WO2023248154A1 - Process for the preparation of viloxazine hydrochloride - Google Patents
Process for the preparation of viloxazine hydrochloride Download PDFInfo
- Publication number
- WO2023248154A1 WO2023248154A1 PCT/IB2023/056417 IB2023056417W WO2023248154A1 WO 2023248154 A1 WO2023248154 A1 WO 2023248154A1 IB 2023056417 W IB2023056417 W IB 2023056417W WO 2023248154 A1 WO2023248154 A1 WO 2023248154A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- viloxazine
- base
- reaction mixture
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- HJOCKFVCMLCPTP-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]morpholine;hydron;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCC1OCCNC1 HJOCKFVCMLCPTP-UHFFFAOYSA-N 0.000 title description 15
- 229960005014 viloxazine hydrochloride Drugs 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 229960001255 viloxazine Drugs 0.000 claims abstract description 37
- YWPHCCPCQOJSGZ-LLVKDONJSA-N (2r)-2-[(2-ethoxyphenoxy)methyl]morpholine Chemical compound CCOC1=CC=CC=C1OC[C@@H]1OCCNC1 YWPHCCPCQOJSGZ-LLVKDONJSA-N 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 28
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 18
- 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 claims description 16
- 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 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 239000003444 phase transfer catalyst Substances 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- MOEFFSWKSMRFRQ-UHFFFAOYSA-N 2-ethoxyphenol Chemical compound CCOC1=CC=CC=C1O MOEFFSWKSMRFRQ-UHFFFAOYSA-N 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 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 3
- COMXZAIDKIXIKT-UHFFFAOYSA-N 2-(benzylamino)ethyl hydrogen sulfate Chemical compound OS(=O)(=O)OCCNCC1=CC=CC=C1 COMXZAIDKIXIKT-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 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 claims 2
- 235000010216 calcium carbonate Nutrition 0.000 claims 1
- 235000014380 magnesium carbonate Nutrition 0.000 claims 1
- 125000003047 N-acetyl group Chemical group 0.000 abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- 239000011541 reaction mixture Substances 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- 239000010410 layer Substances 0.000 description 32
- 239000002585 base Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- RYJNVYZKENJENW-UHFFFAOYSA-N 4-benzyl-2-[(2-ethoxyphenoxy)methyl]morpholine Chemical compound CCOC1=CC=CC=C1OCC1OCCN(CC=2C=CC=CC=2)C1 RYJNVYZKENJENW-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- -1 2-ethoxyphenoxy Chemical group 0.000 description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 231100000024 genotoxic Toxicity 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- DJOGZXNBSUIGKG-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]oxirane Chemical compound CCOC1=CC=CC=C1OCC1OC1 DJOGZXNBSUIGKG-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Natural products CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- BVUHTRYNQIXGLZ-UHFFFAOYSA-N 1-[2-[(2-ethoxyphenoxy)methyl]morpholin-4-yl]ethanone Chemical compound CCOC1=CC=CC=C1OCC1OCCN(C(C)=O)C1 BVUHTRYNQIXGLZ-UHFFFAOYSA-N 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- WSYUEVRAMDSJKL-UHFFFAOYSA-N ethanolamine-o-sulfate Chemical compound NCCOS(O)(=O)=O WSYUEVRAMDSJKL-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
Definitions
- the present invention relates to an improved process for the preparation of viloxazine or its pharmaceutically acceptable salts such as the hydrochloride salt. Further, the present invention relates to novel compounds designated herein as viloxazine acetate, a compound of formula VII, and N-acetyl viloxazine, a compound of formula XI.
- Viloxazine also known by its chemical name ( ⁇ )-2-[(2-ethoxyphenoxy) methylmorpholine, is represented as a compound of formula I (the “compound I”).
- Viloxazine and its pharmaceutically acceptable salts are described in United States Patent No. 3714161 (the US’ 161 patent).
- Viloxazine hydrochloride is currently marketed under the trade name of QELBREETM, which is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).
- Various processes for the synthesis of this therapeutically useful compound are known in the art, for instance the US’ 161 patent describes a process for the preparation of viloxazine.
- United States Patent No. US9403783 discloses a process which involves reaction of epichlorohydrin with 2- ethoxyphenol in the presence of a phase transfer catalyst (PTC) in the preparation of viloxazine. In spite of this, it is desirable to have an improved process for the preparation of viloxazine hydrochloride.
- PTC phase transfer catalyst
- the present invention relates to a process for the preparation of viloxazine, a compound of formula I (the “compound I”), or a pharmaceutically acceptable salt thereof,
- the present invention provides novel compounds, namely, viloxazine acetate, a compound of formula VII (the “compound VII”) and N-acetyl viloxazine, a compound of formula XI (the “compound XI”), which is an impurity.
- the present invention provides viloxazine hydrochloride (HC1), a compound of formula LA, obtained by the process of the present invention, having a content of each of the compounds namely, a compound of formula VIII (the “compound VIII”) in an amount which is less than 1%, a compound of formula IX (the “compound IX”) in an amount which is less than 1%, and a compound of formula X (the “compound X”), which is not detected, as determined by HPLC.
- the chemical structures of the compounds of formulae VIII, IX and X are represented below: DETAILED DESCRIPTION OF THE INVENTION
- the present invention relates to a process for the preparation of viloxazine, a compound of formula I (the “compound I”), or a pharmaceutically acceptable salt thereof, the process comprising the steps of: a) reacting 2-ethoxyphenol, a compound of formula II (the “compound II”) with epichlorohydrin, a compound of formula III (the “compound III”) in the presence of a base and a solvent to obtain a compound of formula IV (the “compound IV”); wherein the base is added in at least two portions; b) reacting the compound IV obtained in the step (a) with (N-benzylamino)ethyl hydrogen sulfate , a compound of formula V (the wherein Bn is C6H5CH2- , in the presence of a base and a solvent to obtain a compound of formula VI (the “compound VI”); wherein the compound V is added in at least two portions; c) reacting the compound VI obtained in the step (b)
- the term “at least” appearing prior to a number is understood to include the number adjacent to the term “at least ”, and all subsequent numbers that could logically be included.
- the phrase “the base is added in at least two portions” would mean 2 or 2.5 or 3 or 3.5 or 4 portions of the base that may be understood by a person of skill in the art from the particular context.
- the compound II is reacted with the compound III, in the presence of a base and a solvent to obtain the compound IV, wherein the base is added in at least two portions, and wherein the compound III is added gradually.
- the term “gradually” means that the addition of the compound m is carried out over a period of 30 min to one hour, or the addition of the compound III is carried out in a dropwise manner over a period of 30 min to one hour.
- the compound II in the step a) of the above process, is reacted with the compound III in the presence of a base and a solvent to obtain the compound IV ; wherein the base is added in at least two portions, and in the absence of a phase transfer catalyst (PTC).
- PTC phase transfer catalyst
- the compound X is a genotoxic impurity.
- the identification of compound X as a genotoxic impurity is made by using knowledge based software Derek Nexus (a product of Lhasa limited), and statistical software Sarah Nexus (a product of Lhasa limited), which provides mutagenicity predictions.
- step a) involving the reaction of the compound II with the compound III when addition of the base is carried out in a single lot, the process results in the formation of an excess of a ‘diol’ impurity, the compound VIII, and the desired compound IV is obtained in a lower yield and less purity.
- the present invention provides a process for the preparation of the compound IV comprising reacting the compound II with the compound III in the presence of a base and a solvent, wherein the compound III is added gradually, and the base is added in at least two portions.
- the step a) of the above process involves reacting the compound II with the compound III to obtain the compound IV, in the presence of a base and a solvent, wherein the compound III is added gradually and the base is added in at least two portions and the reaction is carried out in the absence of a PTC.
- the base may be an inorganic base selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like.
- alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and the like
- metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like
- metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate
- metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like.
- the solvent used in the step a) includes, but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; amides such as dimethyl formamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
- hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cycl
- the step b) of the above process involves reacting the compound IV with the compound V in the presence of a base and a solvent to obtain the compound VI; wherein the compound V is added in at least two portions.
- the step b) of the process of the present invention involves reacting the compound IV with the compound V in the presence of a base and a solvent to obtain the compound VI; wherein the compound V is added in three portions.
- the solvent used in the step b) may be selected from those discussed supra.
- the base used in the step b) may be selected from those discussed supra.
- the step c) of the above process involves subjecting the compound VI to a reduction reaction using a reducing agent in the presence of acetic acid.
- the reducing agent is a hydrogenation catalyst, which may be selected from palladium, platinum, ruthenium, rhodium, or nickel provided on a carrier, such as carbon.
- the reducing agent used in the step c) is palladium on carbon.
- the step c) involves subjecting the compound VI to reduction reaction using a reducing agent in the presence of acetic acid and a solvent.
- the solvent used in the step c) may be selected from those discussed supra.
- the step d) involves reacting the compound VII with a base to obtain the compound I, and optionally converting it to a pharmaceutically acceptable salt thereof.
- the base may be an inorganic base selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like.
- alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like
- metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like
- metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate
- metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like.
- the compound I i.e. viloxazine is converted to its pharmaceutically acceptable salt by treating it with an acid.
- the acid may be selected from the group consisting of hydrochloric acid, oxalic acid, fumaric acid, sulphuric acid, phosphoric acid and the like.
- the compound I in the step of converting viloxazine, the compound I, to its pharmaceutically acceptable salt, the compound I is dissolved in a solvent prior to its reaction with the acid.
- the solvent used for dissolving viloxazine includes, but is not limited to alcoholic solvents such as methanol, ethanol, n-propanol, t-butanol, n-butanol, isopropanol and like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like ; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane,
- the compound I, viloxazine is converted to its hydrochloride salt.
- the step of converting viloxazine to its hydrochloride salt involving addition of hydrochloric acid may be carried out by purging dry hydrogen chloride gas, or by using aqueous hydrochloric acid, or by addition of hydrochloric acid dissolved in a solvent.
- the addition of hydrochloric acid is carried out at a temperature of about 0°C to about reflux temperature of the solvent. Preferably, the addition is carried out at a temperature of about 0°C to about 15°C.
- the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
- the step of converting viloxazine to its hydrochloride salt involves addition of hydrochloric acid dissolved in a solvent.
- the solvent used for dissolving hydrochloric acid may be an ester solvent or an alcohol solvent.
- the ester solvent may be selected from ethyl acetate or isopropyl acetate.
- the alcohol solvent may be selected from methanol, ethanol, n-propanol or isopropanol.
- the present invention provides novel compounds, namely, viloxazine acetate, a compound of formula VII (the “compound VII”) and N-acetyl viloxazine, a compound of formula XI (the “compound XI”).
- the compounds VII and XI are structurally represented below:
- the compound XI i.e. N-acetyl viloxazine having a chemical name of 4-acetyl-2- [(2-ethoxyphenoxy) methyl] morpholine, is formed as an impurity in the process of the present invention.
- the present invention provides compound VII characterized by ’ H NMR (CDCI3, 400 MHz) having peaks at ’ H NMR (400 MHz, DMSO): 7.137 (s, 2H), 6.86-6.962 (m, 4H), 3.852-4.033 (m, 6H), 3.74-3.796 (m, 1H), 2.952-2.982 (m, 1H), 2.689-2.776 (m, 2H), 2.547-2.603 (m, 1H), 1.877 (s, 3H) 1.303-1.337 (t, 3H).
- the present invention provides compound XI characterized by ’ H NMR (CDCI3, 400 MHz) having peaks at ’ H NMR (400 MHz, DMSO): 6.853- 7.020 (m, 4H), 3.950-4.426 (m, 5H), 3.636-3.861 (m, 2H), 3.071-3.528 (m, 2H), 2.618- 2.754 (m, 2H), 2.023 (s, 3H), 1.308-1.343 (t, 3H).
- the present invention provides viloxazine HC1, a compound of formula I- A, obtained by the process of the present invention having a content of a compound of formula VIII in an amount less than 1%, content of a compound of formula IX in less than 1%, and a compound of formula X (a genotoxic impurity) is not detected, as determined by HPLC.
- the compounds VIII, IX and X are structurally represented below:
- Apparatus A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
- Mobile Phase B Acetonitrile: Buffer (80:20, v/v); Buffer: 1.54 gm of Ammonium acetate in 400 ml water adjust pH 8.0 with diluted Ammonia hydroxide solution (5% in water, v/v).
- Diluent Methanol: Water (50:50, v/v); Flow Rate: 1.0 mL/minute; Detection: UV 220 nm; Injection Volume: 20mL; Run time: 55.0 minutes.
- Example 1 Preparation of 2-[(2-ethoxyphenoxy)methyl)oxirane (compound IV) [0051]
- water (500 mL) and sodium hydroxide (14.47 gm) were added followed by addition of 2 -ethoxyphenol (100 gm, compound II) at a temperature ranging from 30°C to 35°C to obtain a reaction mixture.
- the reaction mixture was stirred for 30 min, followed by addition of epichlorohydrin (200.9 gm, the compound III) gradually.
- the reaction mixture was stirred for a period of 6 hrs at a temperature ranging from 30°C to 35°C.
- the layers were separated and the product layer was charged into a solution of water (500 mL) and sodium hydroxide (28.95 gm). The reaction mixture was stirred for 4.0hr at a temperature ranging from 30°C to 35 °C. After completion of the reaction, the layers were separated and the aqueous layer was extracted with toluene. The toluene layer was distilled under vacuum at a temperature ranging from 60°C to 65°C to obtain 135 gm of the compound IV.
- reaction mixture was cooled to a temperature ranging from 10°C to 20°C.
- the pH of reaction mixture was adjusted to 6.5- 7.5 with cone. HC1.
- the layers were separated and the toluene layer was subjected to charcoalization.
- the toluene layer containing the product was filtered through hyflow bed and the filtrate was distilled under vacuum to obtain 140 gm of the compound VI.
- the solution was cooled to a temperature ranging from 0°C to 5°C and the pH was adjusted to 1 - 2 using cone. HC1.
- the reaction mixture was stirred at a temperature ranging from 0°C to 5°C and filtered.
- the solid was dried under vacuum at 50°C to 55°C to obtain 63 gm of viloxazine HC1. Purity> 98% (as determined by HPLC); Compound XI (N-acetyl viloxazine): 0.02%.
- Viloxazine hydrochloride (Compound I-A) obtained in example 3 (60 gm) was dissolved into a mixture of isopropanol (IPA, 270 mL) and water (60 mL) at a temperature ranging from 70°C to 75°C. The reaction mixture was stirred for about 30 min and filtered. To the filtrate, ethyl acetate (420 mL) was added at a temperature ranging from 60°C to 65 °C. The reaction mixture was gradually cooled to a temperature ranging from 0°C to 5°C and filtered to obtain 48 gm of viloxazine hydrochloride.
- IPA isopropanol
- water 60 mL
- the solution was cooled to a temperature ranging from 10°C to 20°C and the pH was adjusted to 1-2 with cone. HC1.
- the reaction mixture was heated to a temperature ranging from 80°C to 85° to obtain a clear solution.
- the reaction mixture was then cooled to a temperature ranging from 20°C to 25 °C.
- the reaction mixture was filtered and dried under vacuum at a temperature ranging from 50°C to 55°C to obtain 93.7 gm of viloxazine HC1 (compound LA).
- the layers were separated, and the layer containing the desired compound was filtered and distilled to obtain the compound IV.
- the compound IV was then dissolved in toluene (700 mL), and charged into a flask containing potassium hydroxide (405.4 gm) and water (672 mL).
- the reaction mixture was heated to a temperature ranging from 50°C to 55°C. This was followed by addition of the compound V in at least two lots each of (72.53 gm) at an interval of 60 mins.
- the reaction mixture was stirred for 18hrs at a temperature ranging from 50°C to 55°C and then cooled.
- the reaction mixture was further cooled to a temperature ranging from 10°C to 15°C and the pH was adjusted to 6.0-7.0 with concentrated HC1 solution.
- the layers were separated and the organic layer was charcoalised and filtered through hyflow.
- the organic layer was charged into autoclave, to this acetic acid (238 mL) and 2.8% Pd/C (50% dry, 10% palladium on carbon) at a hydrogen pressure of 10kg was heated to a temperature ranging from 60°C to 70°C.
- the reaction mixture was maintained at a temperature ranging from 60°C to 70°C and then the reaction mixture was filtered and water was added.
- the aqueous layer was basified with aqueous sodium hydroxide and extracted in toluene.
- the toluene layer was distilled and the distillate was dissolved in IPA (560 ml) followed by addition of concentrated hydrochloric acid to obtain a reaction mixture.
- the reaction mixture was heated to get a clear solution and then cooled.
- the precipitated product was filtered and dried under vacuum to obtain 130.0 gm of viloxazine HC1.
- Example 7 Preparation of viloxazine HC1 (compound I-A) [0057]
- compound IV 100 gm
- acetic acid 500 mL
- 5.0% Pd/C 5.0% dry, 10% palladium on carbon
- a hydrogen pressure of 5.0 kg was applied and the reaction mixture was heated to a temperature ranging from 50°C to 60°C.
- the reaction mixture was filtered and concentrated under vacuum.
- the residue was dissolved in water.
- the aqueous layer was basified with sodium hydroxide and extracted with toluene.
- the toluene layer was distilled to obtain an oil as residue.
- the residue was dissolved in IPA (lOOmL) and water (12.5mL) and then stirred to get a clear solution.
- the solution was cooled to a temperature ranging from 10°C to 20°C and the pH of reaction mixture was adjusted to 1-2 with cone. HC1.
- the reaction mixture was heated to a temperature ranging from 80°C to 85° to obtain a clear solution.
- the reaction mixture was cooled to a temperature ranging from 10°C to 15 °C.
- the reaction mixture was filtered and dried under vacuum at a temperature ranging from 50°C to 55°C to obtain 20.25 g of the compound I-A.
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Abstract
The present invention relates to an improved process for the preparation of viloxazine or its pharmaceutically acceptable salts such as the hydrochloride salt. Further, the present invention relates to a novel compound designated herein as viloxazine acetate, a compound of formula VII, and N-acetyl viloxazine, a compound of formula XI.
Description
PROCESS FOR THE PREPARATION OF VILOXAZINE HYDROCHLORIDE
PRIORITY
[0001] This application claims the benefit of Indian Provisional Application No. 202221035810 filed on June 22, 2022, entitled “Process for the Preparation of Viloxazine hydrochloride”, the contents of which are incorporated herein by reference.
FIELD OF INVENTION
[0002] The present invention relates to an improved process for the preparation of viloxazine or its pharmaceutically acceptable salts such as the hydrochloride salt. Further, the present invention relates to novel compounds designated herein as viloxazine acetate, a compound of formula VII, and N-acetyl viloxazine, a compound of formula XI.
BACKGROUND OF THE INVENTION
[0003] Viloxazine, also known by its chemical name (±)-2-[(2-ethoxyphenoxy) methylmorpholine, is represented as a compound of formula I (the “compound I”).
I
[0004] Viloxazine, and its pharmaceutically acceptable salts are described in United States Patent No. 3714161 (the US’ 161 patent). Viloxazine hydrochloride, is currently marketed under the trade name of QELBREE™, which is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). Various processes for the synthesis of this therapeutically useful compound are known in the art, for instance the US’ 161 patent describes a process for the preparation of viloxazine. Further, United States Patent No. US9403783 discloses a process which involves reaction of epichlorohydrin with 2- ethoxyphenol in the presence of a phase transfer catalyst (PTC) in the preparation of viloxazine. In spite of this, it is desirable to have an improved process for the preparation of viloxazine hydrochloride.
SUMMARY OF THE INVENTION
[0005] The present invention relates to a process for the preparation of viloxazine, a compound of formula I (the “compound I”), or a pharmaceutically acceptable salt thereof,
I the process comprising the steps of: a) reacting 2-ethoxyphenol, a compound of formula II (the “compound II”) with epichlorohydrin, a compound of formula III (the “compound III”)
II III IV in the presence of a base and a solvent to obtain a compound of formula IV (the “compound IV”), wherein the base is added in at least two portions; b) reacting the compound IV obtained in the step (a) with (N-benzylamino) ethyl hydrogen sulfate, a compound of formula V (the “compound V”)
V VI wherein Bn is C6H5CH2-; in the presence of a base and a solvent to obtain a compound of formula VI (the “compound VI”); wherein the compound V is added in at least two portions; c) reacting the compound VI obtained in the step (b) with a reducing agent in the presence of acetic acid to obtain a compound of formula VII (the “compound VII”);
VII and d) reacting the compound VII obtained in the step (c) with a base to obtain the compound I, and optionally converting it to a pharmaceutically acceptable salt thereof.
[0006] The present invention provides novel compounds, namely, viloxazine acetate, a compound of formula VII (the “compound VII”) and N-acetyl viloxazine, a compound of formula XI (the “compound XI”), which is an impurity.
VII XI
[0007] The present invention provides viloxazine hydrochloride (HC1), a compound of formula LA,
obtained by the process of the present invention, having a content of each of the compounds namely, a compound of formula VIII (the “compound VIII”) in an amount which is less than 1%, a compound of formula IX (the “compound IX”) in an amount which is less than 1%, and a compound of formula X (the “compound X”), which is not detected, as determined by HPLC. The chemical structures of the compounds of formulae VIII, IX and X are represented below:
DETAILED DESCRIPTION OF THE INVENTION
[0008] In one aspect, the present invention relates to a process for the preparation of viloxazine, a compound of formula I (the “compound I”), or a pharmaceutically acceptable salt thereof,
the process comprising the steps of: a) reacting 2-ethoxyphenol, a compound of formula II (the “compound II”) with epichlorohydrin, a compound of formula III (the “compound III”)
in the presence of a base and a solvent to obtain a compound of formula IV (the “compound IV”); wherein the base is added in at least two portions; b) reacting the compound IV obtained in the step (a) with (N-benzylamino)ethyl hydrogen sulfate , a compound of formula V (the
wherein Bn is C6H5CH2- , in the presence of a base and a solvent to obtain a compound of formula VI (the “compound VI”); wherein the compound V is added in at least two portions; c) reacting the compound VI obtained in the step (b) with a reducing agent in the presence of acetic acid to obtain a compound of formula VII (the “compound VII”);
VII
and d) reacting the compound VII obtained in the step (c) with a base to obtain the compound I, and optionally converting it to a pharmaceutically acceptable salt thereof.
[0009] As used herein, the term “at least” appearing prior to a number is understood to include the number adjacent to the term “at least ”, and all subsequent numbers that could logically be included. For example, the phrase “the base is added in at least two portions” would mean 2 or 2.5 or 3 or 3.5 or 4 portions of the base that may be understood by a person of skill in the art from the particular context.
[0010] In one embodiment, in the step a) of the above process, the compound II is reacted with the compound III, in the presence of a base and a solvent to obtain the compound IV, wherein the base is added in at least two portions, and wherein the compound III is added gradually.
[0011] As used herein, the term “gradually” means that the addition of the compound m is carried out over a period of 30 min to one hour, or the addition of the compound III is carried out in a dropwise manner over a period of 30 min to one hour.
[0012] In one embodiment, in the step a) of the above process, the compound II is reacted with the compound III in the presence of a base and a solvent to obtain the compound IV ; wherein the base is added in at least two portions, and in the absence of a phase transfer catalyst (PTC). It is known in the art that use of PTC in a process for the preparation of a compound renders the process costly, particularly, in the industrial manufacture of the compound. The present invention addresses this issue, and provides a process which avoids use of a PTC thereby rendering the process cost effective as well as provides the compound I, viloxazine or its pharmaceutically acceptable salts such as hydrochloride salt having a higher purity.
[0013] It was noted that when the base was added in at least two portions in the step a), the content of each of the impurities namely, the compound of formula VIII (the “compound VIII”), the compound of formula IX (the “compound IX”) and the compound of formula X (the “compound X”) formed during reaction of the compound II with the compound III was less than 5% as determined by HPLC (High Performance Liquid Chromatography). The compounds VIII, IX and X are structurally represented below:
X
[0014] The compound X is a genotoxic impurity. The identification of compound X as a genotoxic impurity is made by using knowledge based software Derek Nexus (a product of Lhasa limited), and statistical software Sarah Nexus (a product of Lhasa limited), which provides mutagenicity predictions.
[0015] Inventors of the present invention observed that in the above step a) involving the reaction of the compound II with the compound III,
when addition of the base is carried out in a single lot, the process results in the formation of an excess of a ‘diol’ impurity, the compound VIII, and the desired compound IV is obtained in a lower yield and less purity.
[0016] However, when the addition of the base is carried out in portions of at least two, it was surprisingly observed that, the ‘diol’ impurity (the compound VIII) is formed in much lower quantity, and the desired compound IV is obtained in higher yield and better purity.
[0017] Accordingly, in one embodiment, the present invention provides a process for the preparation of the compound IV comprising reacting the compound II with the compound III in the presence of a base and a solvent, wherein the compound III is added gradually, and the base is added in at least two portions.
[0018] In one embodiment, the step a) of the above process involves reacting the compound II with the compound III to obtain the compound IV, in the presence of a base and a solvent, wherein the compound III is added gradually and the base is added in at least two portions and the reaction is carried out in the absence of a PTC.
[0019] In one embodiment, the base may be an inorganic base selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like.
[0020] In one embodiment, the solvent used in the step a) includes, but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; amides such as dimethyl formamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof. [0021] Further, in respect of the step b) of the above process, the present inventors observed that one of the reactants, i.e. the compound V becomes unstable in the presence of a base, and this results in obtaining the compound VI in lower yield.
[0022] However, it was surprisingly observed that when the compound V was added in at least two portions to the reaction mixture comprising the compound IV, a base and a solvent, the desired compound VI was obtained in higher yield.
[0023] Accordingly, in one embodiment, the step b) of the above process involves reacting the compound IV with the compound V in the presence of a base and a solvent to obtain the compound VI; wherein the compound V is added in at least two portions.
[0024] In one embodiment, the step b) of the process of the present invention involves reacting the compound IV with the compound V in the presence of a base and a solvent to obtain the compound VI; wherein the compound V is added in three portions.
[0025] The solvent used in the step b) may be selected from those discussed supra.
[0026] The base used in the step b) may be selected from those discussed supra.
[0027] In one embodiment, the step c) of the above process involves subjecting the compound VI to a reduction reaction using a reducing agent in the presence of acetic acid. [0028] In an embodiment, the reducing agent is a hydrogenation catalyst, which may be selected from palladium, platinum, ruthenium, rhodium, or nickel provided on a carrier, such as carbon.
[0029] In one embodiment, the reducing agent used in the step c) is palladium on carbon. [0030] In one embodiment, the step c) involves subjecting the compound VI to reduction reaction using a reducing agent in the presence of acetic acid and a solvent.
[0031] The solvent used in the step c) may be selected from those discussed supra.
[0032] In one embodiment, the step d) involves reacting the compound VII with a base to obtain the compound I, and optionally converting it to a pharmaceutically acceptable salt thereof.
[0033] In one embodiment, the base may be an inorganic base selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like.
[0034] In one embodiment, the compound I i.e. viloxazine is converted to its pharmaceutically acceptable salt by treating it with an acid.
[0035] In one embodiment, the acid may be selected from the group consisting of hydrochloric acid, oxalic acid, fumaric acid, sulphuric acid, phosphoric acid and the like. [0036] In one embodiment, in the step of converting viloxazine, the compound I, to its pharmaceutically acceptable salt, the compound I is dissolved in a solvent prior to its reaction with the acid.
[0037] In one embodiment, the solvent used for dissolving viloxazine includes, but is not limited to alcoholic solvents such as methanol, ethanol, n-propanol, t-butanol, n-butanol,
isopropanol and like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like ; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethyl formamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
[0038] In one embodiment, the compound I, viloxazine, is converted to its hydrochloride salt.
[0039] In an embodiment, the step of converting viloxazine to its hydrochloride salt involving addition of hydrochloric acid may be carried out by purging dry hydrogen chloride gas, or by using aqueous hydrochloric acid, or by addition of hydrochloric acid dissolved in a solvent. The addition of hydrochloric acid is carried out at a temperature of about 0°C to about reflux temperature of the solvent. Preferably, the addition is carried out at a temperature of about 0°C to about 15°C.
[0040] As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
[0041] In an embodiment, the step of converting viloxazine to its hydrochloride salt involves addition of hydrochloric acid dissolved in a solvent.
[0042] In an embodiment, the solvent used for dissolving hydrochloric acid may be an ester solvent or an alcohol solvent.
[0043] The ester solvent may be selected from ethyl acetate or isopropyl acetate. The alcohol solvent may be selected from methanol, ethanol, n-propanol or isopropanol.
[0044] In one embodiment, the present invention provides novel compounds, namely, viloxazine acetate, a compound of formula VII (the “compound VII”) and N-acetyl viloxazine, a compound of formula XI (the “compound XI”). The compounds VII and XI are structurally represented below:
VII XI
[0045] The compound XI i.e. N-acetyl viloxazine having a chemical name of 4-acetyl-2- [(2-ethoxyphenoxy) methyl] morpholine, is formed as an impurity in the process of the present invention.
[0046] In one embodiment, the present invention provides compound VII characterized by ’ H NMR (CDCI3, 400 MHz) having peaks at ’ H NMR (400 MHz, DMSO): 7.137 (s, 2H), 6.86-6.962 (m, 4H), 3.852-4.033 (m, 6H), 3.74-3.796 (m, 1H), 2.952-2.982 (m, 1H), 2.689-2.776 (m, 2H), 2.547-2.603 (m, 1H), 1.877 (s, 3H) 1.303-1.337 (t, 3H).
[0047] In one embodiment, the present invention provides compound XI characterized by ’ H NMR (CDCI3, 400 MHz) having peaks at ’ H NMR (400 MHz, DMSO): 6.853- 7.020 (m, 4H), 3.950-4.426 (m, 5H), 3.636-3.861 (m, 2H), 3.071-3.528 (m, 2H), 2.618- 2.754 (m, 2H), 2.023 (s, 3H), 1.308-1.343 (t, 3H).
[0048] In one embodiment, the present invention provides viloxazine HC1, a compound of formula I- A, obtained by the process of the present invention having
a content of a compound of formula VIII in an amount less than 1%, content of a compound of formula IX in less than 1%, and a compound of formula X (a genotoxic impurity) is not detected, as determined by HPLC. The compounds VIII, IX and X are structurally represented below:
X
[0049] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
Examples:
General Methods:
1] HPLC method (Instrumental settings):
[0050] High performance liquid chromatography (HPLC) was performed with the conditions described below for determining purity:
Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software. Column: YMC Triart C18, 150 X 4.6mm, S-5m; Column temperature: 30°C; Sample Cooler temperature: 10°C; Mobile Phase A: Buffer: Acetonitrile (90:10, v/v); Buffer: 1.54 gm of Ammonium acetate in 1800 ml water adjust pH 8.0 with diluted Ammonia hydroxide solution (5% in water, v/v); Mobile Phase B: Acetonitrile: Buffer (80:20, v/v); Buffer: 1.54 gm of Ammonium acetate in 400 ml water adjust pH 8.0 with diluted Ammonia hydroxide solution (5% in water, v/v).
Diluent: Methanol: Water (50:50, v/v); Flow Rate: 1.0 mL/minute; Detection: UV 220 nm; Injection Volume: 20mL; Run time: 55.0 minutes.
Example 1: Preparation of 2-[(2-ethoxyphenoxy)methyl)oxirane (compound IV) [0051] In a round bottom flask, water (500 mL) and sodium hydroxide (14.47 gm) were added followed by addition of 2 -ethoxyphenol (100 gm, compound II) at a temperature ranging from 30°C to 35°C to obtain a reaction mixture. The reaction mixture was stirred for 30 min, followed by addition of epichlorohydrin (200.9 gm, the compound III) gradually. The reaction mixture was stirred for a period of 6 hrs at a temperature ranging from 30°C to 35°C. The layers were separated and the product layer was charged into a solution of water (500 mL) and sodium hydroxide (28.95 gm). The reaction mixture was stirred for 4.0hr at a temperature ranging from 30°C to 35 °C. After completion of the reaction, the layers were separated and the aqueous layer was extracted with toluene. The
toluene layer was distilled under vacuum at a temperature ranging from 60°C to 65°C to obtain 135 gm of the compound IV.
Purity> 95% (as determined by HPLC); Compound VIII: 1.99%; Compound IX: 0.46%; Compound X: 1.31%.
Example 2: Preparation of 4-benzyl-2-[(2-ethoxyphenoxy)methyl)morpholine (compound VI)
[0052] In a round bottom flask, potassium hydroxide (245.52 gm) was dissolved in water (408 mL), to this the compound IV (85 gm) in toluene (425 mL) was added at a temperature ranging from 20°C to 30°C to obtain a reaction mixture. The reaction mixture was heated up to a temperature ranging from 50°C to 55°C. (N-benzylamino) ethyl hydrogen sulfate The (compound V) (43.86 g) was added in three lots in to the reaction mass at a temperature ranging from 50°C to 55°C. The reaction mixture was maintained for about 17 hr. After completion of the reaction, the reaction mixture was cooled to a temperature ranging from 10°C to 20°C. The pH of reaction mixture was adjusted to 6.5- 7.5 with cone. HC1. The layers were separated and the toluene layer was subjected to charcoalization. The toluene layer containing the product was filtered through hyflow bed and the filtrate was distilled under vacuum to obtain 140 gm of the compound VI.
Purity> 90% (as determined by HPLC).
Example 3: Preparation of viloxazine hydrochloride (compound I -A)
[0053] In a round bottom flask, the compound VI (120 gm) was dissolved in acetic acid (600 mL) and to this was added 10% palladium on carbon (3.6 gm). The solution was charged into autoclave and subjected to a hydrogen pressure of 5.0 Kg at a temperature ranging from 50°C to 55°C. After completion of the reaction, the reaction mixture was filtered through hyflo bed, and the filtrate was distilled under vacuum. After washing with water and toluene, the pH of aqueous layer was adjusted to 12 using sodium hydroxide. The toluene layer was distilled under vacuum. To the distillate isopropanol (600 mL) was added and stirred to obtain a clear solution. The solution was cooled to a temperature ranging from 0°C to 5°C and the pH was adjusted to 1 - 2 using cone. HC1. The reaction mixture was stirred at a temperature ranging from 0°C to 5°C and filtered. The solid was dried under vacuum at 50°C to 55°C to obtain 63 gm of viloxazine HC1.
Purity> 98% (as determined by HPLC); Compound XI (N-acetyl viloxazine): 0.02%.
Example 4: Preparation of viloxazine hydrochloride (compound I -A)
[0054] Viloxazine hydrochloride (Compound I-A) obtained in example 3 (60 gm) was dissolved into a mixture of isopropanol (IPA, 270 mL) and water (60 mL) at a temperature ranging from 70°C to 75°C. The reaction mixture was stirred for about 30 min and filtered. To the filtrate, ethyl acetate (420 mL) was added at a temperature ranging from 60°C to 65 °C. The reaction mixture was gradually cooled to a temperature ranging from 0°C to 5°C and filtered to obtain 48 gm of viloxazine hydrochloride.
Purity > 99.8% (as determined by HPLC).
Example 5: Preparation of viloxazine HC1 (compound I-A)
[0055] In a round bottom flask, water (480 mL) and potassium hydroxide (288.84 gm) were charged followed by addition of the compound IV in toluene to obtain a reaction mixture. The compound V was added in three lots at a temperature ranging from 50°C to 55 °C, and stirred for 18 hrs. The reaction mixture was cooled to a temperature ranging from 20°C to 25°C followed by addition of water, and this was neutralised by addition of concentrated hydrochloric acid. The layers were separated and the toluene layer was subjected to charcoalization. This was filtered through hyflow and was charged into an autoclave, to this 3.0% Pd/C (10% palladium on carbon, 50% dry) and acetic acid (168ml) were added and subjected to hydrogen pressure of 5.0 kg. The reaction mixture was heated to a temperature ranging from 50°C to 60°C and maintained for 8 h. After completion of the reaction, the reaction mixture was filtered and pH of the aqueous layer was adjusted to 11.0 with 50% w/v sodium hydroxide solution. The aqueous layer was extracted with toluene, and the toluene layer was distilled under vacuum. To this IPA (400 ml) was added and stirred to get a clear solution. The solution was cooled to a temperature ranging from 10°C to 20°C and the pH was adjusted to 1-2 with cone. HC1. The reaction mixture was heated to a temperature ranging from 80°C to 85° to obtain a clear solution. The reaction mixture was then cooled to a temperature ranging from 20°C to 25 °C. The reaction mixture was filtered and dried under vacuum at a temperature ranging from 50°C to 55°C to obtain 93.7 gm of viloxazine HC1 (compound LA).
Purity > 99.62% (as determined by HPLC).
Example 6: One pot process for preparation of viloxazine HC1 (compound I-A)
[0056] To a round bottom flask, water (500 mL), sodium hydroxide (14.47 gm) and compound II (100g) were charged to obtain a reaction mixture. The reaction mixture was heated to a temperature ranging from 25°C to 35°C, and stirred for 30 mins. To this, compound III (200.89 gm) was added at a temperature ranging from 25°C to 35°C and maintained for 6 hrs. The layers were separated. The product layer was charged into aq. sodium hydroxide solution (28.95 gm) in water (500 mL). The reaction mixture was stirred at a temperature ranging from 25 °C to 35 °C for 4 hrs. The layers were separated, and the layer containing the desired compound was filtered and distilled to obtain the compound IV. The compound IV was then dissolved in toluene (700 mL), and charged into a flask containing potassium hydroxide (405.4 gm) and water (672 mL). The reaction mixture was heated to a temperature ranging from 50°C to 55°C. This was followed by addition of the compound V in at least two lots each of (72.53 gm) at an interval of 60 mins. The reaction mixture was stirred for 18hrs at a temperature ranging from 50°C to 55°C and then cooled. After addition of water the reaction mixture was further cooled to a temperature ranging from 10°C to 15°C and the pH was adjusted to 6.0-7.0 with concentrated HC1 solution. The layers were separated and the organic layer was charcoalised and filtered through hyflow. The organic layer was charged into autoclave, to this acetic acid (238 mL) and 2.8% Pd/C (50% dry, 10% palladium on carbon) at a hydrogen pressure of 10kg was heated to a temperature ranging from 60°C to 70°C. The reaction mixture was maintained at a temperature ranging from 60°C to 70°C and then the reaction mixture was filtered and water was added. The aqueous layer was basified with aqueous sodium hydroxide and extracted in toluene. The toluene layer was distilled and the distillate was dissolved in IPA (560 ml) followed by addition of concentrated hydrochloric acid to obtain a reaction mixture. The reaction mixture was heated to get a clear solution and then cooled. The precipitated product was filtered and dried under vacuum to obtain 130.0 gm of viloxazine HC1.
Purity > 99.8% (as determined by HPLC); Compound VIII: Not detected; Compound IX: Not detected; Compound X: Not detected.
Example 7: Preparation of viloxazine HC1 (compound I-A)
[0057] In an autoclave, compound IV (100 gm), acetic acid (500 mL) and 5.0% Pd/C (50% dry, 10% palladium on carbon) were charged to obtain a reaction mixture. A hydrogen pressure of 5.0 kg was applied and the reaction mixture was heated to a temperature ranging from 50°C to 60°C. After completion of the reaction, the reaction mixture was filtered and concentrated under vacuum. The residue was dissolved in water. The aqueous layer was basified with sodium hydroxide and extracted with toluene. The toluene layer was distilled to obtain an oil as residue. The residue was dissolved in isopropanol (225 mL) and acidified with hydrochloric acid at a temperature ranging from 5°C to 10°C. The reaction mixture was filtered and dried under vacuum to obtain 48.6 gm of the compound LA.
Purity > 98.34% (as determined by HPLC).
Example 8: Preparation of viloxazine HC1 (compound I-A)
[0058] In an autoclave compound IV (10g), methanol (100 mL) and 7.0% Pd/C (50% dry, 10% palladium on carbon) were charged to obtain a reaction mixture. A hydrogen pressure of 5.0 kg was applied and the reaction mixture was heated to a temperature ranging from 50°C-60°C. The reaction mixture was filtered and acidified with concentrated hydrochloric acid. The reaction mixture was filtered and dried under vacuum to obtain 3.6 gm of the compound I- A.
Purity >94.46 % (as determined by HPLC).
Reference Example 9: Preparation of viloxazine HC1
[0059] In a round bottom flask, compound IV (19.4 gm), 2-amino ethyl hydrogen sulfate (70.5 gm), sodium hydroxide (40 gm), ethanol (400 mL) and water (200 mL) were charged to obtain a reaction mixture. The temperature of the reaction mixture was raised to 60°C and stirred for 18 hrs. The reaction mixture was evaporated to dryness under vacuum and the resulting residue was dissolved in water. The reaction mixture was extracted three times with diethyl ether. The combined extracts were dried over magnesium sulphate and evaporated to dryness.
The crude product was dissolved in IPA (20 mL), to this concentrated hydrochloric acid (10.5 mL) and ethyl acetate (75 mL) were added. The reaction mixture was cooled. The product obtained was filtered and dried to obtain 7 gm of the product.
Purity: 85% (as determined by HPLC).
Reference Example 10: Preparation of 2-[(2-ethoxyphenoxy)methyl)oxirane (compound IV)
[0060] In a round bottom flask, water (lOOmL) and sodium hydroxide (5.87g) were added followed by addition of 2-ethoxyphenol (20.0g, compound II) at a temperature ranging from 30-35°C to obtain a reaction mixture. The reaction mixture was stirred for 30 min, followed by addition of epichlorohydrin (40.77 gm, compound III) gradually. The reaction mixture was stirred for 10 hrs at a temperature of 30-35°C. The layers were separated and aq. layer extracted by toluene (40 mL). The combined organic layer washed with water. The organic layer was distilled under vacuum at 50-55°C to obtain 27 gm of compound IV.
Purity: 79.6%, Compound VIII: 8.57%, compound IX: 2.4%, compound X: 6.18% (as determined by HPLC).
Reference Example 11: Preparation of compound VI
[0061] In a round bottom flask, water (120 mL) and potassium hydroxide (72.09 gm) were charged followed by addition of compound IV (25 gm) in toluene to obtain a reaction mixture. The compound V (38.69 gm) was added at a temperature ranging from 50 °C to 55°C and stirred for 18 hrs. The reaction mixture was cooled to a temperature ranging from 20°C to 25 °C followed by addition of water and neutralised by addition of concentrated hydrochloric acid. The layers were separated and toluene layers was subjected to charco alization. (Purity of toluene layer: 80.73% as measured by HPLC, impurity: 5.61%) This was filtered through hyflow and then charged into an autoclave, to this 2.2% Pd/C (10% palladium on carbon, 50% dry) and acetic acid (42 mL) were added and subjected to hydrogen pressure of 10.0 kg. The reaction mixture was heated to a temperature ranging from 60°C to 70°C and maintained for 8 hrs. After completion of reaction, the reaction mixture was filtered and water was added. The pH of the aqueous layer was adjusted to 12.5 with 50% w/v sodium hydroxide solution. The aqueous layer was extracted with toluene. The toluene layer was distilled under vacuum to obtain a residue. The residue was dissolved in IPA (lOOmL) and water (12.5mL) and then stirred to get a clear solution. The solution was cooled to a temperature ranging from 10°C to
20°C and the pH of reaction mixture was adjusted to 1-2 with cone. HC1. The reaction mixture was heated to a temperature ranging from 80°C to 85° to obtain a clear solution. The reaction mixture was cooled to a temperature ranging from 10°C to 15 °C. The reaction mixture was filtered and dried under vacuum at a temperature ranging from 50°C to 55°C to obtain 20.25 g of the compound I-A.
Claims
1. A process for the preparation of viloxazine, a compound of formula I (the “compound I”), or a pharmaceutically acceptable salt thereof,
I the process comprising the steps of: reacting 2-ethoxyphenol, a compound of formula II (the “compound II”) with epichlorohydrin, a compound of formula III (the “compound III”)
in the presence of a base and a solvent to obtain a compound of formula IV (the “compound IV”); wherein the base is added in at least two portions; b) reacting the compound IV obtained in the step (a) with (N-benzylamino)ethyl hydrogen sulfate, a compound of formula V (the
wherein Bn is C6H5CH2-, in the presence of a base and a solvent to obtain a compound of formula VI (the “compound VI”), wherein the compound V is added in at least two portions; and c) reacting the compound VI obtained in the step (b) with a reducing agent in the presence of acetic acid to obtain a compound of formula VII (the “compound VII”);
VII and
d) reacting the compound VII obtained in the step (c) with a base to obtain the compound I, and optionally converting it to a pharmaceutically acceptable salt thereof.
2. The process according to claim 1, wherein the step (a) is carried out in the absence of a phase transfer catalyst (PTC).
3. The process according to claim 1 or claim 2, wherein the base used in steps (a), (b) and (d) is an inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydride, sodium hydride, and potassium hydride.
4. The process according to claim 1 or claim 2, wherein the reducing agent used in the step (c) is a hydrogenation catalyst selected from palladium, platinum, ruthenium, rhodium, or nickel provided on a carrier.
7. The process according to claim 1, wherein in the step (d) the viloxazine, the compound I is converted to its hydrochloride salt represented by the compound of formula I-A (the compound I-A),
8. The process according to claim 7, wherein the hydrochloride salt of viloxazine, the compound I-A is having a content of the compound of formula VIII (the “compound
VIII”) in an amount less than 1%, the compound of formula IX (the “compound IX”) in an amount less than 1% and the compound of formula X (the “compound X”) is not detected, as measured by HPLC, wherein the compounds VIII, IX and X are structurally represented as follows,
X.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US3712890A (en) * | 1969-06-20 | 1973-01-23 | Ici Ltd | Process for making 2-aryloxymethyl morpholines |
US20150126735A1 (en) * | 2010-04-12 | 2015-05-07 | Supernus Pharmaceuticals Inc. | Methods for producing viloxazine salts and novel polymorphs thereof |
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Publication number | Priority date | Publication date | Assignee | Title |
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US3712890A (en) * | 1969-06-20 | 1973-01-23 | Ici Ltd | Process for making 2-aryloxymethyl morpholines |
US20150126735A1 (en) * | 2010-04-12 | 2015-05-07 | Supernus Pharmaceuticals Inc. | Methods for producing viloxazine salts and novel polymorphs thereof |
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