CA2692636A1 - Procede de fabrication de cisatracurium et d'intermediaires associes - Google Patents
Procede de fabrication de cisatracurium et d'intermediaires associes Download PDFInfo
- Publication number
- CA2692636A1 CA2692636A1 CA 2692636 CA2692636A CA2692636A1 CA 2692636 A1 CA2692636 A1 CA 2692636A1 CA 2692636 CA2692636 CA 2692636 CA 2692636 A CA2692636 A CA 2692636A CA 2692636 A1 CA2692636 A1 CA 2692636A1
- Authority
- CA
- Canada
- Prior art keywords
- besylate
- cisatracurium
- compound
- mixture
- organic solvent
- 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.)
- Abandoned
Links
- YXSLJKQTIDHPOT-LJCJQEJUSA-N cisatracurium Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H]1[N@+](CCC(=O)OCCCCCOC(=O)CC[N@+]2(C)[C@@H](C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-LJCJQEJUSA-N 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 59
- 230000008569 process Effects 0.000 title claims abstract description 42
- 229960000358 cisatracurium Drugs 0.000 title description 12
- 239000000543 intermediate Substances 0.000 title description 8
- XXZSQOVSEBAPGS-DONVQRBFSA-L cisatracurium besylate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.[O-]S(=O)(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1C[C@H]1[N@+](CCC(=O)OCCCCCOC(=O)CC[N@+]2(C)[C@@H](C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 XXZSQOVSEBAPGS-DONVQRBFSA-L 0.000 claims abstract description 96
- 229960000970 cisatracurium besylate Drugs 0.000 claims abstract description 96
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 claims abstract description 41
- 150000001450 anions Chemical group 0.000 claims abstract description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 141
- 239000000203 mixture Substances 0.000 claims description 76
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 37
- 239000003960 organic solvent Substances 0.000 claims description 37
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 20
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- -1 besylate anions Chemical class 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 13
- 229910052681 coesite Inorganic materials 0.000 claims description 13
- 229910052906 cristobalite Inorganic materials 0.000 claims description 13
- 229910052682 stishovite Inorganic materials 0.000 claims description 13
- 229910052905 tridymite Inorganic materials 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical group [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052925 anhydrite Inorganic materials 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 239000000377 silicon dioxide Substances 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000012320 chlorinating reagent Substances 0.000 claims description 10
- 239000013557 residual solvent Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 9
- 238000005342 ion exchange Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 230000003213 activating effect Effects 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003456 ion exchange resin Substances 0.000 claims description 6
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 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 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000010533 azeotropic distillation Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012264 purified product Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 150000003738 xylenes Chemical class 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 229920001429 chelating resin Polymers 0.000 claims description 2
- 239000002274 desiccant Substances 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 37
- 238000000746 purification Methods 0.000 abstract description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 abstract description 2
- VGKZBAMIYUHSMU-UHFFFAOYSA-N 4-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylic acid Chemical compound OC(=O)C1CCC(NC(=O)N(CCCl)N=O)CC1 VGKZBAMIYUHSMU-UHFFFAOYSA-N 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000010410 layer Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 229960002945 atracurium besylate Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- XXZSQOVSEBAPGS-UHFFFAOYSA-L atracurium besylate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.[O-]S(=O)(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 XXZSQOVSEBAPGS-UHFFFAOYSA-L 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YXWQTVWJNHKSCC-MRXNPFEDSA-N (R)-tetrahydropapaverine Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-MRXNPFEDSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 229960001862 atracurium Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940035480 nimbex Drugs 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 3
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003929 acidic solution Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base 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
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XAMCLRBWHRRBCN-UHFFFAOYSA-N 5-prop-2-enoyloxypentyl prop-2-enoate Chemical compound C=CC(=O)OCCCCCOC(=O)C=C XAMCLRBWHRRBCN-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000000842 neuromuscular blocking agent Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CBYYUJQXRKBSCV-UHFFFAOYSA-N 3-[1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl]propanoic acid Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCN1CCC(O)=O CBYYUJQXRKBSCV-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- WXNXCEHXYPACJF-ZETCQYMHSA-M N-acetyl-L-leucinate Chemical compound CC(C)C[C@@H](C([O-])=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-M 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
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- UONPYBFUZBTBTJ-UHFFFAOYSA-N benzenesulfonate 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.[O-]S(=O)(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CC[NH+]1C.C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CC[NH+]1C UONPYBFUZBTBTJ-UHFFFAOYSA-N 0.000 description 1
- GLLXELVDCIFBPA-UHFFFAOYSA-M benzenesulfonate;5-[3-[1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1h-isoquinolin-2-ium-2-yl]propanoyloxy]pentyl 3-[1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1h-isoquinolin-2-ium-2-yl]propanoate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 GLLXELVDCIFBPA-UHFFFAOYSA-M 0.000 description 1
- QWICHYWTBZTTRD-UHFFFAOYSA-N benzenesulfonic acid;dihydrate Chemical compound O.O.OS(=O)(=O)C1=CC=CC=C1 QWICHYWTBZTTRD-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000004434 industrial solvent Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000005399 mechanical ventilation Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036640 muscle relaxation Effects 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
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000010887 waste solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/10—Quaternary compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94862107P | 2007-07-09 | 2007-07-09 | |
| US60/948,621 | 2007-07-09 | ||
| PCT/IL2008/000590 WO2009007946A1 (fr) | 2007-07-09 | 2008-05-01 | Procédé de fabrication de cisatracurium et d'intermédiaires associés |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2692636A1 true CA2692636A1 (fr) | 2009-01-15 |
Family
ID=39673234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2692636 Abandoned CA2692636A1 (fr) | 2007-07-09 | 2008-05-01 | Procede de fabrication de cisatracurium et d'intermediaires associes |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US20100256381A1 (fr) |
| EP (1) | EP2176227A1 (fr) |
| BR (1) | BRPI0812625A2 (fr) |
| CA (1) | CA2692636A1 (fr) |
| WO (1) | WO2009007946A1 (fr) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008107887A2 (fr) | 2007-03-08 | 2008-09-12 | Chemagis Ltd. | Procédé de séparation de sels (1r,1'r)-atracurium |
| WO2008117271A1 (fr) * | 2007-03-26 | 2008-10-02 | Chemagis Ltd. | Procédé de séparation de sels de (1r, 1'r)-atracurium |
| US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
| WO2008132748A1 (fr) | 2007-05-01 | 2008-11-06 | Chemagis Ltd. | Procédé de fabrication de composés de cisatracurium et intermédiaires associés |
| US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
| CA2702535A1 (fr) * | 2007-10-29 | 2009-05-07 | Chemagis Ltd. | Nouveaux sels de r,r'-atracurium |
| BRPI0907656A2 (pt) * | 2008-05-01 | 2019-08-27 | Chemagis Ltd | composto para testar a pureza de cisatracúrio, método para testar a pureza de uma amostra de besilato de cisatracúrio, uso de um composto para testar a pureza de cisatracúrio e processo para preparar compostos para testar a pureza de cisatracúrio |
| WO2010128518A2 (fr) * | 2009-05-04 | 2010-11-11 | Gland Pharma Limited | Nouveau procédé pour la préparation de bésylate de cisatracurium |
| CN104557703B (zh) * | 2015-01-27 | 2018-01-16 | 江苏嘉逸医药有限公司 | 一种苯磺顺阿曲库铵精制方法 |
| CN111777554A (zh) * | 2019-04-04 | 2020-10-16 | 山东瑞安药业有限公司 | 一种合成苯磺顺阿曲库铵的方法 |
| CN112047883B (zh) * | 2019-06-06 | 2024-04-19 | 上海特化医药科技有限公司 | 顺苯磺酸阿曲库铵的制备方法 |
| CN113372271A (zh) * | 2020-12-24 | 2021-09-10 | 上海药坦药物研究开发有限公司 | 一种顺苯磺酸阿曲库铵的制备方法 |
| WO2023086696A2 (fr) * | 2021-11-10 | 2023-05-19 | ODH IP Corp. | Appareil et procédés de synthèse en flux continu de cisatracurium |
| CN115947685A (zh) * | 2023-02-07 | 2023-04-11 | 山东铂源药业股份有限公司 | 苯磺顺阿曲库铵手性异构体杂质的制备方法 |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU506657B2 (en) * | 1975-12-10 | 1980-01-17 | Wellcome Foundation Limited, The | Isoquinoline derivatives |
| US4491665A (en) * | 1979-10-19 | 1985-01-01 | Burroughs Wellcome Co. | Method of preparing isomers of bis isoquinolinium compounds |
| US4701460A (en) * | 1980-12-17 | 1987-10-20 | Burroughs Wellcome Co. | Long duration neuromuscular blocking agents |
| GB8418303D0 (en) * | 1984-07-18 | 1984-08-22 | Wellcome Found | Compounds |
| BG41897A1 (en) * | 1985-07-19 | 1987-09-15 | Ivanov | Dichlormethylate of n, n'- 4, 10- dioxa- 3, 11- bis- tetrahydropapaverine and method for its preparation |
| JPS62265266A (ja) * | 1986-05-13 | 1987-11-18 | Takasago Corp | Ｎ−アシル−テトラヒドロイソキノリン類の製造法 |
| US4988815A (en) * | 1989-10-26 | 1991-01-29 | Riker Laboratories, Inc. | 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines |
| US5453510A (en) * | 1990-07-13 | 1995-09-26 | Burroughs Wellcome Co. | Neuromuscular blocking agents |
| US5240939A (en) * | 1991-10-31 | 1993-08-31 | Anaquest, Inc. | Nitrogen bridge tetrahydroisoquinolines |
| DE19535762A1 (de) * | 1995-09-26 | 1997-03-27 | Basf Ag | Verfahren zur Racematspaltung |
| US5684154A (en) * | 1996-02-16 | 1997-11-04 | Abbott Laboratories | Process for the preparation and isolation of atracurium besylate |
| BR9808422B1 (pt) * | 1997-03-25 | 2010-08-24 | composto, composiÇço farmacÊutica, uso de um composto, e, processo para a preparaÇço de um composto. | |
| US7265099B1 (en) * | 1999-08-13 | 2007-09-04 | Organon N.V. | Use of chemical chelators as reversal agents for drug-induced neuromuscular block |
| GB2371862B (en) * | 2000-12-29 | 2004-07-14 | Bioorg Bv | Reference standards for determining the purity or stability of amlodipine maleate and processes therefor |
| US20060009485A1 (en) * | 2005-06-23 | 2006-01-12 | Chemagis Ltd | Method of reprocessing quaternary ammonium-containing neuromuscular blocking agents |
| ATE554769T1 (de) * | 2006-12-06 | 2012-05-15 | Cornell Res Foundation Inc | Neuromuskuläre blocker mit mittlerer dauer und antagonisten advon |
| WO2008107887A2 (fr) * | 2007-03-08 | 2008-09-12 | Chemagis Ltd. | Procédé de séparation de sels (1r,1'r)-atracurium |
| WO2008132748A1 (fr) * | 2007-05-01 | 2008-11-06 | Chemagis Ltd. | Procédé de fabrication de composés de cisatracurium et intermédiaires associés |
| US8357807B2 (en) * | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
| CA2702535A1 (fr) * | 2007-10-29 | 2009-05-07 | Chemagis Ltd. | Nouveaux sels de r,r'-atracurium |
-
2008
- 2008-05-01 CA CA 2692636 patent/CA2692636A1/fr not_active Abandoned
- 2008-05-01 EP EP08738291A patent/EP2176227A1/fr not_active Withdrawn
- 2008-05-01 US US12/667,634 patent/US20100256381A1/en not_active Abandoned
- 2008-05-01 BR BRPI0812625A patent/BRPI0812625A2/pt not_active IP Right Cessation
- 2008-05-01 WO PCT/IL2008/000590 patent/WO2009007946A1/fr not_active Ceased
-
2012
- 2012-10-10 US US13/648,830 patent/US20130041154A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20130041154A1 (en) | 2013-02-14 |
| US20100256381A1 (en) | 2010-10-07 |
| EP2176227A1 (fr) | 2010-04-21 |
| BRPI0812625A2 (pt) | 2019-02-19 |
| WO2009007946A1 (fr) | 2009-01-15 |
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Effective date: 20140501 |