CH493522A - Verfahren zur Herstellung von N-substituierten 14-Hydroxydihydronormorphinen - Google Patents
Verfahren zur Herstellung von N-substituierten 14-HydroxydihydronormorphinenInfo
- Publication number
- CH493522A CH493522A CH1803266A CH1803266A CH493522A CH 493522 A CH493522 A CH 493522A CH 1803266 A CH1803266 A CH 1803266A CH 1803266 A CH1803266 A CH 1803266A CH 493522 A CH493522 A CH 493522A
- Authority
- CH
- Switzerland
- Prior art keywords
- group
- hydroxydihydronormorphinone
- formula
- keto
- morphine
- Prior art date
Links
- 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 title claims abstract description 17
- 229960005181 morphine Drugs 0.000 title claims abstract description 8
- 229940035676 analgesics Drugs 0.000 title abstract description 7
- 239000000730 antalgic agent Substances 0.000 title abstract description 7
- 239000003887 narcotic antagonist Substances 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 3
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 alkyl sulfonic acid Chemical compound 0.000 claims description 23
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 11
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 230000001419 dependent effect Effects 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims description 3
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012965 benzophenone Substances 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000003500 enol ether group Chemical group 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 11
- 241000700159 Rattus Species 0.000 abstract 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 abstract description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 abstract description 2
- 229960005118 oxymorphone Drugs 0.000 abstract description 2
- 230000009291 secondary effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000000155 melt Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 13
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 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 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229930194542 Keto Natural products 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000001241 acetals Chemical class 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- JFWMYCVMQSLLOO-UHFFFAOYSA-N cyclobutanecarbonyl chloride Chemical compound ClC(=O)C1CCC1 JFWMYCVMQSLLOO-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000006637 cyclobutyl carbonyl group Chemical group 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ONBWJWYUHXVEJS-ZTYRTETDSA-N Normorphine Chemical class C([C@@H](NCC1)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ONBWJWYUHXVEJS-ZTYRTETDSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- FLHFTXCMKFVKRP-UHFFFAOYSA-N bromomethylcyclobutane Chemical compound BrCC1CCC1 FLHFTXCMKFVKRP-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- WBMKMLWMIQUJDP-STHHAXOLSA-N (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-ynyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one hydrochloride Chemical compound Cl.Oc1ccc2C[C@H]3N(CC#C)CC[C@@]45[C@@H](Oc1c24)C(=O)CC[C@@]35O WBMKMLWMIQUJDP-STHHAXOLSA-N 0.000 description 1
- MISTZQJSHHTDCF-UHFFFAOYSA-N 1-(1-propoxyethoxy)propane Chemical compound CCCOC(C)OCCC MISTZQJSHHTDCF-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- NBUHTTJGQKIBMR-UHFFFAOYSA-N 4,6-dimethylpyrimidin-5-amine Chemical compound CC1=NC=NC(C)=C1N NBUHTTJGQKIBMR-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000007914 Labor Pain Diseases 0.000 description 1
- 208000035945 Labour pain Diseases 0.000 description 1
- 208000018526 Narcotic-Related disease Diseases 0.000 description 1
- 238000006036 Oppenauer oxidation reaction Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 0.000 description 1
- RNIHFEJHABJCID-UHFFFAOYSA-N cyclobutylmethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1CCC1 RNIHFEJHABJCID-UHFFFAOYSA-N 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000012458 free base Substances 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
- 230000003400 hallucinatory effect Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940051129 meperidine hydrochloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- 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 1
- 239000012452 mother liquor Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960000805 nalbuphine Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
- 201000005040 opiate dependence Diseases 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 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)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52170866A | 1966-01-19 | 1966-01-19 | |
| US677727A US3393197A (en) | 1966-01-19 | 1967-10-24 | Nu-substituted-14-hydroxydihydronormorphines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH493522A true CH493522A (de) | 1970-07-15 |
Family
ID=27060549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1803266A CH493522A (de) | 1966-01-19 | 1966-12-16 | Verfahren zur Herstellung von N-substituierten 14-Hydroxydihydronormorphinen |
Country Status (13)
Families Citing this family (57)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3476757A (en) * | 1966-04-18 | 1969-11-04 | Syntex Corp | Tetrahydropyranyl and tetrahydrofuranyl ethers of benzomorphans and morphanans |
| US4161597A (en) * | 1976-12-20 | 1979-07-17 | Research Corporation | N-alkyl-14-hydroxymorphinans and derivatives |
| GB1593191A (en) * | 1977-03-23 | 1981-07-15 | Reckitt & Colmann Prod Ltd | Derivatives of morphine |
| GB1587831A (en) * | 1977-03-23 | 1981-04-08 | Reckitt & Colmann Prod Ltd | Morphine derivatives |
| US4218454A (en) * | 1977-07-08 | 1980-08-19 | Sri International | N-αMethylcyclopropylmethyl derivatives of normorphine and noroodeine, and analgesic compositions and methods employing the normorphine derivatives |
| US4269843A (en) * | 1978-05-24 | 1981-05-26 | Sri International | N-Sec-alkyl analogs of norcodeine and normorphine and analgesic compositions and methods employing the normorphine derivatives |
| US4272541A (en) * | 1978-06-02 | 1981-06-09 | Miles Laboratories, Inc. | 7,8 and 7-8 Substituted 4,5α-epoxymorphinan-6-one compounds, and methods of treating pain and drug dependence with them |
| US4236008A (en) * | 1978-09-19 | 1980-11-25 | E. I. Du Pont De Nemours And Company | Fluorination of precursors for fluorine analogs of hydrocodone and oxycodone |
| US4241065A (en) * | 1979-07-02 | 1980-12-23 | E. I. Du Pont De Nemours And Company | Fluoro analogs of hydrocodone and oxycodone useful as analgesics, narcotic antagonists or both |
| US4237140A (en) * | 1979-05-18 | 1980-12-02 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetaminophen |
| US4282215A (en) * | 1980-06-17 | 1981-08-04 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetylsalicylic acid, derivative or salt thereof |
| US4366159A (en) * | 1981-09-08 | 1982-12-28 | Michael Richard Magruder | Nalbuphine-narcotic analgesic composition and method of producing analgesia |
| US4404211A (en) * | 1982-06-30 | 1983-09-13 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and flurbiprofen |
| US4404209A (en) * | 1982-06-30 | 1983-09-13 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and sulindac |
| US4404210A (en) * | 1982-06-30 | 1983-09-13 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and ibuprofen |
| US4407804A (en) * | 1982-06-30 | 1983-10-04 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and indomethacin |
| US4404208A (en) * | 1982-06-30 | 1983-09-13 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and tiflamizole |
| US4407805A (en) * | 1982-06-30 | 1983-10-04 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and zomepirac |
| AU565634B2 (en) * | 1982-06-30 | 1987-09-24 | E.I. Du Pont De Nemours And Company | Synergistic compositions of nalbuphine and non-narcotic analgesic compounds |
| US4402962A (en) * | 1982-06-30 | 1983-09-06 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and 4,5-bis(4-methoxyphenyl)-2-(trifluoromethylsulfonyl)-1H-imidazole |
| US4477457A (en) * | 1982-10-28 | 1984-10-16 | E. I. Du Pont De Nemours And Company | Method for inducing anorexia using nalmetrene |
| US4478840A (en) * | 1983-10-11 | 1984-10-23 | E. I. Du Pont De Nemours And Company | Appetite suppressing compositions and methods |
| 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 |
| CA1280695C (en) * | 1985-04-29 | 1991-02-26 | Benigno M. Sulit, Jr. | Nalbuphine-local anesthetic analgesic composition and method of producing analgesia |
| DE4132159A1 (de) * | 1991-09-27 | 1993-04-01 | Boehringer Ingelheim Kg | 14-hydroxy-n-(2-methoxyethyl)-7,8-dihydromorphin und -norisomorphin, verfahren zu deren herstellung und deren verwendung als arzneimittel |
| US5478577A (en) * | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
| AU699114B2 (en) * | 1994-05-31 | 1998-11-19 | Mallinckrodt Chemical, Inc. | The preparation of nalbuphine having low levels of beta-epimer |
| US6348216B1 (en) * | 1996-06-10 | 2002-02-19 | Knoll Pharmaceutical Company | Ibuprofen and narcotic analgesic compositions |
| US6361794B1 (en) | 1996-06-12 | 2002-03-26 | Basf Corporation | Method of making ibuprofen and narcotic analgesic composition |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US7458374B2 (en) | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| US7585493B2 (en) | 2001-05-24 | 2009-09-08 | Alexza Pharmaceuticals, Inc. | Thin-film drug delivery article and method of use |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| US7766013B2 (en) | 2001-06-05 | 2010-08-03 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
| JP2005503425A (ja) * | 2001-05-24 | 2005-02-03 | アレックザ モレキュラー デリヴァリー コーポレイション | 所定の吸入ルートによる薬剤エステルの送出 |
| US7090830B2 (en) | 2001-05-24 | 2006-08-15 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| AU2002316582B2 (en) * | 2001-07-06 | 2007-03-15 | Endo Pharmaceuticals, Inc. | Oral administration of 6-hydroxy-oxymorphone for use as an analgesic |
| ATE376832T1 (de) * | 2001-07-06 | 2007-11-15 | Penwest Pharmaceuticals Co | Verzögert freisetzende formulierungen von oxymorphon |
| US8329216B2 (en) * | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
| WO2003026743A2 (en) * | 2001-09-26 | 2003-04-03 | Penwest Pharmaceuticals Company | Opioid formulations having reduced potential for abuse |
| WO2003051367A1 (en) * | 2001-12-18 | 2003-06-26 | Alexza Molecular Delivery Corporation | Parental analgesic formulations comprising fentanyl and a cannabinoid receptor agonist |
| US20040105818A1 (en) | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
| US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
| WO2004104492A2 (en) | 2003-05-21 | 2004-12-02 | Alexza Pharmaceuticals, Inc. | Optically ignited or electrically ignited self-contained heating unit and drug-supply unit employing same |
| CA2527693C (en) * | 2003-06-04 | 2018-09-18 | Harry G. Brittain | Polymorphic forms of naltrexone |
| US7540286B2 (en) | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| AU2004322756B2 (en) | 2004-08-12 | 2011-04-14 | Alexza Pharmaceuticals, Inc. | Aerosol drug delivery device incorporating percussively activated heat packages |
| US20070093517A1 (en) * | 2005-10-24 | 2007-04-26 | Gary Newton | Local anesthetic compositions |
| US20070212414A1 (en) * | 2006-03-08 | 2007-09-13 | Penwest Pharmaceuticals Co. | Ethanol-resistant sustained release formulations |
| MX2008013594A (es) * | 2006-04-21 | 2009-01-16 | Nektar Therapeutics Al Corp | Reduccion estereoselectiva de una morfinona. |
| US20080216828A1 (en) | 2007-03-09 | 2008-09-11 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
| 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 |
| ES2423180T3 (es) * | 2007-04-16 | 2013-09-18 | Mallinckrodt Llc | Nueva reducción de opiáceos mediante reacción de transferencia de hidrógeno catalítica |
| US20090124650A1 (en) * | 2007-06-21 | 2009-05-14 | Endo Pharmaceuticals, Inc. | Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol |
| US8067596B2 (en) | 2007-12-17 | 2011-11-29 | Mallinckrodt Llc | Processes for the production of (+)- “Nal” morphinan compounds |
| WO2017046814A1 (en) * | 2015-09-14 | 2017-03-23 | Rusan Pharma Limited | A safe and environment friendly process for producing nalbuphine or its pharmaceutically acceptable salts thereof |
| US12214118B2 (en) | 2018-02-02 | 2025-02-04 | Alexza Pharmaceuticals, Inc. | Electrical condensation aerosol device |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3320262A (en) * | 1964-09-22 | 1967-05-16 | Lewenstein | 14 hydroxy morphine and codeine carboxymethyloximes |
-
1966
- 1966-11-20 IL IL26896A patent/IL26896A/en unknown
- 1966-12-16 GB GB56530/66A patent/GB1119270A/en not_active Expired
- 1966-12-16 CH CH1803266A patent/CH493522A/de not_active IP Right Cessation
- 1966-12-19 DE DE1670616A patent/DE1670616C3/de not_active Expired
- 1966-12-19 DE DE1795707A patent/DE1795707C3/de not_active Expired
- 1966-12-20 LU LU52650D patent/LU52650A1/xx unknown
- 1966-12-22 NL NL6618022.A patent/NL165744C/xx not_active IP Right Cessation
- 1966-12-22 SE SE17639/66A patent/SE329402B/xx unknown
- 1966-12-23 NO NO166137A patent/NO120368B/no unknown
- 1966-12-23 DK DK667766AA patent/DK115631B/da not_active IP Right Cessation
- 1966-12-23 AT AT1135867A patent/AT292206B/de not_active IP Right Cessation
- 1966-12-26 ES ES334942A patent/ES334942A1/es not_active Expired
-
1967
- 1967-01-13 FR FR91097A patent/FR6112M/fr not_active Expired
- 1967-10-24 US US677727A patent/US3393197A/en not_active Expired - Lifetime
-
1978
- 1978-05-24 NL NL7805652A patent/NL7805652A/xx not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK115631B (da) | 1969-10-27 |
| GB1119270A (en) | 1968-07-10 |
| DE1795707A1 (de) | 1973-10-11 |
| NL6618022A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1967-07-20 |
| DE1670616C3 (de) | 1978-06-29 |
| DE1670616B2 (de) | 1977-11-10 |
| NL165744B (nl) | 1980-12-15 |
| IL26896A (en) | 1970-11-30 |
| DE1670616A1 (de) | 1970-09-10 |
| NL165744C (nl) | 1981-05-15 |
| FR6112M (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1968-06-17 |
| ES334942A1 (es) | 1968-03-01 |
| LU52650A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1967-02-20 |
| US3393197A (en) | 1968-07-16 |
| NO120368B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1970-10-12 |
| NL7805652A (nl) | 1978-09-29 |
| DE1795707C3 (de) | 1979-12-20 |
| DE1795707B2 (de) | 1979-04-19 |
| AT292206B (de) | 1971-08-25 |
| SE329402B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1970-10-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUE | Assignment |
Owner name: E.I. DU PONT DE NEMOURS & COMPANY |
|
| PL | Patent ceased |