CN102731328B - 一种盐酸安非他酮的制备方法 - Google Patents
一种盐酸安非他酮的制备方法 Download PDFInfo
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- CN102731328B CN102731328B CN201210210411.4A CN201210210411A CN102731328B CN 102731328 B CN102731328 B CN 102731328B CN 201210210411 A CN201210210411 A CN 201210210411A CN 102731328 B CN102731328 B CN 102731328B
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- chloropropiophenone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- IKBZAUYPBWFMDI-UHFFFAOYSA-N 5-bromo-4-methoxy-7-methyl-2,3-dihydro-1h-indene Chemical compound C1=C(Br)C(OC)=C2CCCC2=C1C IKBZAUYPBWFMDI-UHFFFAOYSA-N 0.000 title abstract 2
- 229960004367 bupropion hydrochloride Drugs 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960001058 bupropion Drugs 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 12
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- PQWGFUFROKIJBO-UHFFFAOYSA-N 1-(3-chlorophenyl)propan-1-one Chemical compound CCC(=O)C1=CC=CC(Cl)=C1 PQWGFUFROKIJBO-UHFFFAOYSA-N 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 9
- 239000011707 mineral Substances 0.000 claims description 9
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- -1 2-Methylpropanedioic acid diester Chemical class 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- XDKQUSKHRIUJEO-UHFFFAOYSA-N magnesium;ethanolate Chemical compound [Mg+2].CC[O-].CC[O-] XDKQUSKHRIUJEO-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000007086 side reaction Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000005576 amination reaction Methods 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 235000010755 mineral Nutrition 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 125000001246 bromo group Chemical group Br* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical class CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical class O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical class O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910000103 lithium hydride Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
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- 230000004044 response Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
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- 239000000243 solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VGTCWWMCIQYNFC-UHFFFAOYSA-N acetylene;lithium Chemical compound [Li].C#C VGTCWWMCIQYNFC-UHFFFAOYSA-N 0.000 description 1
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000005844 autocatalytic reaction Methods 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
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- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 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
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
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- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 230000005588 protonation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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Abstract
本发明涉及一种具有抗抑郁作用的盐酸安非他酮的制备方法，其特征是以间氯苯甲酰氯为起始原料，经成酯、水解、溴代、氨基化、成盐等步骤。本发明的有益效果是：本发明提供了一种以间氯苯甲酰氯为起始原料制备安非他酮的方法。该方法应该简单、易行，副反应少，提高了反应收率，降低了生产成本，同时降低对环境的污染。
Description
技术领域
本发明涉及一种具有抗抑郁作用的盐酸安非他酮的制备方法。
背景技术：
盐酸安非他酮，化学名：(±)-1-(3-氯苯基)-2-[(1，1-二甲基乙基)氨基]-1-丙酮·盐酸盐，是一种具有多巴胺能和去甲肾上腺能的抗抑郁剂，临床上主要用于抑郁症的治疗，有报道可以用于戒烟。目前，盐酸安非他酮制备方法主要有三种。
方法一：以间氯苯丙酮为起始原料，溴代后再与叔丁胺进行反应，得安非他酮，再与盐酸反应，得盐酸安非他酮。
溴代方法有两种，一种是用N-溴代丁二酰亚胺(NBS)进行溴代(Reddy，Y.Thirupathi，Synthetic Communications，40(11)，1566-1573；2010)，以间氯苯丙酮计的总收率为75％。这种方法对溴代试剂单耗大，成本高，另一种用液溴直接溴代(Liakina，A.Yu.；Chemistry ofHeterocyclic Compounds；41(8)；1066-1070；2005)，这种溴代方法单步收率高，100％的收率。因此液溴直接溴代是比较好的方法，成本和单耗非常低。
方法二：以间氯苯丙酮为起始原料，氯代后再与叔丁胺进行反应，得安非他酮，再与盐酸反应，得盐酸安非他酮。
氯代方法(CN101407469)以CuCl2为催化剂通入氯气进行氯代，氯代单步收率在92-95％之间，而后与叔丁胺反应后再成盐的收率为85.5％。这种方法虽然从理论比溴代的方法经济，但在实际使用的过程中，有几个无法克服的问题：一是氯气在常温常压下为气体，不易贮存和运输，二是反应时通入的气体的量不好控制，用体积或减重法都不好实现，三是气体通入反应液中，并不能立即被吸收和反应完，因此在反应过程有比较多的氯气从反应体系中逸出，影响氯气的使用效率，同时有可能逸出到生产场所或周边环境中，对人的安全产生威胁和污染大气。
方法三：以α-羟基间氯苯丙酮为原料与三氟甲磺酸酐反应生成磺酸酯中间物，再与叔丁胺反应，最后成盐酸盐。
这种方法(Amarante，Giovanni W.；Tetrahedron Letters；49(23)；3744-3748；2008)从式VIII到安非他酮碱(式II)的收率为75％。所用的起始物料α-羟基间氯苯丙酮(VIII)不能从市场上直接购买得到，制备方法烦琐，步骤长，制备成本非常高，同时由于反应条件为-78～-40℃，为超低温反应，需要特殊的设备，生产上比较难于实现。
三种方法中，方法一适合工业化生产。方法一必需用到起始原料间氯苯丙酮(式V)，现有的制备方法有两种：一种是用苯丙酮做原料，进行氯代[PEARSON，D.E.；POPE.H.W.；Journalof Organic Chemistry，23，1412-19；1958]，其特点是步骤少且简单，但由于因其氯代过程无法避免地生成邻位、对位和二氯代等沸点相近、性质相似的氯代产物，工业化分离提纯非常困难，此外氯代需要用到过量的催化剂无水三氯化铝，使反应后处理困难，大量的废渣不好处理，污染环境。另一种是硝化氯代法制备[Journal of the American Chemical Society；vol.86；(1964)；p684-687]，首先对苯丙酮进行间位硝化，再进行还原，重氮化，最后用氯化亚铜进行氯代，整个过程步骤长，处理麻烦。同时，硝化需要以浓硫酸为催化剂，浓硝酸和浓硫酸作为反应硝化试剂，控制不当有爆炸的危险，此外硝化反应为强酸性溶剂以及产生大量的酸性气体对设备腐蚀严重，且生产后处理产生大量的废酸无法回收，硝化的产物还原需要高温高压加氢设备或铁粉还原产生大量铁泥不易回收污染环境，重氮化反应的产物存在不稳定易爆炸的危险。
鉴于以上原因，需要一种简单、副反应少，安全环保的盐酸安非他酮规模化生产工艺，以提高反应收率，降低安非他酮的生产成本，同时降低对环境的污染。
发明内容
本发明要解决的技术问题。
本发明的目的是：提供一种以间氯苯甲酰氯为起始原料制备安非他酮的方法。该方法应该简单、易行，副反应少，可以明显提高收率，降低生产成本，同时降低对环境的污染。
本发明的技术方案是：
一种盐酸安非他酮的制备方法，其特征在于：
第一步以间氯苯甲酰氯(式VI)为起始原料，在碱性环境下和非质子化溶剂中与2-甲基丙二酸二酯(式VII)反应得到式V所示的中间体；
第二步式V所示的中间体在酸性条件下水解脱羧得到间氯苯丙酮(式IV)；
第三步间氯苯丙酮(式IV)溴代反应，制备α-溴代间氯苯丙酮(式III)；
第四步在质子捕获剂的作用下，α-溴代间氯苯丙酮与叔丁胺反应，制备安非他酮(式II)；
第五步安非他酮与盐酸反应，制备盐酸安非他酮(式I)。
本发明优选的盐酸安非他酮的制备方法，其特征在于，第一步所用非质子化溶剂包括醚类、有机亚砜类、酰胺类、酮类，酯类、烃类、氰类溶剂，或以上溶剂的组合。
本发明优选的盐酸安非他酮的制备方法，其特征在于，第一步中间体V的制备步骤所用的碱为无机强碱或有机强碱。
无机强碱包括氢化锂，氢化钠，氢化钾，氢化钙，氨基锂，氨基钠，氢氧化锂，氢氧化钠，氢氧化钾，氢氧化钙。有机强碱包括各种乙基锂，正丁基锂，苯基锂(钠)，乙炔锂(钠)。
无机碱优先选用氢化锂，氢化钠，氢化钙。有机强碱优先选用叔丁醇钾，乙醇钠，甲醇钠，乙醇镁。
非质子溶剂包括酰胺类、醚类、亚砜类、烃类、酯类和酮类等。其中：酰胺类包括：N，N-二甲基甲酰胺，N，N-二甲基乙酰胺，N-甲基吡咯烷酮；醚类包括乙醚，异丙醚，甲基叔丁基醚，四氢呋喃，二氧六环；亚砜类包括二甲亚砜，环丁砜；烃类包括甲苯，二甲苯，苯，石油醚，正已烷，正庚烷；酮类包括丙酮，丁酮，环戊酮，环已酮；酯类包括乙酸乙酯，乙酸丁酯，丙酸乙酯；腈类包括乙腈，丙腈，丁腈。
本步骤优选的技术方案是选用异丙醚，甲基叔丁基醚、甲苯，二甲苯，丙酮，丁酮做非质子溶剂。
本发明优选的盐酸安非他酮的制备方法，其特征在于，第二步中间体(式V)的水解步骤所用的酸为无机酸和有机酸。
第二步水解所用的酸可以是有机酸、无机酸，或是它们之间的任意混合的酸。其中：有机酸以常温下是液体的为优选，包括羧酸或磺酸，具体的是甲酸，乙酸，丙酸，丙二酸或甲磺酸，但不局限于在常温下为液体的有机酸；无机酸包括硫酸，磷酸，多聚磷酸，高氯酸。
中间体V直接用无机酸水解因反应物和产物溶解度都不好，因此在此步反应中加入适当与水能互溶的有机溶剂是非常必要的。经过优化结果发现，有机酸是非常好的有机溶剂，既解决了原料和产物的溶解度问题，同时也提升了反应速度。因此酸水解脱羧的优选条件是在无机酸水溶液与有机酸的混合液中进行反应，反应时间短，收率高。
本发明第三步的溴代反应，为自身催化的反应，且放热明显，一般需要先将少量的液溴先升温引发反应到无色，再将余量进行低温控温反应，此步反应迅速且收率高，TLC中控反应完全。液溴在常温下为液态，方便贮存，使用量容易控制，不会产生使用过量的问题。
本发明优选的盐酸安非他酮的制备方法，其特征在于，第四步所述质子捕获剂可以是有机碱，或无机碱，或由有机碱与无机碱组成的混合碱。
本发明第四步、第五步反应需要在有机溶剂中进行，在由式III和叔丁胺反应生成氨非他酮的过程中，同时也产生等当量的溴化氢，因此必需加质子捕获剂才能促使反应完全。
有机碱或无机碱都能中和产生的溴化氢，能促进反应。最适合的质子捕获剂无水碱，如氢氧化钾，氢氧化钠，氢氧化锂和碳酸钾。质子捕获剂有机碱最适合为过量的叔丁胺，既做反应试剂，同时也做中和剂，反应完后可以蒸馏回收。其他有机碱如优先选用叔胺类，如三乙胺，二异丙基乙胺，4-二甲氨基吡啶，吡啶，N-甲基哌啶，N-甲基吗啉。反应得到安非他酮的游离碱，除去溶剂后加入醇类溶剂，再加入浓盐酸即成产品式I粗品，精制后得到高纯度的式I。
其中R1可以选自甲基或乙基。
本发明的技术方案是新颖的式V所示的化合物，以及该化合物在制备盐酸安非他酮中的应用。
本发明的有益效果是：本发明提供了一种以间氯苯甲酰氯为起始原料制备安非他酮的方法。该方法应该简单、易行，副反应少，提高了反应收率，降低了生产成本，同时降低对环境的污染。
实施例1 中间体(式V)的制备
将174g 2-甲基丙二酸二乙酯溶解于1000ml无水异丙醚中，冰浴温度下加入40g60％氢化钠，搅拌反应3小时，开始滴加间氯苯甲酰氯175g，滴加完毕，继续反应1小时，然后升温到50℃反应3小时。TLC检测反应完毕。慢慢滴加水，直至无气泡产生为止。再加入水500ml，分流后的有机层再水洗两次，无水硫酸钠干燥，过滤，蒸除异丙醚溶剂，得浅黄色油状物。高真空减压蒸馏(0.1KPa，168-170℃)得到无色油状液体308.7g，收率98.7％。气相检测纯度为99.56％，结构特性：紫外(UV)：λ1max＝245.80，λ1max＝211.40。红外：2983.88cm-1(中)，1755.22cm-1(中)，1732.08cm-1(强)，1732.08cm-1(强)，1689cm-1(强)，1571.99cm-1(中)，1261.45cm-1(中)，1246.02cm-1(强)，1111.00cm-1(强)，1018.41cm-1(中)。1H-NMR(600MHz，CDCl3)：δ＝7.818(s，1H)，7.666-7.677(d，1H)，7.495-7.508(d，1H)，7.351-7.732(t，1H)，4.224-4.247(t，4H)，1.818(s，3H)，1.198-1.283(q，6H)。13C-NMR(125MHz，CDCl3)：δ＝192.355，168.567，136.982，134.608，132.811，129.588，129.095，127.033，65.496，62.458，62.402，20.101，13.773，13.747。
实施例2中间体(式V)的制备
将200g 2-甲基丙二酸二乙酯溶解于1200ml无水甲苯中，再加入固体乙醇镁130g，控温45℃搅拌反应6小时。冰浴，开始滴加间氯苯甲酰氯200g，滴加完毕，继续反应1小时，然后升温到60℃反应8小时。TLC检测反应完毕。冷却后慢慢滴加1mol的稀硫酸水溶液，再加入水300ml，取有机层，水洗两次，无水硫酸钠干燥，过滤，蒸除甲苯溶剂，得米黄色油状物。高真空减压蒸馏(0.1KPa，168-170℃)，得到无色油状液体340.8g，收率94.8％。气相检测纯度为99.64％。红外对比与实施例1制备的中间体(式V)完全一致。
实施例3中间体(式V)的制备
将300g 2-甲基丙二酸二乙酯溶解于1200ml干燥处理过的N，N-二甲基甲酰胺中，冰浴温度下加入193g叔丁醇钾，保温0.5小时，升温到到30℃搅拌反应2小时，然后再继续降温到0℃，滴加间氯苯甲酰氯302g，滴加完毕，继续保温反应1小时，然后升温到50℃反应3小时。TLC检测反应完毕。减压蒸馏除去溶剂，加入水，用二氯甲烷萃取两次，有机层用水洗两次后，无水硫酸钠干燥，过滤，蒸除二氯甲烷溶剂，得浅黄褐色油状物。高真空减压蒸馏(0.1Kpa，168-170℃)得到无色油状液体518.5g，收率96.3％。气相纯度为99.91％。
实施例4间氯苯丙酮(式IV)的制备
称取以上制备的中间体V 100g，加入冰乙酸400ml，搅拌溶解，加入30％的硫酸100ml，加热回流8h，TLC检测反应完毕。冷却后加入2当量的液碱中和硫酸，再减压回收乙酸，得到浅黄色的固体51.4g，收率95.3％，HPLC纯度97.3％。经重结晶得到白色针状结晶间氯苯丙酮48.8g，纯度99.82％。经红外检测与间氯苯丙酮对照品一致，熔点为45-46℃
实施例5 间氯苯丙酮(式IV)的制备
称取以上制备的中间体V 200g，加入丙酸800ml，再加入50％的磷酸300ml，加热回流16h，TLC检测反应完毕。冷却后加入2当量的液碱中和磷酸，再减压回收丙酸，残留油状物加入二氯甲烷萃取2次，合并有机层，碱洗，水洗后经无水硫酸钠干燥，浓缩得浅黄色块状物107.0g，经精制得到间氯苯丙酮100.2g，收率93.3％，HPLC纯度99.72％。经检测与间氯苯丙酮红外图谱，熔点一致。
实施例6
第一步α-溴代间氯苯丙酮的制备(式III)
将间氯苯丙酮50g，溶解于150ml异丙醚中，加入3g液溴加热到35℃进行引发，直接颜色褪去。再慢慢滴加入液小溴74.0g，控温在20℃左右。滴加完毕，继续反应直到HBr气体产生消失为止，TLC点板反应完全，为单一的产物点。减压蒸除溶剂得到α-溴代间氯苯丙酮(式III)，不需纯化直接用于下一步反应。
第二步盐酸安非他酮(式I)的制备
将上步得到的油状物加入400ml乙腈进行溶解，加入叔丁胺44.0g，反应时回流4小时到反应完全，蒸干溶剂，加入二氯甲烷和水溶解，有机层再用5％Na2CO3水溶液洗一次，用无水硫酸钠进行干燥。过滤后浓缩，得油状的安非他酮(式II)，加入异丙醇200ml，并用浓盐酸进行调酸，直到溶液显酸性，冷却析晶，过滤得到盐酸安非他酮(式I)白色粗品79.0g，收率95.3％(以间氯苯丙酮计)。用乙醇和水(9∶1)进行重结晶，得到盐酸安非他酮(式I)精品70.3g，经HPLC检测，纯度99.96％。
Claims (3)
1.一种盐酸安非他酮的制备方法，其特征在于：
第一步以间氯苯甲酰氯为起始原料，在碱性环境下和非质子化溶剂中与2-甲基丙二酸二酯反应得到式V所示的中间体，所述非质子化溶剂选自异丙醚、甲苯、N，N-二甲基甲酰胺之一；所述碱性环境用无机强碱或有机强碱调节，无机强碱或有机强碱选自氢化钠、乙醇镁、叔丁醇钾之一；
第二步式V所示的中间体在酸性条件下水解脱羧得到间氯苯丙酮，所述酸性条件为无机酸和有机酸的混合酸控制的；
第三步间氯苯丙酮溴代反应，制备α-溴代间氯苯丙酮；
第四步在质子捕获剂的作用下，α-溴代间氯苯丙酮(式III)与叔丁胺反应，制备安非他酮；
第五步安非他酮与盐酸反应，制备盐酸安非他酮；
，式中：R1是甲基、乙基。
2.式V所示的化合物，
式中：R1是乙基。
3.权利要求2所述式V化合物在制备盐酸安非他酮中的应用。
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| US6100421A (en) * | 1998-09-18 | 2000-08-08 | Nippon Soda Co., Ltd. | Heterocycle-substituted benzene derivatives and herbicides |
| CN1403433A (zh) * | 2001-09-03 | 2003-03-19 | 江苏四菱染料集团公司 | 由苯甲酰氯合成间氯苯乙酮 |
| CN1549716A (zh) * | 2001-08-27 | 2004-11-24 | ��Ƥ�¹ɷ�����˾ | 用于抗菌试剂的3取代6,7二羟基四氢异喹啉衍生物 |
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| CN1549716A (zh) * | 2001-08-27 | 2004-11-24 | ��Ƥ�¹ɷ�����˾ | 用于抗菌试剂的3取代6,7二羟基四氢异喹啉衍生物 |
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