EP0929514A1 - Procede preparation de fluoxetine - Google Patents
Procede preparation de fluoxetineInfo
- Publication number
- EP0929514A1 EP0929514A1 EP97943082A EP97943082A EP0929514A1 EP 0929514 A1 EP0929514 A1 EP 0929514A1 EP 97943082 A EP97943082 A EP 97943082A EP 97943082 A EP97943082 A EP 97943082A EP 0929514 A1 EP0929514 A1 EP 0929514A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- reaction
- phenyl
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 title description 19
- 229960002464 fluoxetine Drugs 0.000 title description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 239000011541 reaction mixture Substances 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000008096 xylene Substances 0.000 claims abstract description 27
- 239000002253 acid Substances 0.000 claims abstract description 26
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 14
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 238000009835 boiling Methods 0.000 claims abstract description 12
- 230000007062 hydrolysis Effects 0.000 claims abstract description 12
- 239000012074 organic phase Substances 0.000 claims abstract description 12
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims abstract description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 10
- 239000002585 base Substances 0.000 claims abstract description 10
- 150000003673 urethanes Chemical class 0.000 claims abstract description 10
- 238000011109 contamination Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 239000006227 byproduct Substances 0.000 claims abstract description 7
- AUXZZUAGZGDPRQ-UHFFFAOYSA-N ethyl n-methyl-n-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]carbamate Chemical compound C=1C=CC=CC=1C(CCN(C)C(=O)OCC)OC1=CC=C(C(F)(F)F)C=C1 AUXZZUAGZGDPRQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 150000002484 inorganic compounds Chemical class 0.000 claims abstract description 4
- 229910010272 inorganic material Inorganic materials 0.000 claims abstract description 4
- QUFZVVNFYXEIAK-UHFFFAOYSA-N n,n-dimethyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCN(C)C)OC1=CC=C(C(F)(F)F)C=C1 QUFZVVNFYXEIAK-UHFFFAOYSA-N 0.000 claims abstract description 3
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000007858 starting material Substances 0.000 claims description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000001430 anti-depressive effect Effects 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- 239000002609 medium Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- QULYNCCPRWKEMF-UHFFFAOYSA-N parachlorobenzotrifluoride Chemical compound FC(F)(F)C1=CC=C(Cl)C=C1 QULYNCCPRWKEMF-UHFFFAOYSA-N 0.000 description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- XXSDCGNHLFVSET-UHFFFAOYSA-N 3-(methylamino)-1-phenylpropan-1-ol Chemical compound CNCCC(O)C1=CC=CC=C1 XXSDCGNHLFVSET-UHFFFAOYSA-N 0.000 description 3
- BAYGVMXZJBFEMB-UHFFFAOYSA-N 4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C=C1 BAYGVMXZJBFEMB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000001627 detrimental effect Effects 0.000 description 3
- -1 ethoxycarbonyloxy Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940050176 methyl chloride Drugs 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 150000003891 oxalate salts Chemical class 0.000 description 3
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 150000003738 xylenes Chemical class 0.000 description 2
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical compound OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
- VELGOYBSKBKQFF-UHFFFAOYSA-N 3-(dimethylamino)-1-phenylpropan-1-ol Chemical compound CN(C)CCC(O)C1=CC=CC=C1 VELGOYBSKBKQFF-UHFFFAOYSA-N 0.000 description 1
- QMNXJNURJISYMS-UHFFFAOYSA-N 3-(dimethylamino)-1-phenylpropan-1-one Chemical compound CN(C)CCC(=O)C1=CC=CC=C1 QMNXJNURJISYMS-UHFFFAOYSA-N 0.000 description 1
- HOJWFVSHZMXLAP-UHFFFAOYSA-N 3-[benzyl(methyl)amino]-1-phenylpropan-1-ol Chemical compound C=1C=CC=CC=1CN(C)CCC(O)C1=CC=CC=C1 HOJWFVSHZMXLAP-UHFFFAOYSA-N 0.000 description 1
- LNCWFHRJTAQGBG-UHFFFAOYSA-N 3-[benzyl(methyl)amino]-1-phenylpropan-1-one Chemical compound C=1C=CC=CC=1CN(C)CCC(=O)C1=CC=CC=C1 LNCWFHRJTAQGBG-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical group CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- PODSRQPTUWGSQX-UHFFFAOYSA-N [3-[acetyl(methyl)amino]-1-phenylpropyl] methanesulfonate Chemical compound CC(=O)N(C)CCC(OS(C)(=O)=O)C1=CC=CC=C1 PODSRQPTUWGSQX-UHFFFAOYSA-N 0.000 description 1
- GRJUYWRQOKZSMV-UHFFFAOYSA-N [3-[ethoxycarbonyl(methyl)amino]-1-phenylpropyl] methanesulfonate Chemical compound CCOC(=O)N(C)CCC(OS(C)(=O)=O)c1ccccc1 GRJUYWRQOKZSMV-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FAUVJCHYNSLMMQ-UHFFFAOYSA-M potassium;2-hydroxy-5-nitrobenzoic acid;hydroxide Chemical compound [OH-].[K+].OC(=O)C1=CC([N+]([O-])=O)=CC=C1O FAUVJCHYNSLMMQ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 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
- WCTAGTRAWPDFQO-UHFFFAOYSA-K trisodium;hydrogen carbonate;carbonate Chemical compound [Na+].[Na+].[Na+].OC([O-])=O.[O-]C([O-])=O WCTAGTRAWPDFQO-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
Definitions
- fluoxetine is a valuable antidepressant which exhibits its effect by a selective serotonine reuptake inhibiting activity (Hungarian patent N 172.723)
- US patent N Q 4 018,895 the use of fluoxetine for the treatment of depression is described
- N° 173,723 fluoxetine is . prepared as follows The compound 3- dimethylamino-propiophenone is reduced in tetrahydrofurane with diborane, the N,N-d ⁇ methyl-(3-hydroxy-3-phenyl-propyl)- amine thus obtained is treated with hydrochloric acid and thionyl chloride, the N.N-d ⁇ methyl-(3-phenyl-3-chloro-propyl)- amine-hydrochlo ⁇ de is heated to boiling with 4-t ⁇ fluoromethyl- phenol in alkaline medium for 5 days The N.N-dimethyl- ⁇ 3- phenyl-3-[4-(tr ⁇ fluoromethyl)-phenoxy]-propyl ⁇ -amine of the Formula III
- the dimethylamino derivative of the Formula III is reacted with cyanogene bromide, whereupon the N-methyl-N-cyano- ⁇ 3- phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl ⁇ -am ⁇ ne is heated to boiling with ethylene glycol in potassium hydroxide at 130°C for 2 hours.
- the fluoxetine base of the Formula I is purified via the oxalate salt and is finally converted into fluoxetine hydrochlonde by reacting with gaseous hydrogen chloride in ether. This process is accompanied by several drawbacks. On the one hand poisonous materials detrimental to the environment (e.g.
- Ns 204,769 fluoxetine of the Formula I is prepared starting from N-benzyl-N-methyl-(2- benzoyl-ethyl)-amine.
- the starting material is hydrogenated in the presence of a plati ⁇ -palladium catalyst applied on a carbon support in ethyl acetate in an autoclave with hydrogen gas at 50°C at a pressure of 5.10 5 Pa.
- the N-methyl-(3-hydroxy-3- phenyl-propyl)-amine thus obtained selectively is O-arylated with 4-chloro-trifluoromethyl-benzene, in N-methyl-pyrroiidone, in the presence of potassium tertiary butylate and potassium iodide.
- Fluoxetine of the Formula I thus obtained is converted into the hydrochloride.
- the disadvantage of this process is that the N-methyl-benzyl-amine used as starting material is a difficultly available expensive substance.
- a further drawback resides in the fact that the process necessitates the use of a special catalyst and the purification of the product is complicated. In the cited patent the specification and availability of the catalyst is not disclosed.
- N-methyl-(3- hydroxy-3-phenyl-propyl)-amine is reacted in dimethyl sulfoxide with a small excess of sodium amide, whereupon to the homogeneous reaction mixture at 60-80°C a small excess of 4-chloro-trifluoromethyl-benzene or a solution thereof formed with dimethyl sulfoxide is added.
- the reaction having been completed the dimethylsulfoxide or a part of the solvent is distilled off in vacuo.
- the reaction mixture is poured into water, the fluoxetine of the Formula I thus obtained is extracted, converted into hydrochlo ⁇ de and the salt is recrystallized
- fluoxetine of the Formula I is prepared by reacting 4-t ⁇ fluoromethyl-phenol with a molar equivalent amount of N-ethoxycarbonyl-N-methyl- (3-phenyl-3-methanesulfonyloxy-propyl)-amine or N-acetyl-N- methyl-(3-phenyl-3-methanesulfonyloxy-propyl)-amine in the presence of alkali hydroxide in alcohol as medium at 60- 100°C.
- the protective group is split off by treatment with 3-6 N mineral acid (e.g. hydrochloric acid, sulfuric acid, hydrogen bromide) in ethanol or aqueous medium or in aqueous ethanol.
- the reaction is carried out at the boiling point of the reaction mixture.
- the oily fluoxetine base of the Formula I thus obtained is purified on a silica column.
- This process is accompanied by several drawbacks.
- the 4-trifluoromethyl phenol used as starting material is a difficultly available, expensive substance detrimental to health.
- a further disadvantage resides in the fact that two protective groups are to be introduced onto the propyi amine derivative.
- the desired compound of the Formula I is formed as a contaminated oil which must be purified on a silica column.
- the compound of the Formula I is prepared by reducing ethyl benzoyl acetate in methanol as medium with sodium borohydride, reacting the ethyl-3-hydroxy-3-phe ⁇ yl-propionate in alcoholic medium with methyl amine and 0-arylat ⁇ ng the N-methyl-(3-hydroxy-3- phenyl-prop ⁇ on ⁇ c)-am ⁇ de in tetrahydrofurane in the presence of t ⁇ phenyl phosphine and azodicarboxylic acid with 4- tnfluoromethyl-chloro-benzene
- the reaction mixture is worked up reduced to fluoxetine base of the Formula I in tetrahydrofurane with lithium aluminium hydride whereon salt formation is carried out in a manner known per se
- the process necessitates the use of toxical combustible materials injurious to environment and for this reason the process is not suitable for industrial scale production
- a further drawback is that the product obtained is
- Ns T/63144 fluoxetine of the Formula I and acid addition salts are prepared via new intermediates According to this process N N-d ⁇ methyl-(3-hydroxy-3-phenyl-propyl)-am ⁇ ne of the Formula IV
- sodium salt is formed in N,N-dimethyl aceta ide with sodium hydride in a known manner, whereupon the sodium salt thus obtained is O-arylated with 4- chloro-trifluoromethyl-benzene.
- the hydrochlo ⁇ de is formed in toluene as medium with gaseous hydrogen chloride.
- the crude fluoxetine hydrochlo ⁇ de is purified by recrystal zation from hot water and the hot aqueous solution is optionally treated with charcoal. It is noteworthy that it is specifically mentioned in the laid-open patent application that the N- methyl-N-ethoxycarbonyl- ⁇ 3-phenyl-3-[4-(trifluoromethyl)- phenoxy]-propyl ⁇ -amine of the Formula II
- N-benzyl-N-methyl-(3- hydroxy-3-phenyl-propyl)-amine is reacted with 4-chloro- trifluoromethyl-benzene in dimethyl acetamide.
- the N-benzyl- N-methyl- ⁇ 3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl]- amine obtained is reacted with methyl chloro formate, whereupon the N-methyl-N-methoxycarbony!- ⁇ 3-phenyl-3-[4- (t ⁇ fluoromethyl)-phenoxy]-propyl ⁇ -amine thus obtained is hydrolized into fluoxetine of the Formula I in methanol with sodium hydroxide.
- the fluoxetine base is converted into oxalate in a manner known per se
- the drawback of the process is that two protective groups are to be used
- the removal of the two protective groups and the hydrolysis carried out in alkaline-methanoiic medium results in a strongly contaminated base of the Formula I, which is purified through the oxalate salt; the latter step is carried out by converting the oxalate salt into the base and forming hydrochioride from the free base.
- N,N- dimethyl-(3-hydroxy-3-phenyl-propyl)-amine is etherified with 4-chloro-trifluoromethyl-benzene, whereupon the dimethyl derivative thus obtained is demethylated with the less toxical phenyl-chloro formate in the place of the poisonous cyanogene bromide.
- a strongly contaminated product is obtained which is to be purified by HPLC. The process is expensive and unsuitable for industrial scale production. Summary of the invention
- the present invention is based on the recognition that in the course of the preparation of the compound of the Formula I the majority of the contaminations is* formed during the demethylation of the compound of the Formula III on the one hand and during the alkaline hydrolysis and decarboxylation of the compound of the Formula II on the other.
- hydrolysis of the urethane derivative of the Formula II is carried out in the presence of water and optionally n-butanol, in the same reaction mixture, at the boiling point of the reaction mixture.
- reaction of the compound of the Formula III and ethyl chloro formate is carried out in toluene or xylene at 80- 90°C
- One may work preferably by 80-85°C
- reaction medium industrial xylene consisting of a mixture of o-, m- and p_-xylene may also be used
- the xylene isomers do not influence the reaction and for this reason pure xylene isomers may be successfully replaced by the industrial xylene consisting of an isomer mixture
- the reaction is continued until the evolution of methyl chloride gas stops
- the reaction mixture is extracted with an aqueous acid
- aqueous acid For this purpose preferably diluted hydrochloric acid may be used It is preferred to use 0 75-0.85 moles - particularly 0 8 mole - of a diluted mineral acid, particularly diluted hydrochloric acid, related to 1 mole of the starting material of the Formula III
- the contaminations are present in the aqueous acidic phase which can be simply separated from the upper organic layer
- the organic layer is a clear contamination-free solution of the compound of the Formula II and can be directly used for the alkaline hydrolysis without isolating the compound of the Formula II
- the present invention is based on the further recognition that the compound of the Formula II can be hydrolized with an alkali hydroxide in toluene or xylene as medium in the presence of a small amount of water within a very short reaction time to yield the compound of the Formula I
- the recognition is so much the more surprising as it is known from prior art that the t ⁇ fluoromethyl group is
- the hydrolysis of the compound of the Formula II in methanol or ethanol as medium is very time-consuming and requires about 30 hours
- the reaction time may be shortened to about 12-15 hours by carrying out the reaction in ethylene glycol but in this case the quality of the product does not meet the strict requirements of Pharmacopoeia even after repeated purification
- the long reaction time and the severe reaction conditions cause the formation of secondary and tertiary decomposition products having very similar chemical-physical properties to the desired compound of the Formula I and for this reason such contaminations can be removed only very difficultly
- reaction when carrying out the alkaline hydrolysis of the compound of the Formula II in toluene or xylene as medium in the presence of a small amount of water, the reaction becomes complete within 2-10 hours and at the same time by-products and decomposition products are formed either not at all or only in a minimal amount
- the reaction is carried out in the presence of 20-40 ml - preferably 30 ml - of water, related to 1 mole of the urethane derivative of the Formula II.
- the working-up of the reaction mixture can be facilitated by carrying out hydrolysis in the presence of n- butanol added in the same amount as water In this case the reaction mixture is more easy to be filtered and during extraction with water no difficultly decomposable emulsion is formed
- One may proceed preferably by treating the organic phase - obtained on the reaction of the compound of the Formula III with ethyl chloro formate in toluene or xylene as medium, extraction of the reaction mixture with a diluted aqueous acid and separation of the aqueous acidic phase - with alkali hydroxide in the presence of water and n-butanol
- alkali hydroxide sodium hydroxide, potassium hydroxide or a mixture thereof may be used
- the reaction is carried out at the boiling point of the reaction mixture
- the reaction time is 2-4 hours
- the inorganic compounds may be easily removed from the reaction mixture by filtration or cent ⁇ fuging
- the organic phase containing the compound of the Formula I is washed with water, dried and the base of the Formula I is isolated by evaporating the solution
- One may also proceed by directly precipitating a pharmaceutically acceptable acid addition salt from the toluene or xylene solution by adding a solution of the desired mineral acid formed with an organic solvent
- the hydrochlo ⁇ de of the compound of the Formula I is directly precipitated from the toluene or xylene solution with ethyl acetate containing hydrochloric acid
- This method provides directly, without a further purification, Pharmacopoeia-grade compound of the Formula I
- the pharmaceutically acceptable acid addition of the compounds of the Formula I may be formed with inorganic or organic acids (e.g. hydrogen halides, carbonate, hydrogen carbonate, sulfate, acetate, fumerate, maleate
- the reaction mixture is diluted with 25 ml of xylene, whereupon it is extracted with a mixture of 5 ml of concentrated hydrochlo ⁇ d acid and 20 ml of water
- the lower acidic-aqueous phase is separated, the organic layer is washed with 10 ml of an N sodium hydroxide solution
- the xylene phase is separated and diluted with fresh xylene to 140 ml
- the solution contains 22 4 g of N-methyl-N-ethoxycarbonyl- ⁇ 3-phenyl-3-[4-(t ⁇ fiuoro methyl)-phenoxy]-propyl ⁇ -am ⁇ ne (urethane)
- reaction mixture is cooled to 25 C C, filtered in vacuo through a sintered glass filter and the precipitated product is washed with xylene.
- the organic phase is washed three times with 40 ml of water each to pH 4 and dried over anhydrous magnesium sulfate.
- the xylene solution is acidified with a calculated amount of hydrogen chloride in ethyl acetate (hydrogen chloride content about 10-20 %), the precipitated crystals are filtered and dried to constant weight.
- 17.06 g of N-methyl- ⁇ 3-phenyl-3-[4- (trifluoromethyl)-phenoxy]-propyl ⁇ -amine hydrochloride are obtained in the form of white crystals. Yield: 83.95 %.
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Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9602469P | 1996-09-10 | ||
HU9602469A HU226690B1 (en) | 1996-09-10 | 1996-09-10 | Process for producing fluoxetin |
PCT/HU1997/000050 WO1998011054A1 (fr) | 1996-09-10 | 1997-09-10 | Procede preparation de fluoxetine |
Publications (1)
Publication Number | Publication Date |
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EP0929514A1 true EP0929514A1 (fr) | 1999-07-21 |
Family
ID=89994255
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP97943082A Withdrawn EP0929514A1 (fr) | 1996-09-10 | 1997-09-10 | Procede preparation de fluoxetine |
Country Status (7)
Country | Link |
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EP (1) | EP0929514A1 (fr) |
AU (1) | AU4468997A (fr) |
CZ (1) | CZ75299A3 (fr) |
HU (1) | HU226690B1 (fr) |
PL (1) | PL332141A1 (fr) |
SK (1) | SK29099A3 (fr) |
WO (1) | WO1998011054A1 (fr) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6025517A (en) * | 1998-08-03 | 2000-02-15 | Sepracor Inc. | Fluoxetine process from benzoylacetonitrile |
US6316672B1 (en) | 2001-01-31 | 2001-11-13 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
US6313350B1 (en) | 2001-01-31 | 2001-11-06 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
US6310250B1 (en) | 2001-01-31 | 2001-10-30 | Grayson Walker Stowell | Form A of fluoxetine hydrochloride |
US6258853B1 (en) | 2001-01-31 | 2001-07-10 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
US6310251B1 (en) | 2001-01-31 | 2001-10-30 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
US6846957B2 (en) | 2002-11-22 | 2005-01-25 | Board Of Regents, The University Of Texas System | Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US4018895A (en) * | 1974-01-10 | 1977-04-19 | Eli Lilly And Company | Aryloxyphenylpropylamines in treating depression |
IL99316A (en) * | 1991-08-27 | 1995-03-15 | Teva Pharma | Production of fluoxetine and new intermediates |
US5618968A (en) * | 1993-02-05 | 1997-04-08 | Pliva Farmaceutska Kemijska, Prehrambena I Kozmeticka Industrija, Dionicko Drustvo | N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine and the procedure for their preparation |
-
1996
- 1996-09-10 HU HU9602469A patent/HU226690B1/hu unknown
-
1997
- 1997-09-10 EP EP97943082A patent/EP0929514A1/fr not_active Withdrawn
- 1997-09-10 PL PL97332141A patent/PL332141A1/xx unknown
- 1997-09-10 AU AU44689/97A patent/AU4468997A/en not_active Abandoned
- 1997-09-10 CZ CZ99752A patent/CZ75299A3/cs unknown
- 1997-09-10 SK SK290-99A patent/SK29099A3/sk unknown
- 1997-09-10 WO PCT/HU1997/000050 patent/WO1998011054A1/fr not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9811054A1 * |
Also Published As
Publication number | Publication date |
---|---|
HU226690B1 (en) | 2009-06-29 |
PL332141A1 (en) | 1999-08-30 |
HU9602469D0 (en) | 1996-10-28 |
CZ75299A3 (cs) | 1999-09-15 |
HUP9602469A2 (hu) | 1998-09-28 |
AU4468997A (en) | 1998-04-02 |
WO1998011054A1 (fr) | 1998-03-19 |
SK29099A3 (en) | 1999-08-06 |
HUP9602469A3 (en) | 1999-06-28 |
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