IL41562A - History of morphine, their manufacture and the pharmaceutical preparations containing them - Google Patents
History of morphine, their manufacture and the pharmaceutical preparations containing themInfo
- Publication number
- IL41562A IL41562A IL41562A IL4156273A IL41562A IL 41562 A IL41562 A IL 41562A IL 41562 A IL41562 A IL 41562A IL 4156273 A IL4156273 A IL 4156273A IL 41562 A IL41562 A IL 41562A
- Authority
- IL
- Israel
- Prior art keywords
- hydroxy
- acid addition
- addition salts
- cyclopropylmethylmorphinan
- methoxy
- Prior art date
Links
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 229940051807 opiod analgesics morphinan derivative Drugs 0.000 title description 5
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 81
- 239000002253 acid Substances 0.000 claims description 73
- -1 hydroxy, methoxy Chemical group 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 52
- 238000002360 preparation method Methods 0.000 claims description 50
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
- 239000000126 substance Substances 0.000 claims description 25
- YBYCJQQRZPXLHU-UHFFFAOYSA-N 1,2,3,4,5,6,7,8-octahydroisoquinoline Chemical compound C1CNCC2=C1CCCC2 YBYCJQQRZPXLHU-UHFFFAOYSA-N 0.000 claims description 22
- YWGZKZKVJMGGFQ-ZCNNSNEGSA-N (1R,9R,10R)-17-(cyclopropylmethyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-5-ol Chemical compound C([C@@]12C3=CC=C(O)C=C3C[C@@]3([C@@H]1CCCC2)[H])CN3CC1CC1 YWGZKZKVJMGGFQ-ZCNNSNEGSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- LBSHNAQJABPQEF-HBMCJLEFSA-N (1R,9R,10R)-17-(cyclopropylmethyl)-5-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene Chemical compound COC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3CC3CC3 LBSHNAQJABPQEF-HBMCJLEFSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000007858 starting material Substances 0.000 claims description 9
- PPSQYPUJCWWWBV-BDTNDASRSA-N [(1R,9R,10R)-17-(cyclopropylmethyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-5-yl] acetate Chemical compound C(C)(=O)OC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3CC3CC3 PPSQYPUJCWWWBV-BDTNDASRSA-N 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 5
- LXIKNRZDRGRTNU-SQGPQFPESA-N (1R,9R,10R)-17-(cyclopropylmethyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-3-ol Chemical compound OC1=CC=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C12)CCN3CC3CC3 LXIKNRZDRGRTNU-SQGPQFPESA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 7
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims 1
- 125000006307 alkoxy benzyl group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 171
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 104
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 98
- 229910001868 water Inorganic materials 0.000 description 90
- 239000000203 mixture Substances 0.000 description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 64
- 239000000243 solution Substances 0.000 description 59
- 239000002904 solvent Substances 0.000 description 56
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 42
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 37
- 239000000908 ammonium hydroxide Substances 0.000 description 37
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000725 suspension Substances 0.000 description 29
- 238000001953 recrystallisation Methods 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 26
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 26
- PDMHIEDETZUMJB-BBWFWOEESA-N C1CCC[C@H]2[C@H]3CC4=CC(OC)=CC=C4[C@@]12CCN3 Chemical compound C1CCC[C@H]2[C@H]3CC4=CC(OC)=CC=C4[C@@]12CCN3 PDMHIEDETZUMJB-BBWFWOEESA-N 0.000 description 24
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 238000004821 distillation Methods 0.000 description 17
- 229960000443 hydrochloric acid Drugs 0.000 description 17
- 235000011167 hydrochloric acid Nutrition 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- HZFBREWCVYDSFK-ZVDOUQERSA-N cyclopropyl-[(1R,9R,10R)-5-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-17-yl]methanone Chemical compound COC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3C(=O)C3CC3 HZFBREWCVYDSFK-ZVDOUQERSA-N 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- NFSXIELCEYOSOX-VNMUXGFYSA-N P(=O)(O)(O)O.COC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3 Chemical compound P(=O)(O)(O)O.COC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3 NFSXIELCEYOSOX-VNMUXGFYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- LWJLZPYNSKOYBR-XHSDSOJGSA-N morphinan-2-ol Chemical compound C1CCC[C@H]2[C@]3([H])NCC[C@@]21C1=CC=C(O)C=C1C3 LWJLZPYNSKOYBR-XHSDSOJGSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- 239000012280 lithium aluminium hydride Substances 0.000 description 8
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 8
- 229960005181 morphine Drugs 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000002198 insoluble material Substances 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- UYHJTBFEPXNNBQ-NJBQKBHSSA-N 17-(cyclopropylmethyl)-morphinan-2-ol hydrochloride Chemical compound Cl.C([C@@]12CCCC[C@H]2[C@H]2CC=3C1=CC=C(C=3)O)CN2CC1CC1 UYHJTBFEPXNNBQ-NJBQKBHSSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- 229940095064 tartrate Drugs 0.000 description 6
- YPSHMEJCPYEXOU-JJRVBVJISA-N (1R,9R,10R)-3-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene Chemical compound COC1=CC=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C12)CCN3 YPSHMEJCPYEXOU-JJRVBVJISA-N 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000001640 fractional crystallisation Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000010933 acylation Effects 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 229960001367 tartaric acid Drugs 0.000 description 4
- GBFHSQJNPGVNMH-ZRBLBEILSA-N (1R,9R,10R)-17-(cyclohexylmethyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-5-ol Chemical compound OC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3CC3CCCCC3 GBFHSQJNPGVNMH-ZRBLBEILSA-N 0.000 description 3
- VYLZYCCUCRFUEI-WAOWUJCRSA-N (1R,9R,10R)-17-(cyclopropylmethyl)-3-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene Chemical compound COC1=CC=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C12)CCN3CC3CC3 VYLZYCCUCRFUEI-WAOWUJCRSA-N 0.000 description 3
- LGGVQBQRPZGSMO-GVAUOCQISA-N (1R,9R,10R)-5-methoxy-17-(2-phenylethyl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene Chemical compound COC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3CCC3=CC=CC=C3 LGGVQBQRPZGSMO-GVAUOCQISA-N 0.000 description 3
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000002775 capsule 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
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- HUPPMZAZDPCPDA-HDMKZQKVSA-N (1R,9R,10R)-3-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene-17-carbaldehyde Chemical compound COC1=CC=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C12)CCN3C=O HUPPMZAZDPCPDA-HDMKZQKVSA-N 0.000 description 2
- WGOCDJHGPAOYKZ-KSZLIROESA-N (1R,9R,10R)-5-methoxy-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene-17-carbaldehyde Chemical compound COC1=CC=2C[C@@H]3[C@@H]4CCCC[C@@]4(C2C=C1)CCN3C=O WGOCDJHGPAOYKZ-KSZLIROESA-N 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
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- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
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- 230000003197 catalytic effect Effects 0.000 description 1
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
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- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
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- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23371572A | 1972-03-10 | 1972-03-10 | |
| US00299478A US3810899A (en) | 1972-03-10 | 1972-10-20 | 2-hydroxy-n-substituted-morphinan derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL41562A0 IL41562A0 (en) | 1973-04-30 |
| IL41562A true IL41562A (en) | 1977-04-29 |
Family
ID=26927165
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL41562A IL41562A (en) | 1972-03-10 | 1973-02-16 | History of morphine, their manufacture and the pharmaceutical preparations containing them |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US3810899A (is") |
| AU (1) | AU475007B2 (is") |
| CA (1) | CA1014954A (is") |
| CH (2) | CH591449A5 (is") |
| DK (1) | DK138988B (is") |
| FR (1) | FR2181800B1 (is") |
| GB (1) | GB1402502A (is") |
| IL (1) | IL41562A (is") |
| NL (1) | NL7303050A (is") |
| PH (1) | PH11649A (is") |
| SE (1) | SE403908B (is") |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4556712A (en) * | 1981-05-20 | 1985-12-03 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Preparation and racemization of chiral 1-benzyl-1,2,3,4-tetrahydroisoquinolines |
| US4410700A (en) * | 1980-07-03 | 1983-10-18 | The United States Of America As Represented By The Department Of Health And Human Services | Preparation of chiral 1-benzyl-1,2,3,4-tetrahydroisoquinolines by optical resolution |
| US4496762A (en) * | 1983-03-29 | 1985-01-29 | Eastman Kodak Company | Process for the preparation of N-(2-(cyclo-hexen-1-yl)ethyl)-4-methoxybenzeneacetamide |
| US5905153A (en) * | 1996-10-02 | 1999-05-18 | Roche Vitamins Inc. | Process for preparing (9α,13α,14α)-1-(3-methoxy-morphinan-17-yl)alkanones |
| US5849917A (en) * | 1996-10-02 | 1998-12-15 | Roche Vitamins Inc. | Process for the preparation of isoquinoline compounds |
| JP5097770B2 (ja) * | 2006-04-21 | 2012-12-12 | ザック システム エス．ピー．エー． | ドルゾラミドの調製方法 |
-
1972
- 1972-10-20 US US00299478A patent/US3810899A/en not_active Expired - Lifetime
-
1973
- 1973-02-07 CH CH209676A patent/CH591449A5/xx not_active IP Right Cessation
- 1973-02-07 CH CH177473A patent/CH586205A5/xx not_active IP Right Cessation
- 1973-02-15 AU AU52227/73A patent/AU475007B2/en not_active Expired
- 1973-02-16 IL IL41562A patent/IL41562A/en unknown
- 1973-02-27 DK DK106673AA patent/DK138988B/da unknown
- 1973-03-05 NL NL7303050A patent/NL7303050A/xx not_active Application Discontinuation
- 1973-03-08 PH PH14403A patent/PH11649A/en unknown
- 1973-03-08 CA CA165,651A patent/CA1014954A/en not_active Expired
- 1973-03-08 FR FR7308289A patent/FR2181800B1/fr not_active Expired
- 1973-03-09 SE SE7303373A patent/SE403908B/xx unknown
- 1973-03-09 GB GB1142673A patent/GB1402502A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH591449A5 (is") | 1977-09-15 |
| FR2181800A1 (is") | 1973-12-07 |
| DK138988B (da) | 1978-11-27 |
| GB1402502A (en) | 1975-08-13 |
| DK138988C (is") | 1979-05-07 |
| AU5222773A (en) | 1974-08-15 |
| PH11649A (en) | 1978-05-08 |
| FR2181800B1 (is") | 1976-05-14 |
| CH586205A5 (is") | 1977-03-31 |
| IL41562A0 (en) | 1973-04-30 |
| AU475007B2 (en) | 1976-08-12 |
| NL7303050A (is") | 1973-09-12 |
| CA1014954A (en) | 1977-08-02 |
| SE403908B (sv) | 1978-09-11 |
| US3810899A (en) | 1974-05-14 |
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