WO2010128518A2 - Novel process for the preparation of cisatracurium besylate - Google Patents
Novel process for the preparation of cisatracurium besylate Download PDFInfo
- Publication number
- WO2010128518A2 WO2010128518A2 PCT/IN2009/000515 IN2009000515W WO2010128518A2 WO 2010128518 A2 WO2010128518 A2 WO 2010128518A2 IN 2009000515 W IN2009000515 W IN 2009000515W WO 2010128518 A2 WO2010128518 A2 WO 2010128518A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- besylate
- acid
- cisatracurium besylate
- product
- methyl
- Prior art date
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- 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 title claims abstract description 38
- 229960000970 cisatracurium besylate Drugs 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 16
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 16
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 229960002945 atracurium besylate Drugs 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
- XAMCLRBWHRRBCN-UHFFFAOYSA-N 5-prop-2-enoyloxypentyl prop-2-enoate Chemical compound C=CC(=O)OCCCCCOC(=O)C=C XAMCLRBWHRRBCN-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 claims description 9
- WXNXCEHXYPACJF-SSDOTTSWSA-N N-acetyl-D-leucine Chemical compound CC(C)C[C@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-SSDOTTSWSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 8
- 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 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 235000011054 acetic acid Nutrition 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 230000001376 precipitating effect Effects 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229940043375 1,5-pentanediol Drugs 0.000 claims description 5
- YXWQTVWJNHKSCC-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-UHFFFAOYSA-N 0.000 claims description 5
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 claims description 5
- 229940077386 sodium benzenesulfonate Drugs 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- MZSDGDXXBZSFTG-UHFFFAOYSA-M sodium;benzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC=C1 MZSDGDXXBZSFTG-UHFFFAOYSA-M 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 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 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000003818 flash chromatography Methods 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 23
- 229960001862 atracurium Drugs 0.000 description 7
- 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 5
- 239000000463 material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 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 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 description 1
- -1 3-oxo-3, 1 -propanediyl Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000842 neuromuscular blocking agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 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
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention is related to a novel process for the preparation of cisatracurium besylate, more particularly optically and geometrically pure cisatracurium besylate in large scale.
- Atracurium besylate 2,2'-[l,5-pentanediylbis[oxy(3-oxo-3,l-propanediyl)]]bis[l-[(3,4- dimethoxyphenyl) methyl]- 1 ,2,3,4-tetrahydro-6,7-dimethoxy-2- methylisoquinolinium] dibenzenesulfonate is a non polarizing neuromuscular blocking agent was first approved in 1982.
- Cisatracurium besylate is a mixture of Cis-Cis, Cis-Trans and Trans-Trans isomer and also optically inactive.
- Cisatracurium besylate is lR-Cis-l'R-Cis-2,2'-[l,5 pentanediylbis - [oxy(3-oxo-3, 1 -propanediyl)]]bis[ 1 -[(3,4- dimethoxyphenyl) methyl]- 1 ,2,3,4-tetrahydro- 6,7-dimethoxy-2- methylisoquinolinium]dibenzenesulfonate the Cis-Cis isomer of R- Atracurium besylate.
- Cisatracurium besylate has the below structural formula as follows
- Ostrovsky et.al, WO 2008/11721 described a method for separating cisatracurium besylate from the mixture of atracurium isomers using a reverse phase HPLC with a mobile phase in which the isomers are claimed to be stable. However, this is not an industrially viable process.
- Another object of the present invention to provide a novel process for the preparation of cis artacurium besylate which is enatiometrically and isomerically pure.
- Yet another object of the present invention provides a method which is industrially viable and economical process for the production of cisatracurium besylate.
- Another embodiment of the present invention to provide a industrially viable and economical process for the production of cisatracurium besylate.
- Yet another embodiment of the present invention to provide a novel process for the preparation of cis artacurium besylate, which is enatiometrically and isomerically pure.
- Still another embodiment of the present invention to provide a industrially viable separation process to separate the cis-cis isomer from other isomer atracurium besylate.
- the present invention pertains to a novel process for the preparation of cisatracurium besylate involving the followings steps: According to the present invention a novel process for the preparation of cisatracurium besylate comprising:
- step (c) treating the product obtained from step (c) with methyl benzenesulfonate in acetonitrile in the presence of inorganic base yielded IR, l'R-Atracurium besylate; e. separating pure cisatracurium besylate from the product obtained in step (d) by flash chromatography using silica gel (30 to 50 ⁇ ) in the ratio of 1 (substrate): 40 and solvent system comprising dichloromethane, methanol mixture containing benzene sulfonic acid; f.
- cisatracurium besylate was further purified by dissolving the product from step (g) in a mixture of acetonitrile, isopropyl alcohol (IPA) and precipitating in ethyl acetate to yield pure cisatracurium besylate.
- the acrylate used in the step a) of the present invention is preferably methylacrylate, ethyl acrylate, propyl acrylate and the like most preferably methyl acrylate.
- the acid catalyst used in the step a) according to the present invention is benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, most preferably p-toluenesulfonic acid.
- the chiral compound used for the resolution in the step b) of present invention is N- acetyl-L-leucine, N-acetyl-D-leucine and, the like preferably N-acetyl-D-leucine.
- the solvent used for the resolution in the step b) of this novel process is methanol, ethanol, isopropanaol and the like, most preferably isopropanol.
- the preferred temperature for the reaction step (c) is 65-75°C, most preferably 70- 75°C.
- the acid used is acetic acid, formic acid, propionic acid and the like, most preferably acetic acid.
- the product isolated was besylate, oxalate, and mesylate and the like, most preferably oxalate.
- the reaction temperature in step (d) of the present invention is at 15-30 0 C, most preferably 20-25 0 C and the inorganic base used was sodium carbonate, potassium carbonate, sodium bicarbonate and the like, and most preferably sodium bicarbonate.
- the organic solvent used for the reaction was actonitrile or dichloromethane, dichloroethane, and most preferably acetonitrile. Removal of the excess methyl benzenesulfonate after the completion of reaction by extraction with methyl t-butyl ether (MTBE) and the isolation of product by extraction with dichloromethane from the aqueous solution and precipitation with MTBE to yield lRjl'R-atracurium besylate.
- MTBE methyl t-butyl ether
- step(d) facilitate in situ isolation of base from the reaction mixture. Since sodium carbonate is a strong base compare with sodium bicarbonate, it is not suitable to use as a base in the reaction because the product formed during the reaction becomes unstable in such a high pH and also gives some side products.
- the solvent system used to separate the cis-cis isomer according to the present invention is a mixture of dichloromethane: methanol: benzenesulfonic acid in the ratio of 6 to 10% of methanol in dichloromethane containing 0.05% benzenesulfonic acid, which results in high yield, better resolution and improved purity
- a process for the removal of unchanged R-tetrahydropapaverine by converting it into amide using acetic anhydride A process for the preparation of 1R,1'R-Atracurium besylate from IR 5 I 1 R -2,2'-(3,l l-dioxo-4,10-dioxotridecylene)-bis-(l,2,3,4-tetrahydro- 6,7-dimethoxy-2-methyl-l-veratryliso-quinolium dioxalate in the claim 1 in step d),wherein, the inorganic base used is sodium bicarbonate, sodium carbonate or potassium carbonate and most preferably sodium bicarbonate.
- Lyophilisation is not a recommended process for this drug, because it this drug is unstable in basic medium and also not a industrially viable method.
- methylbenzene sulfonate was effected by extraction with solvents like toluene, ethyl acetate, methyl tertiary butyl ether or diethyl ether and most preferably methyl tertiary butyl ether.
- the product was isolated from aqueous solution by extraction with dichloromethane and the precipitation of the product with diethyl ether.
- the step f) the particle size of silica gel used for the separation of Cis-Cis isomer is 30-50 ⁇ .
- the racemic tetrahydropaverine (THP) hydrochloride (2kg) was dissolved in water (20Lit) and basified with ammonia solution (900 ml) with stirring.
- the THP base was extracted with dichloromethane (2xlOLit), and the organic layer washed with water and brine.
- Dichloromethane from the extract was distilled out completely and the gummy material obtained dissolved in IPA (15 Lit) and added to N-acetyl-D-leucine with stirring.
- the mixture was heated under reflux for 30 minutes to get a clear solution, cooled to RT and the solution kept aside overnight.
- the crystallized material was filtered, dried under vacuum and again recrystallised from IPA, to yield pure R-teterahydropapaverine salt (greater than 99.5% enantiomeric pure).
- R-Tetrahydropapaverine-N-Acetyl-L-Leucine salt (1 kg) was dissolved in water (lOLit) and basified with ammonia solution (375 ml) with stirring. The base was extracted with dichloromethane (2x5Lit). The organic layer was washed with water and brine. The dichloromethane was distilled out and to the gummy material was added 1, 5-pentanediol diacrylate (162 ml) and acetic acid (51ml) and the mixture stirred at 70-75 0 C under nitrogen atmosphere for 5 to 6 hrs.
- Cis-Cis isomer from IR, l'R -Atracurium beyslate
- Cis-Cis isomer from IR, l'R -Atracurium beyslate
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Abstract
The present invention is related to a novel process for the preparation of cisatracurium besylate, more particularly optically and geometrically pure cisatracurium besylate in large scale.
Description
NOVEL PROCESS FOR THE PREPARATION OF CISATRACURIUM BESYLATE
FIELD OF INVENTION
The present invention is related to a novel process for the preparation of cisatracurium besylate, more particularly optically and geometrically pure cisatracurium besylate in large scale.
BACKGROUND OF THE INVENTION
Atracurium besylate , 2,2'-[l,5-pentanediylbis[oxy(3-oxo-3,l-propanediyl)]]bis[l-[(3,4- dimethoxyphenyl) methyl]- 1 ,2,3,4-tetrahydro-6,7-dimethoxy-2- methylisoquinolinium] dibenzenesulfonate is a non polarizing neuromuscular blocking agent was first approved in 1982.
Atracurium besylate is a mixture of Cis-Cis, Cis-Trans and Trans-Trans isomer and also optically inactive. Cisatracurium besylate is lR-Cis-l'R-Cis-2,2'-[l,5 pentanediylbis - [oxy(3-oxo-3, 1 -propanediyl)]]bis[ 1 -[(3,4- dimethoxyphenyl) methyl]- 1 ,2,3,4-tetrahydro- 6,7-dimethoxy-2- methylisoquinolinium]dibenzenesulfonate the Cis-Cis isomer of R- Atracurium besylate.
Cisatracurium besylate has the below structural formula as follows
Derek A.Hill, et.al, in their patents US 5,453,510 and 5,556,987, described the preparation of cisatracurium besylate.This process involves : condensation of 1, 5- pentanediol with 3-bromopropionic acid in the presence of para-toluenesulfonic acid followed by dehydrobromination using triethylamine to yield 1, 5-pentamethylene diacrylate; resolution of tetrahydropapaverine was reported using N-acetyl-L-leucine in methanol/ether mixture. This resolution method, however, gave poor yields and the product contained 3% of enantiomeric impurity; the condensation of R- tetrahydropapaverine-N-acetyl-L-leucine salt with 1, 5-pentamethylene diacrylate in the presence of acetic acid , followed by conversion to oxalate using oxalic acid in acetone yields (lR,l'R)-2,2'-(3,l l-dioxo-4,10-dioxotridecylene)-bis-(l, 2,3,4- tetrahydro-6,7-dimethoxy-2-methyl-l-veratryliso-quinolium dioxalate. This process, however, did not describe a method for removal of unchanged tetrahydropapaverine; the product obtained was converted into IR, l'R-Atracurium besylate by quaternization with methyl benzenesulfonate to yield geometrical isomers. The final product was obtained by lyophilization which is commercially expensive; from the isomeric mixture the Cis-Cis isomer was separated by column chromatography using Silica Gel as stationary phase and dichloromethane, methanol mixture containing benzene sulfonic acid as an eluent. This process employs single mobile phase to elute the product and gives poor yields.
John.B.Stealake, et.al, in their patent, US 4,179,507, disclosed a process for the preparation of quaternary ammonium compounds such as Atracurium besylate, Atracurium mesylate, R-atracurium besylate etc, however, the patent does not describe process for getting cisatracurium besylate.
Naddaka et.al, in their patents WO 2008/132748 and WO 2008/132746, revealed a process for producing isoquinolium compounds and for converting them into cisatracurium besylate.However the purity of the product reported was not satisfactory.
ARAD, Oded et.al, WO 2008/107887, reported a method for chromatographically separating the isomers of (IR, l'R) atracurium besylate by HPLC in the absence of strong acid using silica gel HPLC column and eluting the compound containing, an polar aprotic co solvent and a week acid.However,this is commercially expensive .
Ostrovsky et.al, WO 2008/11721, described a method for separating cisatracurium besylate from the mixture of atracurium isomers using a reverse phase HPLC with a mobile phase in which the isomers are claimed to be stable. However, this is not an industrially viable process.
Therefore it is an object of the present invention to provide a novel process for the preparation of cis artacurium besylate.
Another object of the present invention to provide a novel process for the preparation of cis artacurium besylate which is enatiometrically and isomerically pure.
Yet another object of the present invention provides a method which is industrially viable and economical process for the production of cisatracurium besylate.
BRIEF SUMMARY OF THE INVENTION
According to the present invention a novel process for the preparation of cisatracurium besylate comprising:
a) condensing 1, 5-pentane diol with methylacrylate in the presence of para- toluenesufonic acid to obtain 1, 5-pentamethylenediacrylate; b) resolution of tetrahydropapaverine using N-acetyl-D-leucine in isopropyl alcohol to yield R-tetrahydropapaverine with enantiomeric purity greater than 99.5%; c) condensing R-tetrahydropapverine with 1,5-Pentamethylenediacrylate in acetic acid medium to yield lR,l'R)-2,2'-(3,l l-dioxo-4,10-dioxotridecylene)-bis- (l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-l-veratryliso-quinolium dioxalate and excess of R-tetrahydropapaverine present in the reaction mixture by treating
the said reaction mixture with acetic anhydride in toluene to form an amide wherein the said amide formed is dissolved in acetone and removed from the product; d) treating the product obtained from step (c) with methyl benzenesulfonate in acetonitrile in the presence of inorganic base yielded IR, l'R-Atracurium besylate; e) separating pure cisatracurium besylate from the product obtained in step (d) by flash chromatography using silica gel (30 to 50μ) in the ratio of l(substrate): 40 and solvent system comprising dichloromethane, methanol mixture containing benzene sulfonic acid; f) washing the eluted fractions with water and then with sodium benzenesulfonate and/or 10% sodium chloride solution to remove excess methanol and benzene sulfonicacid; g) evaporating the solvent and precipitating the product with ether to yield fairly pure cisatracurium besylate; h) cisatracurium besylate was further purified by dissolving the product from step (g) in a mixture of acetonitrile, isopropyl alcohol (IPA) and precipitating in ethyl acetate to yield pure cisatracurium besylate.
Another embodiment of the present invention to provide a industrially viable and economical process for the production of cisatracurium besylate.
Yet another embodiment of the present invention to provide a novel process for the preparation of cis artacurium besylate, which is enatiometrically and isomerically pure.
Still another embodiment of the present invention to provide a industrially viable separation process to separate the cis-cis isomer from other isomer atracurium besylate.
DETAILED DESCRIPTION OF PRESENT INVENTION:
The present invention pertains to a novel process for the preparation of cisatracurium besylate involving the followings steps:
According to the present invention a novel process for the preparation of cisatracurium besylate comprising:
a. condensing 1, 5-pentane diol with methylacrylate in the presence of para- toluenesufonic acid to obtain 1, 5-pentamethylenediacrylate; b. resolution of tetrahydropapaverine using N-acetyl-D-leucine in isopropyl alcohol to yield R-tetrahydropapaverine with enantiomeric purity greater than 99.5%; c. condensing R-tetrahydropapverine with 1,5-Pentamethylenediacrylate in acetic acid medium to yield lR,l'R)-2,2'-(3,l l-dioxo-4,10-dioxotridecylene)-bis- (l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-l-veratryliso-quinolium dioxalate and excess of R-tetrahydropapaverine present in the reaction mixture by treating the said reaction mixture with acetic anhydride in toluene to form an amide wherein the said amide formed is dissolved in acetone and removed from the product; d. treating the product obtained from step (c) with methyl benzenesulfonate in acetonitrile in the presence of inorganic base yielded IR, l'R-Atracurium besylate; e. separating pure cisatracurium besylate from the product obtained in step (d) by flash chromatography using silica gel (30 to 50μ) in the ratio of 1 (substrate): 40 and solvent system comprising dichloromethane, methanol mixture containing benzene sulfonic acid; f. washing the eluted fractions with water and then with sodium benzenesulfonate and/or 10% sodium chloride solution to remove excess methanol and benzene sulfonicacid; g. evaporating the solvent and precipitating the product with ether to yield fairly pure cisatracurium besylate; h. cisatracurium besylate was further purified by dissolving the product from step (g) in a mixture of acetonitrile, isopropyl alcohol (IPA) and precipitating in ethyl acetate to yield pure cisatracurium besylate.
The acrylate used in the step a) of the present invention is preferably methylacrylate, ethyl acrylate, propyl acrylate and the like most preferably methyl acrylate.
The acid catalyst used in the step a) according to the present invention is benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, most preferably p-toluenesulfonic acid.
The chiral compound used for the resolution in the step b) of present invention is N- acetyl-L-leucine, N-acetyl-D-leucine and, the like preferably N-acetyl-D-leucine. The solvent used for the resolution in the step b) of this novel process is methanol, ethanol, isopropanaol and the like, most preferably isopropanol.
The preferred temperature for the reaction step (c) is 65-75°C, most preferably 70- 75°C.The acid used is acetic acid, formic acid, propionic acid and the like, most preferably acetic acid. The product isolated was besylate, oxalate, and mesylate and the like, most preferably oxalate.
Separation of side products are cumbersome, which is controlled before forming by using molar excess of R-tertrahydropaverine in step (c) that prevents forming the said side products. Excess of the said R-tertrahydropaverine present in the reaction mixture after completion of reaction is removed by amide formation.
The reaction temperature in step (d) of the present invention is at 15-300C, most preferably 20-250C and the inorganic base used was sodium carbonate, potassium carbonate, sodium bicarbonate and the like, and most preferably sodium bicarbonate. The organic solvent used for the reaction was actonitrile or dichloromethane, dichloroethane, and most preferably acetonitrile. Removal of the excess methyl benzenesulfonate after the completion of reaction by extraction with methyl t-butyl ether (MTBE) and the isolation of product by extraction with dichloromethane from the aqueous solution and precipitation with MTBE to yield lRjl'R-atracurium besylate.
STEP I
CH2=CH CO2CH3
P-TOLENE SULFONIC ACID
STEPII
Acetic acid Acetic anhydride
METHYLBENZENE SULFONATE
STEP IV
IR l'R-ATRACURIUM
STEP III
1 R.1 'R-ATRACURIUM BESYLATE
CISATRACURIUM BESYLATE
Using sodium bicarbonate in step(d) facilitate in situ isolation of base from the reaction mixture. Since sodium carbonate is a strong base compare with sodium bicarbonate, it is not suitable to use as a base in the reaction because the product formed during the reaction becomes unstable in such a high pH and also gives some side products.
Separating the cis-cis isomer from cis-trans, trans-trans reaction mixture, using silica gel (30 to 50μ) wherein the ratio of the said reaction mixture with respect to silica gel isl: 80 to 1 :20, most preferably 1 :40.
The solvent system used to separate the cis-cis isomer according to the present invention is a mixture of dichloromethane: methanol: benzenesulfonic acid in the ratio of 6 to 10% of methanol in dichloromethane containing 0.05% benzenesulfonic acid, which results in high yield, better resolution and improved purity
A process for the removal of unchanged R-tetrahydropapaverine by converting it into amide using acetic anhydride. A process for the preparation of 1R,1'R-Atracurium besylate from IR5I1R -2,2'-(3,l l-dioxo-4,10-dioxotridecylene)-bis-(l,2,3,4-tetrahydro- 6,7-dimethoxy-2-methyl-l-veratryliso-quinolium dioxalate in the claim 1 in step d),wherein, the inorganic base used is sodium bicarbonate, sodium carbonate or potassium carbonate and most preferably sodium bicarbonate.
Lyophilisation is not a recommended process for this drug, because it this drug is unstable in basic medium and also not a industrially viable method.
The removal of excess methylbenzene sulfonate was effected by extraction with solvents like toluene, ethyl acetate, methyl tertiary butyl ether or diethyl ether and most preferably methyl tertiary butyl ether.
The product was isolated from aqueous solution by extraction with dichloromethane and the precipitation of the product with diethyl ether. The step f) the particle size of silica gel used for the separation of Cis-Cis isomer is 30-50μ.
Examples I:
Synthesis of 1, 5-Pentanediol diacrylate:
A mixture of 1, 5-Pentane diol (1 kg), methyl acrylate (lOLit) and p-toluenesulfonic acid in a 20 lit reactor was heated to 90-1000C with stirring under nitrogen atmosphere. Further methyl acrylate (7 lit) was added drop by drop while a mixture of methyl acrylate and methanol are distilled at the same temperature for 6 to 8 hrs. Progress of the reaction
is monitored by TLC.After completion of the reaction, the excess methyl acrylate was distilled out completely under vacuum. The reaction mixture was cooled to room temperature, diluted with pet ether (1OL it), and the mixture washed once with aqueous 5% sodium bi carbonate followed by brine. The pet ether from the extract was distilled out, followed by high vacuum distillation of the product at less than lmm of Hg at 130- 1400C to yield pure 1, 5-Penatanediol diacrylate (1 kg)
Examples II:
Resolution of Tetrahydropapverine:
The racemic tetrahydropaverine (THP) hydrochloride (2kg) was dissolved in water (20Lit) and basified with ammonia solution (900 ml) with stirring. The THP base was extracted with dichloromethane (2xlOLit), and the organic layer washed with water and brine. Dichloromethane from the extract was distilled out completely and the gummy material obtained dissolved in IPA (15 Lit) and added to N-acetyl-D-leucine with stirring. The mixture was heated under reflux for 30 minutes to get a clear solution, cooled to RT and the solution kept aside overnight. The crystallized material was filtered, dried under vacuum and again recrystallised from IPA, to yield pure R-teterahydropapaverine salt (greater than 99.5% enantiomeric pure).
Examples III:
Preparation of R-Atracurium oxalate:
R-Tetrahydropapaverine-N-Acetyl-L-Leucine salt (1 kg) was dissolved in water (lOLit) and basified with ammonia solution (375 ml) with stirring. The base was extracted with dichloromethane (2x5Lit).The organic layer was washed with water and brine. The dichloromethane was distilled out and to the gummy material was added 1, 5-pentanediol diacrylate (162 ml) and acetic acid (51ml) and the mixture stirred at 70-750C under nitrogen atmosphere for 5 to 6 hrs. The reaction mixture in toluene (1 lit) was stirred with
acetic anhydride (80 ml) at 70-75°C for 30 minutes, cooled and diluted with acetone (5 Lit). To the mixture oxalic acid (380 g) in acetone (5 lit) was added and kept at 2 to 8°C overnight. The solid formed was filtered and dried to yield R-Atracurium oxalate (50Og).
Examples III:
Preparation of IR, l'R -Atracurium beyslate:
To a suspension of R-atracurium oxalate (50Og) in acetonitrile (1.25 Lit), were added methyl benzenesulfonate (750ml) and sodium bicarbonate (235g). The reaction mixture stirred at 20-25°C for 48 hrs, filtered and the filtrate was diluted with water and extracted with methyl t- butyl ether.The aqueous layer was then extracted with dichloromethane. The extract was concentrated and the product from concentrate precipitated by pouring into methyl t- butyl ether .The material was filtered and dried under vacuum to yield IR, 1 'R -Atracurium beyslate (500g)
Examples IV:
Separation of Cis-Cis isomer from IR, l'R -Atracurium beyslate
Silica Gel (30-50μ) (8 kg) was stirred with dichloromethane in methanol (8%) containing benzene sulfonic acid and the slurry loaded into the SS column 15 cm Dia x 150 cm length. The solvent was eluted under pressure (0.5 to 1 kg/cm2). IR, I1R -Atracurium beyslate(geometrical mixture) was dissolved in dichloromethane and loaded into the column and eluted with dichloromethane in methanol(8%) containing benzenesulfonic acid (.05 to .1%) followed by dichloromethane in methanol(10%) containing benzenesulfonic acid. The fractions containing pure Cis-Cis isomer as monitored by HPLC was collected and washed once with water followed by 10%sodium benzene sulfonate and or 10% sodium chloride solution. The dichloromethane solution was concentrated and the product precipitated with MTBE to yield fairly pure cistatracurium besylate. (7Og)
Examples V:
Purification of Cis-Cis isomer from IR, l'R -Atracurium beyslate
The crude cistaracurium besylate (10Og), obtained in example IV, was dissolved in a mixture of acetonitrile-IPA mixture (5 lit) and the product was precipitated with ethyl acetate at 0-50C with stirring. The supernatant liquid was siphoned out and the gummy material dissolved in dichloromethane and poured into diethyl ether to yield pure cisatracurium besylate. (7Og)
Claims
We claim;
1) A process for the preparation of cistarcurium besylate comprising of: a) condensing 1, 5-pentane diol with methylacrylate in the presence of para- toluenesufonic acid to obtain 1, 5-pentamethylenediacrylate; b) resolution of tetrahydropapaverine using N-acetyl-D-leucine in isopropyl alcohol to yield R-tetrahydropapaverine with enantiomeric purity greater than 99.5%; c) condensing R-tetrahydropapverine with 1,5-Pentamethylenediacrylate in acetic acid medium to yield lR,l'R)-2,2'-(3,l l-dioxo-4,10-dioxotridecylene)-bis-
( 1 ,2,3,4-tetrahydro-6,7-dimethoxy-2 -methyl- 1 -veratryliso-quinolium dioxalate and excess of R-tetrahydropapaverine present in the reaction mixture by treating the said reaction mixture with acetic anhydride in toluene to form an amide wherein the said amide formed is dissolved in acetone and removed from the product; d) treating the product obtained from step (c) with methyl benzenesulfonate in acetonitrile in the presence of inorganic base yielded IR, l'R-Atracurium besylate; e) separating pure cisatracurium besylate from the product obtained in step (d) by flash chromatography using silica gel (30 to 50μ) in the ratio of 1 (substrate): 40 and solvent system comprising dichloromethane, methanol mixture containing benzene sulfonic acid; f) washing the eluted fractions with water and then with sodium benzenesulfonate and/or 10% sodium chloride solution to remove excess methanol and benzene sulfonicacid; g) evaporating the solvent and precipitating the product with ether to yield fairly pure cisatracurium besylate; h) cisatracurium besylate was further purified by dissolving the product from step (g) in a mixture of acetonitrile, isopropyl alcohol (IPA) and precipitating in ethyl acetate to yield pure cisatracurium besylate.
2. A process of preparing cisatracurium besylate as claimed in claim 1, wherein the acrylate used in the step a) is preferably methylacrylate, ethyl acrylate, propyl acrylate and the like most preferably methyl acrylate and the acid catalyst used is benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, most preferably p-toluenesulfonic acid.
3. A process of preparing cisatracurium besylate as claimed in claim 1, wherein the chiral compound used for the resolution in the step b) is N-acetyl-L-leucine, N- acetyl-D-leucine and,the like preferably N-acetyl-D-leucine and the solvent used for the resolution is methanol, ethanol, isopropanaol and the like, most preferably isopropanol.
4. A process of preparing cisatracurium besylate as claimed in claim 1, wherein the preferred temperature for the reaction step (c) is 65-75°CC, most preferably 70- 75°C.The acid used is acetic acid, formic acid, propionic acid and the like, most preferably acetic acid. The product isolated was besylate, oxalate, and mesylate and the like, most preferably oxalate.
5. A process of preparing cisatracurium besylate as claimed in claim 1, wherein the reaction temperature in step (d) of the present invention is at 15-300C, most preferably 20-250C and the inorganic base used was sodium carbonate, potassium carbonate, sodium bicarbonate and the like, and most preferably sodium bicarbonate. The organic solvent used for the reaction was actonitrile or dichloromethane, dichloroethane, and most preferably acetonitrile. Removal of the excess methyl benzenesulfonate after the completion of reaction by extraction with methyl t-butyl ether (MTBE) and the isolation of product by extraction with dichloromethane from the aqueous solution and precipitation with MTBE to yield lR,l'R-atracurium besylate.
6. A process of preparing cisatracurium besylate as claimed in any preceding claim, wherein separating the cis-cis isomer from cis-trans, trans-trans reaction mixture, using silica gel (30 to 50μ) wherein the ratio of the said reaction mixture with respect to silica gel is 1 : 80 to 1 :20, most preferably 1 :40.
7. A process of preparing cisatracurium besylate as claimed in any preceding claim, wherein the solvent system used to separate the cis-cis isomer according to the present invention is a mixture of dichloromethane: methanol: benzenesulfonic acid in the ratio of 6 to 10% of methanol in dichloromethane containing 0.05% benzenesulfonic acid.
8. A process for the preparation of IR, l'R -2, 2'-(3, 1 l-dioxo-4, 10- dioxotridecylene)-bis-(l, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-methyl-l- veratryliso-quinolium dioxalate with enatiomeric purity greater than 99.5%.
9. A process of preparing cisatracurium besylate as claimed in claim 1, wherein, in the step g) the product was obtained from fractions after washings with water, 10% sodium benzenesulfonate and or 10% sodium chloride, precipitating with diethyl ether.
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| CN102249998A (en) * | 2011-06-20 | 2011-11-23 | 浙江仙琚制药股份有限公司 | Method for preparing cisatracurium besylate |
| US8293912B2 (en) | 2007-05-01 | 2012-10-23 | Chemagis Ltd. | Process for producing cisatracurium compounds and associated intermediates |
| US8354537B2 (en) | 2007-10-29 | 2013-01-15 | Chemagis Ltd. | R,R1-atracurium salts |
| US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
| US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
| CN102898370A (en) * | 2012-11-11 | 2013-01-30 | 苏州二叶制药有限公司 | Cis-atracurium besilate for injection |
| US8461338B2 (en) | 2007-03-08 | 2013-06-11 | Chemagis Ltd. | (1R, 1′R)-atracurium salts separation process |
| CN104557703A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Cisatracurium besilate refining method |
| CN107353248A (en) * | 2017-08-31 | 2017-11-17 | 江苏海悦康医药科技有限公司 | A kind of novel crystal forms Cisatracurium besylate and its purification process |
| CN112979547A (en) * | 2021-03-15 | 2021-06-18 | 江苏诚信药业有限公司 | Purification method of cisatracurium besilate |
| CN114014806A (en) * | 2021-12-03 | 2022-02-08 | 江苏诚信药业有限公司 | Novel crystal form cisatracurium besylate and crystallization method thereof |
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| GB9015473D0 (en) * | 1990-07-13 | 1990-08-29 | Wellcome Found | Neuromuscular blocking agents |
| WO2009007946A1 (en) * | 2007-07-09 | 2009-01-15 | Chemagis Ltd. | Process for producing cisatracurium and associated intermediates |
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- 2009-09-22 WO PCT/IN2009/000515 patent/WO2010128518A2/en active Application Filing
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| US8461338B2 (en) | 2007-03-08 | 2013-06-11 | Chemagis Ltd. | (1R, 1′R)-atracurium salts separation process |
| US8293912B2 (en) | 2007-05-01 | 2012-10-23 | Chemagis Ltd. | Process for producing cisatracurium compounds and associated intermediates |
| US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
| US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
| US8354537B2 (en) | 2007-10-29 | 2013-01-15 | Chemagis Ltd. | R,R1-atracurium salts |
| CN102249998A (en) * | 2011-06-20 | 2011-11-23 | 浙江仙琚制药股份有限公司 | Method for preparing cisatracurium besylate |
| CN102898370A (en) * | 2012-11-11 | 2013-01-30 | 苏州二叶制药有限公司 | Cis-atracurium besilate for injection |
| CN104557703A (en) * | 2015-01-27 | 2015-04-29 | 江苏嘉逸医药有限公司 | Cisatracurium besilate refining method |
| CN107353248A (en) * | 2017-08-31 | 2017-11-17 | 江苏海悦康医药科技有限公司 | A kind of novel crystal forms Cisatracurium besylate and its purification process |
| CN112979547A (en) * | 2021-03-15 | 2021-06-18 | 江苏诚信药业有限公司 | Purification method of cisatracurium besilate |
| CN114014806A (en) * | 2021-12-03 | 2022-02-08 | 江苏诚信药业有限公司 | Novel crystal form cisatracurium besylate and crystallization method thereof |
| CN115819340A (en) * | 2022-11-28 | 2023-03-21 | 珠海润都制药股份有限公司 | Refining method of cisatracurium besilate |
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| WO2010128518A3 (en) | 2013-02-28 |
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