 2010-08-25 | Durect Corporation | Methods useful for the treatment of pain, arthritic conditions, or inflammation associated with a chronic condition |
| US8461337B2 (en) | 2007-12-17 | 2013-06-11 | Mallinckrodt Llc | Sinomenine derivatives and processes for their synthesis |
| ES2569655T3 (es) | 2007-12-17 | 2016-05-12 | Mallinckrodt Llc | Procedimientos para la producción de compuestos de (+)-'nal' morfinano |
| WO2009111162A1 (en) | 2008-02-29 | 2009-09-11 | Mallinckrodt Inc. | Process for the preparation of 3-hydroxymorphinan derivatives |
| US8440686B2 (en) * | 2008-04-24 | 2013-05-14 | Janssen Pharmaceutica Nv | Nalmefene prodrugs |
| PL2285780T3 (pl) * | 2008-05-27 | 2016-02-29 | SpecGx LLC | Sposoby i związki do wytwarzania normorfinanów |
| EP2331508B1 (en) | 2008-09-03 | 2014-11-12 | Mallinckrodt LLC | Substituted berbines and processes for their synthesis |
| US8080661B2 (en) * | 2008-09-30 | 2011-12-20 | Mallinckrodt Llc | Processes for the synthesis of tertiary amines |
| US20100260844A1 (en) | 2008-11-03 | 2010-10-14 | Scicinski Jan J | Oral pharmaceutical dosage forms |
| UA102916C2 (uk) | 2009-07-02 | 2013-08-27 | Кемфарм, Інк. | Композиція на основі кон'югату гідрокодону з бензойною кислотою, похідними бензойної кислоти або гетероарилкарбоновою кислотою, проліки, спосіб лікування від зловживань |
| US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
| ES2666404T3 (es) | 2010-06-11 | 2018-05-04 | Rhodes Technologies | Procesos catalizados por metales de transición para la preparación de compuestos de N-alilo y uso de los mismos |
| EP2580218B1 (en) | 2010-06-11 | 2015-02-25 | Rhodes Technologies | Process for n-dealkylation of tertiary amines |
| US8703950B2 (en) | 2010-07-02 | 2014-04-22 | Johnson Matthey Public Limited Co. | Low ABUK oxycodone, its salts and methods of making same |
| RU2448709C1 (ru) * | 2011-02-01 | 2012-04-27 | Учреждение Российской академии наук Институт проблем химико-энергетических технологий Сибирского отделения РАН (ИПХЭТ СО РАН) | Способ получения налтрексона |
| TWI560170B (en) * | 2011-12-06 | 2016-12-01 | Lundbeck & Co As H | Process for recovery of nalmefene hydrochloride |
| US9315514B2 (en) | 2012-08-27 | 2016-04-19 | Rhodes Technologies | 1,3-dioxanomorphides and 1,3-dioxanocodides |
| JP6141444B2 (ja) | 2012-12-14 | 2017-06-07 | パーデュー、ファーマ、リミテッド、パートナーシップ | スピロ環式モルフィナンおよびこれらの使用 |
| EP2931725B1 (en) | 2012-12-14 | 2017-02-15 | Purdue Pharma LP | Nitrogen containing morphinan derivatives and the use thereof |
| TWI513697B (zh) | 2012-12-14 | 2015-12-21 | Purdue Pharma Lp | 吡啶酮並嗎啡喃類似物及其對類鴉片受體之生物活性 |
| TW201441199A (zh) | 2012-12-28 | 2014-11-01 | Purdue Pharma Lp | 經取代之嗎啡喃類及其用途 |
| JP6159416B2 (ja) | 2012-12-28 | 2017-07-05 | パーデュー、ファーマ、リミテッド、パートナーシップ | ７，８−環式モルフィナン類似体 |
| MX2015008624A (es) | 2012-12-31 | 2016-12-08 | Rhodes Tech | PROCESO PARA PREPARAR 6A, 14A-ETENOMORFINANOS 7ß SUSTITUIDOS Y 6A, 14A-ETANOMORFINANOS 7ß-SUSTITUIDOS. |
| US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
| EP2829541A1 (en) * | 2013-07-26 | 2015-01-28 | Siegfried AG | Novel synthesis of noroxymorphone from morphine |
| US9120800B2 (en) | 2013-08-02 | 2015-09-01 | Johnson Matthey Public Limited Company | Process for the preparation of oxymorphone alkaloid and oxymorphone salts |
| US9988392B2 (en) | 2013-12-26 | 2018-06-05 | Purdue Pharma L.P. | 7-beta-alkyl analogs of orvinols |
| EP3087079B1 (en) | 2013-12-26 | 2019-04-03 | Purdue Pharma LP | Opioid receptor modulating oxabicyclo[2.2.2]octane morphinans |
| US9340542B2 (en) | 2013-12-26 | 2016-05-17 | Purdue Pharma L.P. | Propellane-based compounds and the use thereof |
| WO2015097547A1 (en) | 2013-12-26 | 2015-07-02 | Purdue Pharma L.P. | 10-substituted morphinan hydantoins |
| US9902726B2 (en) | 2013-12-30 | 2018-02-27 | Purdue Pharma L.P. | Pyridone-sulfone morphinan analogs as opioid receptor ligands |
| BR112017011069A2 (pt) | 2014-11-25 | 2018-07-10 | Kempharm Inc | ácido benzóico, derivados e ácido benzóico e conjugados de ácido heteroaril carboxílico de oxicodona |
| EP3252055B1 (en) | 2016-05-31 | 2018-09-19 | Alcaliber Investigacion Desarrollo e Innovacion SLU | Process for obtaining 3,14-diacetyloxymorphone from oripavine |
| US9737530B1 (en) | 2016-06-23 | 2017-08-22 | Collegium Pharmaceutical, Inc. | Process of making stable abuse-deterrent oral formulations |
| SG11201811760VA (en) | 2016-07-06 | 2019-01-30 | Durect Corp | Oral dosage form with drug composition, barrier layer and drug layer |
| LT3559010T (lt) | 2016-12-23 | 2022-10-10 | Minoryx Therapeutics S.L. | 5-[[4-[2-[5-(1-hidroksietil)-2-piridinil]etoksi]fenil]metil]-2,4-tiazolidindiono ir jo druskų gavimo būdas |
| SK592017A3 (sk) | 2017-07-04 | 2019-01-08 | Saneca Pharmaceuticals A. S. | Spôsob prípravy morfínanových zlúčenín |
| WO2019165298A1 (en) | 2018-02-23 | 2019-08-29 | Rhodes Technologies | Novel opioid compounds and uses thereof |
| CN110054656B (zh) * | 2019-05-28 | 2021-02-02 | 宜昌人福药业有限责任公司 | 一种10-羰基/羟基吗啡-6-葡萄糖苷酸的合成方法 |
| US11613547B2 (en) | 2019-07-08 | 2023-03-28 | University Of Health Sciences & Pharmacy In St. Louis | G-protein biased opioid receptor agonist/analgesics with reduced arrestin recruitment |
| KR20220140711A (ko) | 2020-01-13 | 2022-10-18 | 듀렉트 코퍼레이션 | 불순물이 감소된 지속 방출 약물 전달 시스템 및 관련 방법 |
| CN114621239A (zh) * | 2020-12-10 | 2022-06-14 | 鲁南制药集团股份有限公司 | 一种纳曲酮的制备方法 |
| WO2022144911A1 (en) * | 2020-12-28 | 2022-07-07 | Navin Saxena Research & Technology Pvt. Ltd. | Novel process for the synthesis of noroxymorphone from morphine |
| EP4277702A1 (en) | 2021-01-12 | 2023-11-22 | Durect Corporation | Sustained release drug delivery systems and related methods |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3819636A (en) * | 1970-09-15 | 1974-06-25 | American Home Prod | 4a,10-(methaniminomethano)phenanthrene derivatives |
| US4795813A (en) * | 1981-08-17 | 1989-01-03 | The Florida Board Of Regents On Behalf Of The Florida State University | Synthesis of derivatives of codeine and other 3-O-alkylmorphines |
| US4639520A (en) * | 1984-03-27 | 1987-01-27 | Mallinckrodt, Inc. | Preparation of 14-hydroxy-N-ethoxy-carbonyl-norcodeinone |
| FR2562072B1 (fr) * | 1984-03-27 | 1989-07-07 | Mallinckrodt Inc | Procede de preparation de la noroxymorphone a partir de la morphine, et composes intermediaires utilises dans ce procede |
| US5112975A (en) * | 1984-03-27 | 1992-05-12 | Mallinckrodt Specialty Chemicals Company | Preparation of noroxymorphone from morphine |
| US4668685A (en) * | 1984-07-05 | 1987-05-26 | E.I. Du Pont De Nemours And Company | Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists |
| US4912114A (en) * | 1988-03-18 | 1990-03-27 | Sandoz Ltd. | Morphinan derivatives |
-
1997
- 1997-07-11 US US08/893,464 patent/US5869669A/en not_active Expired - Fee Related
-
1998
- 1998-07-10 WO PCT/US1998/013592 patent/WO1999002529A1/en not_active Ceased
- 1998-07-10 JP JP2000502051A patent/JP2001518444A/ja active Pending
- 1998-07-10 RU RU2000100062/04A patent/RU2183636C2/ru not_active IP Right Cessation
- 1998-07-10 IL IL13379298A patent/IL133792A0/xx unknown
- 1998-07-10 AU AU83791/98A patent/AU740822B2/en not_active Ceased
- 1998-07-10 CN CNB988088169A patent/CN1152880C/zh not_active Expired - Fee Related
- 1998-07-10 EP EP98934213A patent/EP1000065B1/en not_active Revoked
- 1998-07-10 SK SK10-2000A patent/SK102000A3/sk unknown
- 1998-07-10 CA CA002296035A patent/CA2296035C/en not_active Expired - Fee Related
- 1998-07-10 DE DE69829379T patent/DE69829379D1/de not_active Expired - Lifetime
- 1998-07-10 KR KR20007000252A patent/KR100363486B1/ko not_active Expired - Fee Related
- 1998-07-10 HU HU0003918A patent/HUP0003918A3/hu unknown
- 1998-07-10 TR TR2000/00033T patent/TR200000033T2/xx unknown
- 1998-07-10 ZA ZA986144A patent/ZA986144B/xx unknown
- 1998-07-10 AT AT98934213T patent/ATE291023T1/de not_active IP Right Cessation
- 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
- 1998-07-16 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 US09/116,284 patent/US5922876A/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
Also Published As
| Publication number | Publication date |
|---|---|
| AU740822B2 (en) | 2001-11-15 |
| US5952495A (en) | 1999-09-14 |
| CA2296035A1 (en) | 1999-01-21 |
| JP2001518444A (ja) | 2001-10-16 |
| TW505648B (en) | 2002-10-11 |
| NO20000111L (no) | 2000-02-25 |
| HK1028025A1 (en) | 2001-02-02 |
| US6013796A (en) | 2000-01-11 |
| CN1272845A (zh) | 2000-11-08 |
| EP1000065A4 (en) | 2001-09-12 |
| ZA986144B (en) | 1999-05-19 |
| DE69829379D1 (de) | 2005-04-21 |
| CN1152880C (zh) | 2004-06-09 |
| EP1000065B1 (en) | 2005-03-16 |
| IL133792A0 (en) | 2001-04-30 |
| US6008354A (en) | 1999-12-28 |
| EP1000065A1 (en) | 2000-05-17 |
| US5948788A (en) | 1999-09-07 |
| US5869669A (en) | 1999-02-09 |
| US5922876A (en) | 1999-07-13 |
| IN1998KO01500A (en:Method) | 2005-03-11 |
| HUP0003918A3 (en) | 2003-04-28 |
| HUP0003918A2 (hu) | 2001-07-30 |
| AU8379198A (en) | 1999-02-08 |
| KR100363486B1 (ko) | 2002-12-16 |
| TR200000033T2 (tr) | 2000-12-21 |
| ATE291023T1 (de) | 2005-04-15 |
| NO20000111D0 (no) | 2000-01-10 |
| US6008355A (en) | 1999-12-28 |
| KR20010021693A (ko) | 2001-03-15 |
| RU2183636C2 (ru) | 2002-06-20 |
| WO1999002529A1 (en) | 1999-01-21 |
| SK102000A3 (en) | 2000-07-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2296035C (en) | Preparation of oxymorphone, oxycodone and derivatives | |
| JP2001518444A5 (en:Method) | ||
| US6365742B1 (en) | Preparation of opiates, intermediates and uses of salts | |
| EP2222678B1 (en) | Processes for the production of (+)-'nal' morphinan compounds | |
| US5112975A (en) | Preparation of noroxymorphone from morphine | |
| WO1997044317A9 (en) | Novel methods of o-demethylation and n-deprotection | |
| EP1893616B1 (en) | A synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs | |
| US20020045755A1 (en) | Novel methods of O-demethylation and N-deprotection | |
| EP0158476B1 (en) | Preparation of noroxymorphone from morphine | |
| US5071985A (en) | Process for the preparation of morphinane derivatives | |
| AU2018268173B2 (en) | Preparation of buprenorphine | |
| EP1664061A4 (en) | PROCESS FOR SYNTHESIS OF MORPHINAN COMPOUNDS AND INTERMEDIATE PRODUCTS THEREOF | |
| EP0159823B1 (en) | Preparation of 14-hydroxy-n-ethoxy-carbonyl-norcodeinone | |
| Ninan et al. | An improved synthesis of noroxymorphone | |
| HK1028025B (en) | Preparation of oxymorphone, oxycodone and derivatives | |
| CN101646675A (zh) | 季n-烷基吗啡喃生物碱盐的制备方法 | |
| US20040181070A1 (en) | Process and intermediates for the preparation of 4-aryl piperidines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |