CN110831924A - Preparation method of levetiracetam - Google Patents
Preparation method of levetiracetam Download PDFInfo
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- CN110831924A CN110831924A CN201780092607.9A CN201780092607A CN110831924A CN 110831924 A CN110831924 A CN 110831924A CN 201780092607 A CN201780092607 A CN 201780092607A CN 110831924 A CN110831924 A CN 110831924A
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- Prior art keywords
- reaction
- ethyl
- oxo
- temperature
- pyrrolidine
- Prior art date
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Links
- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 32
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 6
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 34
- 239000002994 raw material Substances 0.000 claims abstract description 14
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- YAQLSKVCTLCIIE-UHFFFAOYSA-M 2-bromobutanoate Chemical compound CCC(Br)C([O-])=O YAQLSKVCTLCIIE-UHFFFAOYSA-M 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 65
- 239000003795 chemical substances by application Substances 0.000 claims description 33
- -1 1-dimethylethyl Chemical group 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 230000000813 microbial effect Effects 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 238000004321 preservation Methods 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 claims description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 claims description 2
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 claims description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000007444 cell Immobilization Methods 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000000706 filtrate Substances 0.000 description 49
- 238000003756 stirring Methods 0.000 description 42
- 239000012074 organic phase Substances 0.000 description 39
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 34
- 238000004821 distillation Methods 0.000 description 27
- 238000001914 filtration Methods 0.000 description 27
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 23
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 23
- 238000010438 heat treatment Methods 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 238000001816 cooling Methods 0.000 description 20
- 238000001035 drying Methods 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 241000235349 Ascomycota Species 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- ONQBOTKLCMXPOF-UHFFFAOYSA-N 1-ethylpyrrolidine Chemical compound CCN1CCCC1 ONQBOTKLCMXPOF-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000002699 waste material Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- UFQQDNMQADCHGH-UHFFFAOYSA-N methyl 2-bromobutanoate Chemical compound CCC(Br)C(=O)OC UFQQDNMQADCHGH-UHFFFAOYSA-N 0.000 description 5
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 239000002912 waste gas Substances 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- HDBMIDJFXOYCGK-DFWYDOINSA-N (2s)-2-aminobutanamide;hydrochloride Chemical compound Cl.CC[C@H](N)C(N)=O HDBMIDJFXOYCGK-DFWYDOINSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- IODGAONBTQRGGG-LURJTMIESA-N Levetiracetam acid Chemical compound CC[C@@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-LURJTMIESA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000002068 microbial inoculum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- IODGAONBTQRGGG-ZCFIWIBFSA-N (2r)-2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CC[C@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-ZCFIWIBFSA-N 0.000 description 1
- HNNJFUDLLWOVKZ-UHFFFAOYSA-N 2-aminobutanamide Chemical compound CCC(N)C(N)=O HNNJFUDLLWOVKZ-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical class CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical class CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
Abstract
The preparation method of levetiracetam is characterized by using 2-bromobutanoate and 2-pyrrolidone as raw materials, generating (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate under the action of an alkaline reagent, obtaining (S) - α -ethyl-2-oxo-1-pyrrolidine acetate through resolution under the action of ester hydrolase, and finally obtaining levetiracetam through ammonolysis.
Description
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of levetiracetam.
Levetiracetam is a broad-spectrum antiepileptic drug developed by UCB company of Belgium with high efficiency and small toxic and side effects, is mainly used for treating local and secondary generalized epilepsy, and has a chemical name of (S) - α -ethyl-2-oxo-1-pyrrolidine acetamide, and has a structural formula as follows:
at present, a plurality of reports exist on the preparation method of levetiracetam at home and abroad, and a chemical resolution method is mainly adopted. Two types of synthesis methods are commonly used in industry:
(1) racemic (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetic acid which is developed by UCB company of Belgian is used as a raw material, and (R) - α -methylbenzylamine is used as a resolving agent, is resolved in benzene and is treated with alkali to obtain (S) - α -ethyl-2-oxo-1-pyrrolidine acetic acid, (S) - α -ethyl-2-oxo-1-pyrrolidine acetic acid reacts with ethyl chloroformate, and is ammonolyzed to obtain levetiracetam, wherein the synthetic route is shown as follows:
(2) taking 2-aminobutanamide as a raw material, and obtaining (S) -2-aminobutanamide hydrochloride by L-tartaric acid resolution, ammonia dissociation and hydrogen chloride salification. (S) -2-aminobutanamide hydrochloride reacts with 4-chlorobutyryl chloride, and levetiracetam is obtained through cyclization, wherein the synthetic route is as follows:
the synthesis routes adopt the traditional chemical resolution method to construct the chiral center, and have long process routes and low atom utilization rate. Meanwhile, solvents and reagents used in the chemical resolution method are harmful to the environment, and the amount of three wastes (waste water, waste gas and waste residues) is large, so that the industrial application is limited to a certain extent.
Disclosure of Invention
The invention aims to provide a novel method for preparing levetiracetam. The method has simple process and little environmental pollution.
The method for preparing levetiracetam provided by the invention comprises the following steps:
(1) taking 2-bromobutyrate shown in formula (II) and 2-pyrrolidone shown in formula (III) as raw materials, reacting under the action of an alkaline reagent to obtain (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate shown in formula (IV),
(2) the (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate shown in the formula (IV) obtained in the step (1) is resolved under the action of ester hydrolase to obtain (S) - α -ethyl-2-oxo-1-pyrrolidine acetate shown in the formula (V),
(3) adding an ammoniation reagent into the (S) - α -ethyl-2-oxo-1-pyrrolidine acetate (V) obtained in the step (2) for ammonolysis reaction to obtain levetiracetam,
r in the above formulae (II), (IV) and (V) is C1～C6Alkyl radical, wherein C1～C6Alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, R preferably being methyl. X in the formula II and the formula III is bromine or chlorine.
In the above-mentioned synthetic method of levetiracetam, the basic agent in step (1) is an inorganic base selected from metal hydrides and alkali metal alkoxides, preferably sodium hydride, sodium tert-butoxide or potassium tert-butoxide. The molar ratio of the dosage of the alkaline reagent to the 2-pyrrolidone (III) in the step (1) is 0.9: 1-2: 1, and the preferred dosage is 0.9: 1-1.1: 1.
The molar ratio of the 2-pyrrolidone (III) to the 2-bromobutyrate (II) in the step (1) is 0.9: 1-1.5: 1, and the further optimization is 0.95: 1-1.2: 1.
The reaction temperature in the step (1) is 50-100 ℃, and more preferably 60-80 ℃.
The reaction in step (1) is carried out in an organic solvent, which is an aprotic organic solvent, preferably toluene, N-dimethylformamide or tetrahydrofuran.
In the synthetic method of levetiracetam, the step (1) further comprises the following post-treatment of adding water for quenching reaction, extracting and layering by using an extracting agent, collecting an organic phase, drying by using a drying agent, filtering, and distilling the filtrate to obtain (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate (IV). the extracting agent is not particularly limited as long as the extracting agent is immiscible with water and can dissolve (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate (IV). the extracting agent is selected from toluene, dichloromethane or ethyl acetate, the drying agent is anhydrous magnesium sulfate or anhydrous sodium sulfate, the distillation is vacuum distillation, the temperature of the vacuum distillation is 20-100 ℃, preferably 40-70 ℃, the pressure of the vacuum distillation is-0.05-0.1 MPa, and the pressure values in the context of the application are relative to standard atmospheric pressure, namely the difference between the absolute pressure and the standard atmospheric pressure.
In the method for synthesizing levetiracetam, the ester hydrolase in the step (2) is an immobilized microbial inoculum obtained by processing a methyl ascomycete bacterial solution by a cell immobilization method, the methyl ascomycete is classified and named as cxzy-L013 strain of methyl ascomycete (Methylpilasp.), is preserved in China center for type culture Collection in 2016, 9.18.18.year, and has the preservation number of CCTCC NO: m2016494. The above immobilized bacteria agent can be referred to Chinese patent publication CN 106591179A.
The immobilized bacteria agent can specifically hydrolyze (R) - α -ethyl-2-oxo-1-pyrrolidine acetic ester in racemic (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetic ester (IV) into corresponding acid, dissolve in a water phase by salification, and extract (S) - α -ethyl-2-oxo-1-pyrrolidine acetic ester (V) by an organic solvent.
The amount of the immobilized microbial inoculum is 1 to 40 percent of the mass of (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetic ester (IV) by wet weight, and more preferably 2 to 20 percent of the mass of (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetic ester (IV).
The enzymolysis reaction in the step (2) is carried out in a solvent, and the solvent is water. And water is used as a solvent, so that an organic solvent is avoided, and the method is more economic and environment-friendly.
In the enzymolysis reaction in the step (2), the mass percentage concentration of the substrate (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate (IV) is 20-70%, and the preferable concentration is 30-50%.
The temperature of the enzymolysis reaction in the step (2) is 20-50 ℃, the pH is 6.0-9.0, the enzymolysis reaction needs proper temperature and pH, and the reaction activity of the enzyme is reduced when the temperature and the pH exceed the corresponding ranges, preferably, the temperature of the enzymolysis reaction is 25-40 ℃, the pH is 7.0-8.0, and the reaction is stopped when the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1% through HPLC detection.
The pH of the enzymatic hydrolysis reaction is controlled by adding an aqueous solution of a base selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, or alkali metal hydroxides, preferably, the alkali metal carbonates are selected from the group consisting of sodium carbonate and potassium carbonate, the alkali metal bicarbonates are selected from the group consisting of sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxides are selected from the group consisting of sodium hydroxide and potassium hydroxide, (R) - α -ethyl-2-oxo-1-pyrrolidineacetic acid obtained after hydrolysis by a ester hydrolase is reacted with the base to form the corresponding salts, which are soluble in the aqueous phase.
In the synthetic method of levetiracetam, the step (2) further comprises the following post-treatment of filtering, recovering the immobilized microbial agent, adding an organic solvent into the filtrate for extraction and layering, collecting an organic phase, drying by using a drying agent, filtering, and distilling the filtrate to obtain (S) - α -ethyl-2-oxo-1-pyrrolidine acetate (V), wherein the recovered immobilized microbial agent can be recycled, the organic solvent used for extraction in the post-treatment of the step (2) is preferably selected from toluene, dichloromethane or ethyl acetate, the drying agent in the post-treatment of the step (2) is preferably anhydrous magnesium sulfate or anhydrous sodium sulfate, the distillation in the post-treatment of the step (2) is preferably reduced pressure distillation, the temperature of the reduced pressure distillation is 20-100 ℃, further preferably 40-70 ℃, and the pressure of the reduced pressure distillation is-0.05-0.1 MPa.
In the method for synthesizing levetiracetam, the ammoniating reagent used in step (3) is ammonia gas, ammonia water, ammonium formate or ammonium acetate. Preferably, the ammoniation reagent is preferably selected from ammonia gas and ammonia water, and the inorganic ammonia raw materials are easy to obtain, low in cost and small in environmental pollution. Further preferably, the ammoniating agent is ammonia gas.
The aminolysis reaction described in step (3) is carried out in a protic solvent. Preferably the protic solvent is selected from C1～C6Alcohol and water, and more preferably methanol, ethanol and water. C1～C6The alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, and the butanols, pentanols and hexanols and their various isomers.
And (3) when the ammoniation reagent in the step (3) is ammonia gas, the temperature of the ammonolysis reaction is 0-50 ℃, and the pressure of the ammonolysis reaction is 0.1-0.8 MPa. Preferably, the temperature of the ammonolysis reaction is 20-35 ℃, and the pressure of the ammonolysis reaction is 0.2-0.5 MPa. And (4) detecting the ammonolysis reaction by TLC until no raw material is left, wherein the ammonolysis reaction is complete, and the time of the ammonolysis reaction is 12-48 hours.
In the synthetic method of levetiracetam, the step (3) further comprises post-treatment, wherein the post-treatment specifically comprises the following steps: and after the ammonolysis reaction is finished, collecting filtrate, distilling the obtained filtrate to recover the solvent, and obtaining a crude product of the levetiracetam. Adding an organic solvent for recrystallization to obtain the levetiracetam.
The organic solvent used for recrystallization in the step (3) is selected from C1～C4One or more of alcohols, ketones, esters and ethers. C above1～C4The alcohol is selected from methanol, ethanol, isopropanol or butanol; the ketones are selected from acetone, butanone or methyl isobutyl ketone; the above ester is ethyl acetate; the above ether is methyl t-butyl ether. Preferably, the organic solvent used for recrystallization is selected from one or a mixture of acetone, ethyl acetate or methyl isobutyl ketone.
In the synthetic method of levetiracetam, the temperature of recrystallization in the post-treatment in the step (3) is-20 ℃. Preferably, the temperature of recrystallization is-5 to 5 ℃.
Compared with the prior art, the invention has the following advantages:
1. the levetiracetam preparation method of the invention adopts ester hydrolase to realize resolution. The enzymolysis reaction process adopts green solvent water as a resolution solvent, thereby saving the cost and protecting the environment.
2. Compared with chemical catalysis, biological enzyme catalysis has the advantages of high enantioselectivity, low energy consumption, few byproducts, few three wastes (waste water, waste gas and waste residues) and the like.
3. The reaction route provided by the invention has no harsh reaction conditions, easily obtained raw materials, simple operation, high yield, recoverable reaction solvent and small amount of three wastes (waste water, waste gas and waste residue). Meanwhile, the levetiracetam obtained by the reaction has high HPLC purity and optical purity which both reach over 99.5 percent and completely meet the requirements of industrial production.
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention only, but not to limit the scope of the invention.
Example 1
And (3) substitution reaction: under the protection of nitrogen, adding toluene (180g) and 60% NaH (27.6g, 0.69mol) into a reaction bottle, cooling to 0 ℃ under stirring, controlling the temperature to be in a range of-5 ℃, and slowly dropwise adding a toluene (50g) solution of 2-pyrrolidone (58.7g, 0.69 mol). After the dropwise addition is finished, the temperature is controlled within the range of 0-10 ℃, the stirring is carried out for 30 minutes, the temperature is raised to 60 ℃, the temperature is controlled within the range of 60-80 ℃, and methyl 2-bromobutyrate (125.0g, 0.69mol) is slowly dropwise added. After the dropwise addition is completed, the temperature is kept at 60-80 ℃ for carrying out substitution reaction for 6 hours. After the substitution reaction is finished, the temperature is reduced to 20 ℃, and H is slowly dripped2O (100g) quenching reaction, layering, collecting an organic phase, adding an extractant toluene (100g) into a water phase, stirring for 30 minutes, standing for 30 minutes, layering, collecting and combining the organic phase, adding anhydrous magnesium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting filtrate, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation pressure to be-0.07 to-0.08 MPa, controlling the temperature to be 50-60 ℃, carrying out reduced pressure distillation until no liquid flows out any more, and obtaining (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate, wherein the yield is 122.3g, the yield is 95.7%, and the HPLC purity is 98.3%.
Adding (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (90g, 0.49mol) and H into a reaction bottle for enzymolysis reaction2O(210g) And heating to 30 ℃ under stirring, adding an immobilized microbial agent (namely immobilized methyl ascomycete with the preservation number of CCTCC NO: m2016494) (15g), controlling temperature at 25-35 deg.C, and adding 20% Na dropwise2CO3The pH of a reaction system is kept to be 7.0-8.0, the reaction is stopped when the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is detected to be less than 1% by HPLC, the reaction is filtered, the immobilized microbial agent is recovered, an extracting agent toluene (100g) is added into the filtrate, the mixture is stirred for 30 minutes, the mixture is kept stand for 30 minutes and layered, an organic phase is collected, the extraction operation is repeated for 3 times, the organic phase is combined, anhydrous magnesium sulfate (10g) is added into the organic phase, the mixture is stirred and dried for 30 minutes, the filtrate is filtered, the filtrate is collected, the reduced pressure distillation is carried out on the filtrate, the reduced pressure distillation pressure is-0.07 to-0.08 MPa, the temperature is controlled to be 50-60 ℃, the reduced pressure distillation is carried out until no liquid flows out, and the (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is obtained, the yield is 42.4g, the yield is 47.1%, the.
Ammonolysis reaction, adding (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (20g, 0.11mol) and methanol (120g) into a high-pressure reaction kettle, cooling to-10 deg.C under stirring, and filling ammonia (NH)3) Closing a valve when the mixture is saturated, heating to 25 ℃, carrying out an ammonolysis reaction at the temperature of 20-30 ℃ and the pressure of a reaction kettle of 0.2-0.3 MPa, after the reaction is carried out for 24 hours, detecting no raw material (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate by TLC (thin layer chromatography), collecting filtrate after the ammonolysis reaction is completed, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation pressure to be-0.06-0.07 MPa and the temperature to be 40-60 ℃ to obtain solid, adding acetone (100g) to dissolve the solid, heating to reflux and clear solution, slowly cooling to 0 ℃, carrying out thermal insulation crystallization for 2-4 hours, filtering and drying to obtain levetiracetam, wherein the yield is 16.2g, the yield is 88.1%, the purity is 99.8%, and the isomer is 0.11%.
Example 2
And (3) substitution reaction: under the protection of nitrogen, adding toluene (180g) and 60% NaH (30.4g, 0.76mol) into a reaction bottle, cooling to 0 ℃ under stirring, controlling the temperature to be in a range of-5 ℃, and slowly dropwise adding a toluene (50g) solution of 2-pyrrolidone (64.7g, 0.76 mol).After the dropwise addition is finished, the temperature is controlled within the range of 0-10 ℃, the stirring is carried out for 30 minutes, the temperature is raised to 60 ℃, the temperature is controlled within the range of 60-80 ℃, and methyl 2-bromobutyrate (125.0g, 0.69mol) is slowly dropwise added. After the dropwise addition is completed, the temperature is kept at 60-80 ℃ for carrying out a substitution reaction for 6 hours. After the substitution reaction is finished, the temperature is reduced to 20 ℃, and H is slowly dripped2O (100g) quenching reaction, layering, collecting an organic phase, adding an extractant toluene (100g) into a water phase, stirring for 30 minutes, standing for 30 minutes, layering, collecting and combining the organic phase, adding anhydrous magnesium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting filtrate, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation pressure to be-0.07 to-0.08 MPa, controlling the temperature to be 50-60 ℃, carrying out reduced pressure distillation until no liquid flows out any more, and obtaining (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate, wherein the yield is 120.9g, the yield is 94.6%, and the HPLC purity is 97.6%.
Adding (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (120g, 0.65mol) and H into a reaction bottle for enzymolysis reaction2O (120g), heating to 30 ℃ under stirring, adding immobilized bacteria (i.e. immobilized methyl ascomycete, preservation number CCTCC NO: M2016494) (15g), controlling temperature within 25-35 ℃, and dropwise adding 20% Na2CO3The pH of a reaction system is kept to be 7.0-8.0, the reaction is stopped when the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is detected to be less than 1% by HPLC, the reaction is filtered, the immobilized microbial agent is recovered, an extracting agent toluene (100g) is added into the filtrate, the mixture is stirred for 30 minutes, the mixture is kept stand for 30 minutes and layered, an organic phase is collected, the extraction operation is repeated for 3 times, the organic phase is combined, anhydrous magnesium sulfate (10g) is added into the organic phase, the mixture is stirred and dried for 30 minutes, the filtrate is filtered, the filtrate is collected, the reduced pressure distillation is carried out on the filtrate, the reduced pressure distillation pressure is-0.07 to-0.08 MPa, the temperature is controlled to be 50-60 ℃, the reduced pressure distillation is carried out until no liquid flows out, and the (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is obtained, the yield is 56.5g, the yield is 47.4%, the.
And (2) carrying out ammonolysis reaction, namely adding (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (20g, 0.11mol) and methanol (120g) into a high-pressure reaction kettle, cooling to-10 ℃ under stirring, filling NH3 until saturation, closing a valve, heating to 25 ℃, carrying out ammonolysis reaction at the temperature of 20-30 ℃ and the pressure of the reaction kettle of 0.3-0.4 MPa, after the reaction is carried out for 19 hours, detecting no raw material (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate by TLC (thin-layer chromatography), collecting filtrate after the ammonolysis reaction is finished, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation pressure to-0.06-0.07 MPa, controlling the temperature to 40-60 ℃, obtaining solid, adding acetone (100g) to dissolve the solid, heating to reflux, slowly cooling to 0 ℃, carrying out heat preservation and crystallization for 2-4 hours, and carrying out filtration, and drying to obtain levetiracetam yield, 90.3%, purity isomer, and purity of 0.9: 0.06.
Example 3
The substitution reaction comprises the steps of adding N, N-dimethylformamide (180g) and 60% NaH (27.6g, 0.69mol) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃ under stirring, controlling the temperature to be in the range of-5 ℃, slowly dropwise adding a N, N-dimethylformamide (50g) solution of 2-pyrrolidone (58.7g, 0.69mol), after dropwise adding, controlling the temperature to be in the range of 0-10 ℃, stirring for 30 minutes, heating to 60 ℃, controlling the temperature to be in the range of 60-80 ℃, slowly dropwise adding methyl 2-bromobutyrate (125.0g, 0.69mol), after dropwise adding, keeping the temperature at 60-80 ℃ for substitution reaction for 6 hours, cooling to 20 ℃ after the substitution reaction is finished, slowly dropwise adding H2O (100g) for reaction, layering, collecting an organic phase, adding an extractant ethyl acetate (100g multiplied by 3) into an aqueous phase, stirring for 30 minutes, standing for 30 minutes, layering, collecting a combined organic phase, adding distilled water into an organic phase, distilling the organic phase, adding no more water, distilling, filtering, reducing the yield, drying, controlling the yield to be equal to 0.7-80%, filtering, reducing the yield of ethyl acetate, filtering to 10.7-7 MPa, filtering, reducing the yield of ethyl acetate, and drying to obtain a filtrate, and obtaining the filtrate, wherein the yield is equal to 1.7-7-60-80% of the yield of the ethyl acetate.
Adding (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (120g, 0.65mol) and H2O (120g) into a reaction bottle, heating to 30 ℃ under stirring, adding an immobilized microbial agent (namely, immobilized methyl ascomycete with the preservation number of CCTCC NO: M2016494) (15g), controlling the temperature to be within the range of 25-35 ℃, dropwise adding a saturated NaHCO3 solution, keeping the pH of a reaction system to be 7.0-8.0, stopping the reaction when the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1% through HPLC detection, filtering, recovering the immobilized microbial agent, adding an extracting agent toluene (100g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, combining the organic phases, adding anhydrous magnesium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting the filtrate, distilling the filtrate under the reduced pressure of 0.08-0.539 distillation, controlling the temperature of ethyl pyrrolidine methyl acetate to be NO more than 0.07-50.7.0.7-8.0%, and controlling the yield of the ethyl pyrrolidine liquid to be NO more than 1-17% and obtaining the yield of the isomer by HPLC.
And (2) carrying out ammonolysis reaction, namely adding (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (20g, 0.11mol) and methanol (120g) into a high-pressure reaction kettle, cooling to-10 ℃ under stirring, filling NH3 until saturation, closing a valve, heating to 25 ℃, carrying out ammonolysis reaction at the temperature of 20-30 ℃ and the pressure of the reaction kettle of 0.4-0.5 MPa, detecting no raw material (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate residue by TLC (thin layer chromatography) after the reaction is carried out for 15 hours, collecting filtrate after the ammonolysis reaction is finished, carrying out reduced pressure distillation on the filtrate at the reduced pressure of-0.06-0.07 MPa, controlling the temperature at 40-60 ℃ to obtain solid, adding acetone (100g) to dissolve the solid, heating to reflux and dissolving, slowly cooling to 0 ℃, carrying out heat preservation and crystallization for 2-4 hours, filtering, and drying to obtain levetiracetam yield, 88.7%, purity, and purity of 0.8: 09% isomer.
Example 4
The substitution reaction comprises the steps of adding tetrahydrofuran (180g) and 60% NaH (27.6g, 0.69mol) into a reaction bottle under the protection of nitrogen, reducing the temperature to 0 ℃ under stirring, controlling the temperature to be in the range of-5 ℃, slowly dropwise adding a tetrahydrofuran (50g) solution of 2-pyrrolidone (58.7g, 0.69mol), after dropwise adding, controlling the temperature to be in the range of 0-10 ℃, stirring for 30 minutes, heating to 60 ℃, controlling the temperature to be in the range of 60-70 ℃, slowly dropwise adding methyl 2-bromobutyrate (125.0g, 0.69mol), after dropwise adding, keeping the temperature to be 60-70 ℃ for substitution reaction for 6 hours, reducing the temperature to 20 ℃ after substitution reaction, slowly dropwise adding H2O (100g) for quenching reaction, layering, collecting an organic phase, adding an extractant ethyl acetate (100g multiplied by 3), stirring for 30 minutes, standing for 30 minutes, layering, collecting a combined organic phase, adding anhydrous magnesium sulfate (10g) into the organic phase, distilling for 30 minutes, filtering, distilling the filtrate under reduced pressure, filtering, controlling the yield of ethyl acetate to be 0.0-95-0.0.95-95%, and controlling the yield of ethyl acetate (0.95-95 MPa).
Adding (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (120g, 0.65mol) and H2O (120g) into a reaction bottle, heating to 30 ℃ under stirring, adding an immobilized microbial agent (namely, immobilized methyl ascomycete with the preservation number of CCTCC NO: M2016494) (15g), controlling the temperature to be within the range of 25-35 ℃, dropwise adding a 30% NaOH solution, keeping the pH of a reaction system to be 7.0-8.0, stopping the reaction when the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1% through HPLC detection, filtering, recovering the immobilized microbial agent, adding an extracting agent toluene (100g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, combining the organic phases, adding anhydrous magnesium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting the filtrate, distilling the filtrate under the reduced pressure of 0.08-0.08 MPa, controlling the yield of ethyl pyrrolidine liquid to be NO more than 1.6-35.8.6-95% and obtaining the yield of the ethyl pyrrolidine liquid with HPLC.
And (2) carrying out ammonolysis reaction, namely adding (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (20g, 0.11mol) and methanol (120g) into a high-pressure reaction kettle, cooling to-10 ℃ under stirring, filling NH3 until saturation, closing a valve, heating to 35 ℃, carrying out ammonolysis reaction at the temperature of 30-40 ℃ and the pressure of the reaction kettle of 0.3-0.4 MPa, detecting no raw material (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate residue by TLC (thin layer chromatography) after the reaction is carried out for 17 hours, collecting filtrate after the ammonolysis reaction is finished, carrying out reduced pressure distillation on the filtrate at the reduced pressure of-0.06-0.07 MPa, controlling the temperature at 40-60 ℃ to obtain solid, adding acetone (100g) to dissolve the solid, heating to reflux and dissolving, slowly cooling to 0 ℃, carrying out heat preservation and crystallization for 2-4 hours, filtering, and drying to obtain levetiracetam yield, 89.2%, 99.2%, 99.8% purity and 0.15% isomer.
Example 5
The substitution reaction comprises the steps of adding toluene (180g) and 60% NaH (27.6g, 0.69mol) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃ under stirring, controlling the temperature to be in the range of-5 ℃, slowly dropwise adding a toluene (50g) solution of 2-pyrrolidone (58.7g, 0.69mol), after dropwise adding, controlling the temperature to be in the range of 0-10 ℃, stirring for 30 minutes, heating to 60 ℃, controlling the temperature to be in the range of 60-80 ℃, slowly dropwise adding methyl 2-bromobutyrate (125.0g, 0.69mol), after dropwise adding, keeping the temperature to be 60-80 ℃ for substitution reaction for 6 hours, cooling to 20 ℃ after substitution reaction, slowly dropwise adding H2O (100g) for quenching reaction, layering, collecting an organic phase, adding an extractant toluene (100g) into an aqueous phase, stirring for 30 minutes, standing for 30 minutes, layering, collecting and merging the organic phase, adding anhydrous sodium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting filtrate, distilling the filtrate under reduced pressure, and controlling the yield of ethyl pyrrolidine to be 0.1-95-0.0.0-95%, and controlling the yield of ethyl acetate to be not more-1-95 MPa.
Adding (R/S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (120g, 0.65mol) and H2O (120g) into a reaction bottle, heating to 30 ℃ under stirring, adding an immobilized microbial agent (namely, immobilized methyl ascomycete with the preservation number of CCTCC NO: M2016494) (3g), controlling the temperature to be within the range of 25-35 ℃, dropwise adding a 20% Na2CO3 solution, keeping the pH of the reaction system to be 7.0-8.0, detecting the reaction by HPLC until the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate is less than 1%, stopping the reaction, filtering, recovering the immobilized microbial agent, adding an extracting agent toluene (100g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, combining the organic phases, adding anhydrous magnesium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting the filtrate, distilling the filtrate under reduced pressure, distilling the reduced pressure, the methyl acetate to be 0.08-0.08%, controlling the yield of the ethyl pyrrolidine to be NO more than 1.6-8.0.7-8.0.0.0% and controlling the yield of the ethyl pyrrolidine to be NO more, and the yield to be NO more than 46-8.8.0.0.8% by HPLC, and obtaining the yield of the ethyl pyrrolidine isomer by HPLC.
And (2) carrying out ammonolysis reaction, namely adding (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate (20g, 0.11mol) and methanol (120g) into a high-pressure reaction kettle, cooling to-10 ℃ under stirring, filling NH3 until saturation, closing a valve, heating to 25 ℃, carrying out ammonolysis reaction at the temperature of 20-30 ℃ and the pressure of the reaction kettle of 0.3-0.4 MPa, detecting no raw material (S) - α -ethyl-2-oxo-1-pyrrolidine methyl acetate residue by TLC (thin layer chromatography) after the reaction is carried out for 19 hours, collecting filtrate after the ammonolysis reaction is finished, carrying out reduced pressure distillation on the filtrate, controlling the reduced pressure distillation pressure to-0.06-0.07 MPa, controlling the temperature to 40-60 ℃ to obtain solid, adding ethyl acetate (100g) to dissolve the solid, heating to reflux and dissolving, slowly cooling to 0 ℃, carrying out heat preservation and crystallization for 2-4 hours, filtering, and drying to obtain levetiracetam yield, purity of 16.1%, purity of 99.7% and purity of 0.10% of HPLC isomer.
Example 6
The substitution reaction comprises the steps of adding toluene (180g) and 60% NaH (27.6g, 0.69mol) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃ under stirring, controlling the temperature to be in the range of-5 ℃, slowly dropwise adding a toluene (50g) solution of 2-pyrrolidone (58.7g, 0.69mol), after dropwise adding, controlling the temperature to be in the range of 0-10 ℃, stirring for 30 minutes, heating to 60 ℃, controlling the temperature to be in the range of 60-80 ℃, slowly dropwise adding ethyl 2-bromobutyrate (134.6g, 0.69mol), after dropwise adding, keeping the temperature to be 60-80 ℃ for substitution reaction for 6 hours, cooling to 20 ℃ after substitution reaction, slowly dropwise adding H2O (100g) for quenching reaction, layering, collecting an organic phase, adding an extractant toluene (100g) into an aqueous phase, stirring for 30 minutes, standing for 30 minutes, layering, collecting and merging the organic phase, adding anhydrous (10g) into the organic phase, stirring and drying for 30 minutes, filtering and collecting filtrate, distilling the filtrate, and distilling the filtrate under reduced pressure to obtain ethyl acetate liquid with the yield of-0.84-7 MPa, wherein the ethyl acetate yield is controlled to be in the range of-1.8-1 MPa.
Adding (R/S) - α -ethyl-2-oxo-1-pyrrolidine ethyl acetate (130g, 0.65mol) and H2O (130g) into a reaction bottle, heating to 30 ℃ under stirring, adding an immobilized microbial agent (namely, immobilized methyl ascomycete with the preservation number of CCTCC NO: M2016494) (15g), controlling the temperature to be within the range of 25-35 ℃, dropwise adding a 20% Na2CO3 solution, keeping the pH of the reaction system to be 7.0-8.0, stopping the reaction when the isomer (R) - α -ethyl-2-oxo-1-pyrrolidine ethyl acetate is less than 1% through HPLC detection, filtering, recovering the immobilized microbial agent, adding an extracting agent toluene (100g) into the filtrate, stirring for 30 minutes, standing for 30 minutes, layering, collecting an organic phase, repeating the extraction operation for 3 times, combining the organic phases, adding anhydrous magnesium sulfate (10g) into the organic phase, stirring and drying for 30 minutes, filtering, collecting the filtrate, distilling the filtrate under reduced pressure, distilling the reduced pressure to be 0.08-0.7-0.08%, controlling the yield of ethyl acetate to be NO more than 0.7.7-8.7.7-8.7% through HPLC detection, and obtaining the yield of the isomer.
And (2) carrying out ammonolysis reaction, namely adding (S) - α -ethyl-2-oxo-1-pyrrolidine ethyl acetate (20g, 0.10mol) and ethanol (120g) into a high-pressure reaction kettle, cooling to-10 ℃ under stirring, filling NH3 until saturation, closing a valve, heating to 25 ℃, carrying out ammonolysis reaction at the temperature of 20-30 ℃ and the pressure of the reaction kettle of 0.3-0.4 MPa, detecting no raw material (S) - α -ethyl-2-oxo-1-pyrrolidine ethyl acetate residue by TLC (thin layer chromatography) after the reaction is carried out for 22 hours, collecting filtrate after the ammonolysis reaction is finished, carrying out reduced pressure distillation on the filtrate at the reduced pressure of-0.06-0.07 MPa, controlling the temperature at 40-60 ℃ to obtain solid, adding acetone (100g) to dissolve the solid, heating to reflux and dissolving, slowly cooling to 0 ℃, carrying out heat preservation and crystallization for 2-4 hours, filtering, and drying to obtain levetiracetam yield, 90.2%, purity, 99.8% and 0.09% isomer.
Claims (14)
- A process for preparing levetiracetam comprising the steps of:(1) taking 2-bromobutyrate shown in formula (II) and 2-pyrrolidone shown in formula (III) as raw materials, reacting under the action of an alkaline reagent to obtain (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate shown in formula (IV),
(2) resolving the (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate obtained in the step (1) under the action of ester hydrolase to obtain (S) - α -ethyl-2-oxo-1-pyrrolidine acetate,
(3) adding an ammoniation reagent into the (S) - α -ethyl-2-oxo-1-pyrrolidine acetate obtained in the step (2) for ammonolysis reaction to obtain levetiracetam,r in the above formulae (II), (IV) and (V) is C1～C6Alkyl radical, wherein C1～C6The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylpropyl, 2-dimethylpropyl, 1-dimethylpropyl, 11, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. - The method of claim 1, wherein R in formulas (II), (IV) and (V) is methyl.
- The process according to claim 1, wherein the alkaline agent in step (1) is selected from metal hydrides or alkali metal alkoxides, further preferably sodium hydride; the molar ratio of the dosage of the alkaline reagent to the 2-pyrrolidone is 0.9: 1-2: 1, and the preferred ratio is 0.9: 1-1.1: 1.
- The method according to claim 1, wherein the molar ratio of 2-pyrrolidone to 2-bromobutyrate ester in step (1) is 0.9: 1 to 1.5: 1, and more preferably 0.95: 1 to 1.2: 1.
- The process according to claim 1, wherein the reaction temperature in step (1) is 50 to 100 ℃, more preferably 60 to 80 ℃.
- The process according to claim 1, wherein the reaction of step (1) is carried out in an organic solvent selected from toluene, N-dimethylformamide or tetrahydrofuran.
- The method according to claim 1, wherein the ester hydrolase in step (2) is an immobilized microbial agent, the immobilized microbial agent is a Methylospora capsulata treated by a cell immobilization method, and the preservation number of the Methylospora capsulata is CCTCC NO: m2016494.
- The process of claim 7, wherein the reaction of step (2) is carried out in water.
- The method according to claim 7, wherein the concentration of (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate in step (2) is 20-70% by weight, preferably 30-50% by weight.
- The method according to claim 7, wherein the amount of the immobilized bacteria agent in the step (2) in the reaction is 1-40% by weight, more preferably 2-20% by weight of (R/S) - α -ethyl-2-oxo-1-pyrrolidine acetate.
- The method for preparing levetiracetam according to claim 7, wherein the reaction temperature in step (2) is 20-50 ℃, and the pH is 6.0-9.0; the preferable reaction temperature is 25-40 ℃ and the pH is 7.0-8.0.
- The method according to claim 1, wherein the ammoniating agent in step (3) is ammonia gas, ammonia water, ammonium formate or ammonium acetate.
- The method according to claim 12, wherein the ammoniation reagent in step (3) is ammonia gas, the temperature of the ammonolysis reaction is 0-50 ℃, and the pressure of the ammonolysis reaction is 0.1-0.8 MPa; further preferably, the temperature of the ammonolysis reaction is 20-35 ℃, and the pressure of the ammonolysis reaction is 0.2-0.5 MPa.
- The process of claim 1, wherein the ammonolysis reaction in step (3) is carried out in a solvent selected from the group consisting of methanol, ethanol and water.
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| CN110590635A (en) * | 2019-10-11 | 2019-12-20 | 山东理工职业学院 | Preparation method of levetiracetam and intermediate thereof |
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| EP1419144B1 (en) * | 2001-08-10 | 2008-10-08 | UCB Pharma S.A. | Oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues |
| CN102851238A (en) * | 2012-08-10 | 2013-01-02 | 上海应用技术学院 | Sphingobacterium and method for preparing levetiracetam acid by utilizing same |
| CN102994429A (en) * | 2012-12-05 | 2013-03-27 | 浙江工业大学 | Method for preparing (S)-alpha-ethyl-2-oxyen-1-pyrrolidine acetic acid ester through microorganism catalysis and bacterial strain |
| CN105063120A (en) * | 2015-08-25 | 2015-11-18 | 浙江昌明药业有限公司 | Preparation method of levetiracetam |
| CN106591179A (en) * | 2016-12-05 | 2017-04-26 | 长兴制药股份有限公司 | Methylopila sp.cxzy-L013 and application thereof to preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetate by selective resolution |
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| EP1419144B1 (en) * | 2001-08-10 | 2008-10-08 | UCB Pharma S.A. | Oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues |
| CN102851238A (en) * | 2012-08-10 | 2013-01-02 | 上海应用技术学院 | Sphingobacterium and method for preparing levetiracetam acid by utilizing same |
| CN102994429A (en) * | 2012-12-05 | 2013-03-27 | 浙江工业大学 | Method for preparing (S)-alpha-ethyl-2-oxyen-1-pyrrolidine acetic acid ester through microorganism catalysis and bacterial strain |
| CN105063120A (en) * | 2015-08-25 | 2015-11-18 | 浙江昌明药业有限公司 | Preparation method of levetiracetam |
| CN106591179A (en) * | 2016-12-05 | 2017-04-26 | 长兴制药股份有限公司 | Methylopila sp.cxzy-L013 and application thereof to preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetate by selective resolution |
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