JP2006509745A - 第四級ｎ−アルキルモルフィナンアルカロイド塩の製造方法 - Google Patents
第四級ｎ−アルキルモルフィナンアルカロイド塩の製造方法 Download PDFInfo
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- JP2006509745A JP2006509745A JP2004551830A JP2004551830A JP2006509745A JP 2006509745 A JP2006509745 A JP 2006509745A JP 2004551830 A JP2004551830 A JP 2004551830A JP 2004551830 A JP2004551830 A JP 2004551830A JP 2006509745 A JP2006509745 A JP 2006509745A
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- Prior art keywords
- methyl
- aprotic dipolar
- solvent
- hydroxy
- pyrrolidinone
- 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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- 229930013053 morphinan alkaloid Natural products 0.000 title claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 81
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 claims abstract description 24
- -1 N-substituted morphinan Chemical class 0.000 claims abstract description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 82
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical group BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 81
- 239000000047 product Substances 0.000 claims description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 229940102396 methyl bromide Drugs 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000004423 acyloxy group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 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 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 239000002168 alkylating agent Substances 0.000 claims description 16
- 229940100198 alkylating agent Drugs 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 15
- 239000002244 precipitate Substances 0.000 claims description 13
- 229930013930 alkaloid Natural products 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000000758 substrate Substances 0.000 claims description 12
- 150000003797 alkaloid derivatives Chemical class 0.000 claims description 10
- 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 claims description 10
- 150000001450 anions Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229960004127 naloxone Drugs 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 6
- 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 claims description 6
- 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 claims description 6
- 229960003086 naltrexone Drugs 0.000 claims description 6
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical class C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 claims description 5
- 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 claims description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 229960000805 nalbuphine Drugs 0.000 claims description 3
- 229960005297 nalmefene Drugs 0.000 claims description 3
- 229960005118 oxymorphone Drugs 0.000 claims description 3
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical group 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 claims description 3
- DYHDRNAXUHIHMW-KFIKYVJASA-N (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C=C[C@@]35O.COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C=C[C@@]35O DYHDRNAXUHIHMW-KFIKYVJASA-N 0.000 claims description 2
- FVVZCYAZJLEMGV-GPLBXWCQSA-N (4r,4ar,7ar,12bs)-9-hydroxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O FVVZCYAZJLEMGV-GPLBXWCQSA-N 0.000 claims description 2
- NETZHAKZCGBWSS-QUPQZYKRSA-N (4r,4as,7ar,12bs)-3-(cyclobutylmethyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7,9-triol Chemical compound C([C@@]12[C@@]3(O)CCC(O)[C@@H]1OC=1C(O)=CC=C(C2=1)C[C@]31[H])CN1CC1CCC1 NETZHAKZCGBWSS-QUPQZYKRSA-N 0.000 claims description 2
- 101100167365 Caenorhabditis elegans cha-1 gene Proteins 0.000 claims description 2
- 229960004126 codeine Drugs 0.000 claims description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 229960005181 morphine Drugs 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 229930003945 thebaine Natural products 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- RSSHKMSIEMOBQX-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 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)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C RSSHKMSIEMOBQX-KFIKYVJASA-N 0.000 claims 1
- GJOVVPXDEXUSTC-OWCLPIDISA-N Norbutorphanol Chemical compound C1CCC[C@@]2(O)[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 GJOVVPXDEXUSTC-OWCLPIDISA-N 0.000 claims 1
- 239000012298 atmosphere Substances 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 238000003756 stirring Methods 0.000 description 21
- DQCKKXVULJGBQN-UWFFTQNDSA-N (4r,4as,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound C([C@@]12[C@@]3(O)CCC(=O)C1OC=1C(O)=CC=C(C2=1)C[C@]31[H])CN1CC1CC1 DQCKKXVULJGBQN-UWFFTQNDSA-N 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- 239000002585 base Substances 0.000 description 17
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- 230000015572 biosynthetic process Effects 0.000 description 13
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- 239000007789 gas Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 9
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 238000007126 N-alkylation reaction Methods 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 159000000000 sodium salts Chemical class 0.000 description 4
- IFGIYSGOEZJNBE-KNLJMPJLSA-N (4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one;bromide Chemical compound [Br-].C[N+]1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)CC1CC1 IFGIYSGOEZJNBE-KNLJMPJLSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 229940050176 methyl chloride Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 0 CC[C@@](*)*([C@@](C1)N*CC2)[C@]2(C*C)c2c1ccc(C)c2O Chemical compound CC[C@@](*)*([C@@](C1)N*CC2)[C@]2(C*C)c2c1ccc(C)c2O 0.000 description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 208000030247 mild fever Diseases 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 230000000631 nonopiate Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42474802P | 2002-11-08 | 2002-11-08 | |
| US42558002P | 2002-11-12 | 2002-11-12 | |
| PCT/US2003/035463 WO2004043964A2 (en) | 2002-11-08 | 2003-11-05 | Process for the preparation of quaternary n-alkyl morphinan alkaloid salts |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006509745A true JP2006509745A (ja) | 2006-03-23 |
| JP2006509745A5 JP2006509745A5 (https=) | 2007-08-16 |
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| JP2004551830A Pending JP2006509745A (ja) | 2002-11-08 | 2003-11-05 | 第四級ｎ−アルキルモルフィナンアルカロイド塩の製造方法 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US7285665B2 (https=) |
| EP (1) | EP1562953B1 (https=) |
| JP (1) | JP2006509745A (https=) |
| AT (1) | ATE444295T1 (https=) |
| AU (1) | AU2003290630B2 (https=) |
| CA (1) | CA2504262C (https=) |
| DE (1) | DE60329520D1 (https=) |
| ES (1) | ES2332453T3 (https=) |
| MX (1) | MXPA05004759A (https=) |
| PT (1) | PT1562953E (https=) |
| WO (1) | WO2004043964A2 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2010520288A (ja) * | 2007-03-06 | 2010-06-10 | マリンクロット インコーポレイテッド | 第４級ｎ−アルキルモルフィナンアルカロイド塩の調製のための方法 |
| JP2010522756A (ja) * | 2007-03-29 | 2010-07-08 | プロジェニックス ファーマシューティカルズ，インコーポレーテッド | 結晶形およびその使用 |
| JP2010535814A (ja) * | 2007-08-09 | 2010-11-25 | レンセラール ポリテクニック インスティチュート | 第四級オピオイドカルボキサミド |
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| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| ES2714198T3 (es) | 2005-03-07 | 2019-05-27 | Univ Chicago | Uso de antagonistas opioideos para atenuar la proliferación y la migración de células endoteliales |
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| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| AR057035A1 (es) | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SíNTESIS DE (R)-N-METILNALTREXONA, COMPOSICIONES FARMACÉUTICAS Y USOS |
| AR057325A1 (es) * | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | Sintesis de (s)-n-metilnaltrexona, composiciones farmaceuticas y usos |
| AU2013200437B2 (en) * | 2005-05-25 | 2015-01-15 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone, process for its synthesis and its pharmaceutical use |
| TWI489984B (zh) | 2006-08-04 | 2015-07-01 | Wyeth Corp | 用於非經腸道傳輸化合物之配方及其用途 |
| TW200815451A (en) * | 2006-08-04 | 2008-04-01 | Wyeth Corp | 6-carboxy-normorphinan derivatives, synthesis and uses thereof |
| US8115002B2 (en) | 2006-09-20 | 2012-02-14 | Mallinckrodt Llc | Preparation of substituted morphinan-6-ones and salts and intermediates thereof |
| FR2906252B1 (fr) * | 2006-09-21 | 2008-11-28 | Sanofi Aventis Sa | Procede de preparation d'halogenures de n-aklyl naltrexone |
| WO2008064150A1 (en) * | 2006-11-22 | 2008-05-29 | Progenics Pharmaceuticals, Inc. | Processes for synthesizing quaternary 4,5-epoxy-morphinan analogs and isolating their n-stereoisomers |
| US20080176884A1 (en) * | 2006-11-22 | 2008-07-24 | Progenics Pharmaceuticals, Inc. | 7,8-Saturated-4,5-Epoxy-Morphinanium Analogs |
| US9040726B2 (en) | 2007-03-06 | 2015-05-26 | Mallinckrodt Llc | Process for the preparation of quaternary N-alkyl morphinan alkaloid salts |
| SI2565195T1 (sl) | 2007-03-29 | 2015-09-30 | Wyeth Llc | Periferalni opioidni receptorji in antagonisti in njih uporaba |
| CL2008000905A1 (es) | 2007-03-29 | 2008-08-22 | Progenics Pharm Inc | Compuestos derivados de morfina, antagonistas del receptor opioide periferico; metodo de preparacion; composicion farmaceutica; y uso para reducir los efectos de la actividad opioide endogena. |
| WO2008138383A1 (de) * | 2007-05-16 | 2008-11-20 | Cilag Ag | Verfahren zur herstellung von n-methylnaltrexonbromid |
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| EP2019105A1 (en) * | 2007-07-19 | 2009-01-28 | Siegfried Ltd. | Process for the preparation of quaternary n-alkyl morphine or morphinane alkaloid derivatives |
| US20110112129A2 (en) * | 2007-11-26 | 2011-05-12 | Pharmacofore, Inc. | Peripheral Phenolic Opioid Antagonist |
| EP2240489A1 (en) | 2008-02-06 | 2010-10-20 | Progenics Pharmaceuticals, Inc. | Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone |
| WO2009103004A1 (en) * | 2008-02-14 | 2009-08-20 | Alkermes, Inc. | Selective opioid compounds |
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| CA2676881C (en) | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
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| EP2398807A1 (en) | 2009-02-23 | 2011-12-28 | Mallinckrodt LLC | (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives |
| CN102325777B (zh) | 2009-02-23 | 2015-08-12 | 马林克罗特公司 | (+)-吗啡喃*n-氧化物及其制备方法 |
| KR20120088537A (ko) | 2009-04-24 | 2012-08-08 | 브럭 유니버시티 | 모르피난 및 모르피논 화합물의 제조방법 |
| US8829020B2 (en) | 2009-07-16 | 2014-09-09 | Mallinckrodt Llc | Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers |
| AU2011263416B2 (en) | 2010-06-11 | 2014-04-10 | Rhodes Technologies | Process for N-dealkylation of tertiary amines |
| CA2802295C (en) | 2010-06-11 | 2016-09-20 | Rhodes Technologies | Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof |
| CN103917543A (zh) | 2011-09-08 | 2014-07-09 | 马林克罗特有限公司 | 在不分离中间体的情况下制备生物碱 |
| WO2015082932A1 (en) | 2013-12-05 | 2015-06-11 | The University Of Bath | Novel opioid compounds and their uses |
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-
2003
- 2003-11-05 AT AT03783211T patent/ATE444295T1/de active
- 2003-11-05 WO PCT/US2003/035463 patent/WO2004043964A2/en not_active Ceased
- 2003-11-05 PT PT03783211T patent/PT1562953E/pt unknown
- 2003-11-05 MX MXPA05004759A patent/MXPA05004759A/es active IP Right Grant
- 2003-11-05 AU AU2003290630A patent/AU2003290630B2/en not_active Expired
- 2003-11-05 EP EP03783211A patent/EP1562953B1/en not_active Expired - Lifetime
- 2003-11-05 JP JP2004551830A patent/JP2006509745A/ja active Pending
- 2003-11-05 DE DE60329520T patent/DE60329520D1/de not_active Expired - Lifetime
- 2003-11-05 ES ES03783211T patent/ES2332453T3/es not_active Expired - Lifetime
- 2003-11-05 CA CA2504262A patent/CA2504262C/en not_active Expired - Lifetime
- 2003-11-05 US US10/530,446 patent/US7285665B2/en not_active Expired - Lifetime
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| US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
| WO2001014382A1 (en) * | 1999-08-23 | 2001-03-01 | Toray Industries, Inc. | Analgesics containing as the active ingredient quaternary ammonium salt derivatives of morphinan |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010520288A (ja) * | 2007-03-06 | 2010-06-10 | マリンクロット インコーポレイテッド | 第４級ｎ−アルキルモルフィナンアルカロイド塩の調製のための方法 |
| JP2011098988A (ja) * | 2007-03-06 | 2011-05-19 | Mallinckrodt Inc | 第４級ｎ−アルキルモルフィナンアルカロイド塩の調製のための方法 |
| JP2016210815A (ja) * | 2007-03-06 | 2016-12-15 | マリンクロッド エルエルシー | 第４級ｎ−アルキルモルフィナンアルカロイド塩の調製のための方法 |
| JP2010522756A (ja) * | 2007-03-29 | 2010-07-08 | プロジェニックス ファーマシューティカルズ，インコーポレーテッド | 結晶形およびその使用 |
| JP2014240400A (ja) * | 2007-03-29 | 2014-12-25 | プロジェニックス ファーマシューティカルズ，インコーポレーテッド | 結晶形およびその使用 |
| JP2016196490A (ja) * | 2007-03-29 | 2016-11-24 | プロジェニックス ファーマシューティカルズ，インコーポレーテッド | 結晶形およびその使用 |
| JP2018123150A (ja) * | 2007-03-29 | 2018-08-09 | プロジェニックス ファーマシューティカルズ，インコーポレーテッド | 結晶形およびその使用 |
| JP2020079263A (ja) * | 2007-03-29 | 2020-05-28 | プロジェニックス ファーマシューティカルズ，インコーポレーテッド | 結晶形およびその使用 |
| JP2010535814A (ja) * | 2007-08-09 | 2010-11-25 | レンセラール ポリテクニック インスティチュート | 第四級オピオイドカルボキサミド |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003290630A1 (en) | 2004-06-03 |
| ATE444295T1 (de) | 2009-10-15 |
| US7285665B2 (en) | 2007-10-23 |
| DE60329520D1 (de) | 2009-11-12 |
| WO2004043964A2 (en) | 2004-05-27 |
| CA2504262C (en) | 2012-01-10 |
| PT1562953E (pt) | 2009-11-19 |
| AU2003290630B2 (en) | 2009-01-29 |
| WO2004043964A3 (en) | 2004-08-26 |
| EP1562953A2 (en) | 2005-08-17 |
| US20060014771A1 (en) | 2006-01-19 |
| EP1562953B1 (en) | 2009-09-30 |
| ES2332453T3 (es) | 2010-02-05 |
| CA2504262A1 (en) | 2004-05-27 |
| MXPA05004759A (es) | 2005-08-02 |
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