CN113234004A - Novel preparation process of brivaracetam - Google Patents
Novel preparation process of brivaracetam Download PDFInfo
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- CN113234004A CN113234004A CN202110477847.9A CN202110477847A CN113234004A CN 113234004 A CN113234004 A CN 113234004A CN 202110477847 A CN202110477847 A CN 202110477847A CN 113234004 A CN113234004 A CN 113234004A
- Authority
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- China
- Prior art keywords
- solvent
- reaction
- halogenated
- acylation
- preparation process
- Prior art date
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- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 title claims abstract description 29
- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000005917 acylation reaction Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000010933 acylation Effects 0.000 claims abstract description 10
- -1 methylene-hexanoyl halide Chemical class 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000000758 substrate Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 230000002140 halogenating effect Effects 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 2
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims 1
- 239000004210 ether based solvent Substances 0.000 claims 1
- 239000012336 iodinating agent Substances 0.000 claims 1
- HNNJFUDLLWOVKZ-UHFFFAOYSA-N 2-aminobutanamide Chemical compound CCC(N)C(N)=O HNNJFUDLLWOVKZ-UHFFFAOYSA-N 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- HNNJFUDLLWOVKZ-VKHMYHEASA-N (2s)-2-aminobutanamide Chemical compound CC[C@H](N)C(N)=O HNNJFUDLLWOVKZ-VKHMYHEASA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QBRLLRVQUASVRZ-UHFFFAOYSA-N CCCC(CC(Cl)=O)=CBr Chemical compound CCCC(CC(Cl)=O)=CBr QBRLLRVQUASVRZ-UHFFFAOYSA-N 0.000 description 3
- VDAHLWCNBVXQHQ-UHFFFAOYSA-N CCCC(CC(O)=O)=CBr Chemical compound CCCC(CC(O)=O)=CBr VDAHLWCNBVXQHQ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NCBVCRLVTCSQAG-ZCFIWIBFSA-N (4r)-4-propylpyrrolidin-2-one Chemical compound CCC[C@H]1CNC(=O)C1 NCBVCRLVTCSQAG-ZCFIWIBFSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001314 paroxysmal effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- WCVRQHFDJLLWFE-RXMQYKEDSA-N (2r)-pentane-1,2-diol Chemical compound CCC[C@@H](O)CO WCVRQHFDJLLWFE-RXMQYKEDSA-N 0.000 description 1
- HDBMIDJFXOYCGK-DFWYDOINSA-N (2s)-2-aminobutanamide;hydrochloride Chemical compound Cl.CC[C@H](N)C(N)=O HDBMIDJFXOYCGK-DFWYDOINSA-N 0.000 description 1
- NVTUTJMZAZZKAZ-ZCFIWIBFSA-N (4r)-4-propyloxolan-2-one Chemical compound CCC[C@H]1COC(=O)C1 NVTUTJMZAZZKAZ-ZCFIWIBFSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- MIYUTMZDGYBCOY-UHFFFAOYSA-N 3-(iodomethyl)hexanoic acid Chemical compound CCCC(CI)CC(O)=O MIYUTMZDGYBCOY-UHFFFAOYSA-N 0.000 description 1
- WFBZQQBFFLRIMV-UHFFFAOYSA-N 3-(iodomethyl)hexanoyl chloride Chemical compound CCCC(CI)CC(Cl)=O WFBZQQBFFLRIMV-UHFFFAOYSA-N 0.000 description 1
- NVTUTJMZAZZKAZ-UHFFFAOYSA-N 4-propyloxolan-2-one Chemical compound CCCC1COC(=O)C1 NVTUTJMZAZZKAZ-UHFFFAOYSA-N 0.000 description 1
- NCBVCRLVTCSQAG-UHFFFAOYSA-N 4-propylpyrrolidin-2-one Chemical compound CCCC1CNC(=O)C1 NCBVCRLVTCSQAG-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 101710084141 Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- 206010057040 Temperature intolerance Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- VIHAEDVKXSOUAT-UHFFFAOYSA-N but-2-en-4-olide Chemical compound O=C1OCC=C1 VIHAEDVKXSOUAT-UHFFFAOYSA-N 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- HCWOVPZEAFLXPL-UHFFFAOYSA-N diphenyl propanedioate Chemical compound C=1C=CC=CC=1OC(=O)CC(=O)OC1=CC=CC=C1 HCWOVPZEAFLXPL-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SJRXWMQZUAOMRJ-UHFFFAOYSA-N ethyl 2-hexenoate Chemical compound CCCC=CC(=O)OCC SJRXWMQZUAOMRJ-UHFFFAOYSA-N 0.000 description 1
- CRUVGEHKMFFRSF-UHFFFAOYSA-N ethyl 3-(nitromethyl)hexanoate Chemical compound CCCC(C[N+]([O-])=O)CC(=O)OCC CRUVGEHKMFFRSF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 230000008543 heat sensitivity Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UFQQDNMQADCHGH-UHFFFAOYSA-N methyl 2-bromobutanoate Chemical compound CCC(Br)C(=O)OC UFQQDNMQADCHGH-UHFFFAOYSA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000001052 transient 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmacy, in particular to a novel preparation process of brivaracetam, which directly obtains brivaracetam by utilizing L-2-aminobutanamide and 3-halogenated methylene-hexanoyl halide, avoids using a phase transfer catalyst, improves the product yield, simplifies the process steps and improves the production efficiency; the method comprises the following steps: s1, preparing 3-halogenated methylene-hexanoic halide by taking R-4-n-propyl-dihydrofuran-2-ketone as a raw material through halogenated acylation reaction in a halogenated acylation solvent; s2, reacting and post-treating under the condition of a single organic solvent to obtain the brivaracetam by using 3-halogenated methylene-caproyl halide as a substrate under the alkaline condition without a phase transfer catalyst.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a novel preparation process of brivaracetam.
Background
Epilepsy is a nervous system disease with repeated attacks, the attacks are paroxysmal abnormal high-frequency discharge generated by hyperexcitability of neurons of local brain focuses caused by different causes, and the paroxysmal abnormal high-frequency discharge spreads around to cause transient cerebral dysfunction, and the epilepsy is a syndrome of bravaracetam (brivaracetam): 2S-2- ((4R) -2-oxo-4-n-propyl-1-pyrrolidinyl) butanamide, a highly selective and affinity ligand for synaptic vesicle protein 2A, is approved for the adjuvant treatment of partial seizures in adults and juvenile epilepsy above 16 years old, with or without secondary generalized seizures;
the currently available literature contains several synthetic pathways for brivaracetam:
beno I t M, (J.M.C.2004,47, 530-: reacting 2(5H) -furanone serving as a starting material with n-propyl magnesium bromide to obtain racemic 4-n-propyl-dihydrofuran-2-one, reacting with iodotrimethylsilane to obtain ring-opened 3- (iodomethyl) hexanoic acid, chlorinating to obtain 3- (iodomethyl) hexanoic acid chloride, further reacting with (S) -aminobutanamide to obtain racemic brivaracetam, and separating by chiral preparation equipment to finally obtain brivaracetam;
patent No. CN101263113B discloses a preparation route of bravaracetam: according to the method, 2-ethyl hexenoate is used as a starting material, ethyl 3-nitromethylhexanoate is obtained through Michael addition, racemic 4-n-propyl pyrrolidone is obtained through hydrogenation and cyclization, optically pure (R) -4-n-propyl pyrrolidone is obtained through manual preparative chromatographic separation, then the optically pure (R) -4-n-propyl pyrrolidone is reacted with methyl 2-bromobutyrate to obtain methyl 2S-2- (2-oxo-4-n-propyl-1-pyrrolidinyl) butyrate, partial racemic bravaracetam is obtained through ammonolysis, and finally high-purity bravaracetam is obtained through preparative chromatographic separation;
the two routes both need to be separated and purified by a manual preparation column to obtain high-purity brivaracetam, and have high production cost and poor industrial feasibility;
patent WO2007065634 discloses a preparation route of brivaracetam, which uses n-pentene as a starting material, obtains (R) -2-hydroxypentanol through asymmetric hydroxylation reaction, obtains (4R) -4-propyl-ethylene sulfite through reaction with thionyl chloride, obtains (4R) -4-propyl-ethylene sulfate through oxidation of ruthenium trichloride hydrate and sodium periodate, obtains (S) -6, 6-dimethyl-1-propyl-5, 7-dioxa helix 2.5 octane-4, 8-diketone through reaction with dimethyl malonate, obtains a mixture of a pair of position isomers through reaction with (S) -aminobutanamide, obtains brivaracetam through methyl esterification and decarboxylation, and has low yield, more impurities, difficult separation and high cost;
patent CN105646319 discloses a preparation route of brivaracetam, which uses diphenyl malonate as starting material, reacts with (R) -epichlorohydrin to obtain 2-oxo-3-oxabicyclo [3.1.0] hexane-1-phenyl formate, then reacts with ethyl magnesium bromide under the catalysis of cuprous iodide to obtain 2-oxo-4-propyl-tetrahydrofuran-3-phenyl formate, and then undergoes high temperature decarboxylation to obtain (R) -4-propyl-dihydrofuran-2-one, and then undergoes ring opening by trimethyl bromosilane, and forms ester with methanol to obtain (R) -3-bromomethyl hexanoate, and finally condenses with (S) -aminobutanamide under high temperature condition to obtain brivaracetam, which is easy to degrade at high temperature, the impurities are more, and the separation is difficult;
in the existing preparation and production process of the brivaracetam, the brivaracetam is generally obtained by taking L-2-aminobutanamide as a raw material and performing a synthesis reaction with a reaction intermediate product BT-7, but the required reaction raw material is unstable in a free L-2-aminobutanamide state and easy to hang on the wall and operate, so that the yield of a finished product is low, crystal water exists in the intermediate product prepared before ring closing, the influence of water in the ring closing step is large, the drying problem is difficult to solve, the intermediate product before ring closing is very unstable in state, easy to decompose by visible light, poor in heat sensitivity and difficult to purify, so that the preparation effect of the brivaracetam is poor and the efficiency is low; although patents CN108409557A, CN109134406A and CN106588740A use a method of preparing bravaracetam by reacting L-2-aminobutanamide with 3-halomethylene-hexanoyl chloride/bromine under alkaline conditions in the presence of a phase transfer catalyst, the yield of continuous reaction varies from 59 to 75%; thereby leading to poor preparation effect on the brivaracetam, easy occurrence of impurities and low production efficiency and yield.
Disclosure of Invention
In order to solve the technical problems, the invention provides a novel preparation process of the brivaracetam, which directly obtains the brivaracetam by using the L-2-aminobutanamide and the 3-halogenated methylene-hexanoyl halide, avoids using a phase transfer catalyst, improves the product yield, simplifies the process steps, and improves the production efficiency.
The novel preparation process of the brivaracetam takes 3-halogenated methylene-caproyl halide as a substrate, and the brivaracetam is prepared by reaction and post-treatment under the condition of a single organic solvent without a phase transfer catalyst under the alkaline condition.
The reaction formula of the process is shown as follows:
wherein X1，X2Identical or different, selected from fluorine, chlorine, bromine and iodine.
In one embodiment of the invention, the base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide; preferably sodium hydroxide, potassium tert-butoxide; most preferably selected from sodium hydroxide.
In one embodiment of the invention, the molar ratio of the compound of formula II to the base is 1:3 to 1: 7; most preferably 1: 3.5.
In one embodiment of the present invention, the organic solvent is at least one selected from the group consisting of dichloromethane, chloroform, 1-, 2-dichloroethane, acetonitrile, methyl t-butyl ether, thionyl chloride, N-dimethylformamide, tetrahydrofuran, and diethyl ether; preferably dichloromethane and trichloromethane; most preferred is dichloromethane.
In one embodiment of the present invention, the mass ratio of the solvent to the compound (ii) is 10: 1-30: 1; most preferably 15: 1.
In one embodiment of the invention, the reaction temperature is from 10 ℃ to 30 ℃, most preferably from 23 ℃ to 25 ℃.
A preparation method of a brivaracetam intermediate compound II comprises the following steps: the method for preparing the compound shown in the formula II by taking R-4-n-propyl-dihydrofuran-2-ketone (formula III) as a raw material through halogenated acylation is characterized in that the synthetic route is as follows:
wherein X1，X2Identical or different, respectively selected from chlorine, bromine or iodine.
In one embodiment of the present invention,
1)X1and X2When the same, selected from chlorine and bromine; the halogenated acylation reaction is completed in the same system;
2) when X is present1And X2At different times, X1Selected from chlorine or bromine, X2Selected from chlorine, bromine or iodine; firstly, carrying out halogenation reaction and then carrying out acylation reaction.
In one embodiment of the present invention, the halogenated acylated solvent is selected from protic solvents; preferably selected from toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether; most preferably toluene.
In one embodiment of the present invention, the temperature of the haloacylation reaction is not higher than the reflux temperature of the solvent; preferably 20 ℃ to 40 ℃, most preferably 25 ℃.
In one embodiment of the invention, the volume-to-mass ratio of the halogenated acylation reaction solvent to the compound III is 1mL/g to 100 mL/g; most preferably 10 mL/g.
In one embodiment of the present invention, the halogenating agent used for the halogenating acylation is selected from the group consisting of phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, hydrogen bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride; most preferably selected from hydrobromic acid or thionyl chloride.
In one embodiment of the present invention, the molar ratio of the halogenating agent used for the haloacylation to the compound iii is 1: 1-5: 1; most preferably 1.5: 1.
In one embodiment of the present invention, when X is2In the case of bromine, the halogenated reaction solvent is selected from water, acetic acid, and most preferably from water.
In one embodiment of the present invention, when X is2When the organic solvent is iodine, the halogenated reaction organic solvent is selected from one or more of an ether solvent, an aromatic hydrocarbon solvent and a nitrile solvent; tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dichloromethane, trichloromethane are preferred; most preferred is dichloromethane.
In one embodiment of the invention, the volume-to-mass ratio of the halogenated reaction solvent to the compound III is 1mL/g to 100 mL/g; preferably 6 to 10 mL/g.
In one embodiment of the present invention, the halogenation temperature is not higher than the reflux temperature of the solvent; preferably 10 ℃ to 30 ℃, most preferably 25 ℃.
In one embodiment of the invention, the halogenating reagent used in the halogenation reaction is selected from hydrogen bromide.
In one embodiment of the present invention, when X is2When iodine, the halogenating reaction iodination reagent is selected from iodine, iodotrimethylsilane and N-iodosuccinimide; most preferably selected from the group consisting of trimethyl iodosilanes.
In one embodiment of the invention, the acylating agent is selected from the group consisting of dibromosulfoxide, thionyl chloride, oxalyl bromide, oxalyl chloride, tert-valeryl chloride; most preferred is thionyl chloride.
In one embodiment of the invention, the acylation reaction is selected from the group consisting of aprotic solvents; tetrahydrofuran, acetonitrile, dichloromethane, trichloromethane and toluene are preferred; most preferred is dichloromethane.
In one embodiment of the invention, the reaction temperature of the acylation reaction is not higher than the reflux temperature of the solvent used; preferably 10 ℃ to 30 ℃, most preferably 25 ℃.
In one embodiment of the invention, the molar ratio of the acylation reagent to the compound III is 1: 1-1: 3; most preferably 1: 1.5.
In one embodiment of the invention, the volume-to-mass ratio of the acylation reaction solvent to the compound III is 1mL/g to 100 mL/g; preferably 8 mL/g.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a method for preparing bravaracetam by directly reacting L-2-aminobutanamide and 3-halogenated methylene-hexanoic halide under an alkaline condition.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1
Preparation of 3-bromomethylene-hexanoic acid (Compound IV-1)
At room temperature, adding 33% hydrobromic acid solution (222g) and a compound III (48g) into a reaction kettle, heating to 30-80 ℃, stirring and reacting for 2-5 hours, discharging gas violently in the reaction process, detecting by TLC, and removing the compound III to finish the reaction. After the reaction is finished, the temperature is reduced to room temperature, a proper amount of water (50g) is added into the reaction kettle, the mixture is stirred for 10 minutes, the mixture is kept stand for phase separation, and a lower organic phase is collected. The upper aqueous phase was extracted with n-heptane, the organic phases were combined and concentrated to dryness under reduced pressure. A pale yellow oily liquid was obtained. The yield is 90-110%.
Example 2
Preparation of 3-bromomethylene-hexanoyl chloride (Compound II-1)
Dichloromethane (176.3g) and a compound IV-1 (86g) are added into a reaction kettle, thionyl chloride (86.8g) is dropwise added at the temperature of 0-40 ℃, the heat release is not obvious in the dropwise adding process, but the gas is obviously discharged at the initial stage, and a tail gas absorption device is needed. And after the addition, keeping the room temperature and stirring for 5-10 hours. And (3) TLC detection, stopping reaction, concentrating under reduced pressure, concentrating by using a water pump, and distilling until no fraction is separated to obtain a compound II-1 which is a light yellow liquid, wherein the molar yield of the two steps is 95-104%.
Example 3
Preparation of brivaracetam
At room temperature, dichloromethane (802.1g) and L-2-aminobutanamide hydrochloride (64.6g) were added to a reaction vessel, sodium hydroxide (35.4g) was added in portions, the internal temperature was controlled to 10 to 30 ℃, stirring was carried out at a constant temperature for 1 hour, anhydrous sodium sulfate (110.4g) was added, and drying was carried out for 1 hour. Adding dichloromethane (802.1g) and sodium hydroxide (24.9g) again, controlling the temperature to be 10-30 ℃, adding dichloromethane (260.4g) solution of a compound II (87.5g) in a flowing mode, controlling the temperature to be obvious in the process of adding in the flowing mode, enabling the feed liquid to become thick along with the addition of the compound II, stirring for about 30min to become thin, stirring and preserving the temperature for 4h, dotting the plate, after the reaction is finished, dropwise adding hydrochloric acid, adjusting the pH value to be 7-8, controlling the temperature to be below 30 ℃ in the process of dropwise adding, filtering, and repeatedly measuring the pH value. And leaching the filter cake with dichloromethane, separating the solution, washing the organic phase with saturated brine, separating the solution, washing the organic phase with purified water, removing water from the oil phase of the separated solution with anhydrous sodium sulfate, stirring for 2 hours until the material liquid is clear, filtering, leaching the filter cake with dichloromethane, evaporating the filtrate under reduced pressure to dryness, adding n-heptane to carry dichloro for 2 times, and adding 400g of n-heptane for recrystallization. White powdery solid is obtained, and the product is dried by blowing at 30 ℃ to obtain 65.3 g. The molar yield was 80%.
1H NMR(400MHz,DMSO-d6)δ7.33(s,1H),6.99(s,1H),4.30(dd,J＝10.3,5.4Hz,1H),3.37(t,J＝8.7Hz,1H),3.11(dd,J＝9.5,7.0Hz,1H),2.38(dd,J＝16.1,8.5Hz,1H),2.23(p,J＝7.6Hz,1H),1.98(dd,J＝16.1,8.0Hz,1H),1.78(dp,J＝13.9,7.2Hz,1H),1.56(ddt,J＝17.5,14.3,7.4Hz,1H),1.45–1.21(m,4H),0.88(t,J＝7.1Hz,3H),0.77(t,J＝7.3Hz,3H).
The embodiment provides a method for preparing the brivaracetam by directly reacting the L-2-aminobutanamide and the 3-halogenated methylene-hexanoic acid halide under the alkaline condition, compared with the traditional method, the method has the advantages of simplified operation, improved product yield, avoidance of purification of unstable intermediates, avoidance of use of phase transfer catalysts, simplified process steps, reduction of impurity generation by dropwise addition and increased yield.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A novel preparation process of brivaracetam is characterized in that S1 is prepared by taking R-4-n-propyl-dihydrofuran-2-ketone (formula III) as a raw material and preparing 3-halogenated methylene-caproyl halide (formula II) through halogenated acylation reaction in a halogenated acylation solvent; s2, and reacting and post-treating the product under alkaline condition without phase transfer catalyst by using 3-halogenated methylene-caproyl halide (formula II) as substrate and single organic solvent to obtain the product.
2. The novel preparation process of bravaracetam as claimed in claim 1, wherein the reaction formula of the process is as follows:
wherein X1，X2Identical or different, selected from chlorine, bromine and iodine.
3. The novel preparation process of bravaracetam as claimed in claim 1, wherein the base is at least one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride and lithium diisopropylamide, and the molar ratio of the formula II to the base is 1: 3-1: 7.
4. The novel preparation process of bravaracetam as claimed in claim 1, wherein the organic solvent is at least one selected from dichloromethane, chloroform, 1-, 2-dichloroethane, acetonitrile, methyl tert-butyl ether, thionyl chloride, N-dimethylformamide, tetrahydrofuran and diethyl ether, and the mass ratio of the solvent to the formula II is 10: 1-30: 1.
5. The novel preparation process of bravaracetam as claimed in claim 1, wherein the reaction temperature in S2 is 10-30 ℃.
6. The novel preparation process of brivaracetam as claimed in claim 1, wherein the halogenated acylation solvent is selected from protic solvents, the temperature of the halogenated acylation reaction is lower than the reflux temperature of the solvent, and the volume-to-mass ratio of the halogenated acylation solvent to the compound of formula III is 1 mL/g-100 mL/g.
7. The novel preparation process of bravaracetam as claimed in claim 1, wherein the halogenating agent used in the halogenating acylation is selected from phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, hydrogen bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and thionyl chloride, the molar ratio of the halogenating agent to compound III is 1: 1-5: 1, the halogenating reaction solvent is selected from one or more of water, acetic acid, ether solvents, aromatic solvents and nitrile solvents, the volume-to-mass ratio of the halogenating reaction solvent to compound III is 1 mL/g-100 mL/g, the halogenating reaction temperature is lower than the reflux temperature of the solvent, and the halogenating reaction iodinating agent is selected from iodine, trimethyl iodosilane and N-iodosuccinimide.
8. The novel preparation process of brivaracetam as claimed in claim 1, wherein acylation reagent used in halogenated acylation is selected from dibromosulfoxide, thionyl chloride, oxalyl bromide, oxalyl chloride and tert-valeryl chloride, acylation reaction solvent is selected from aprotic solvent, the reaction temperature of acylation reaction is lower than the reflux temperature of the used solvent, the molar ratio of acylation reaction reagent to compound III is 1: 1-1: 3, and the volume-to-mass ratio of acylation reaction solvent to compound III is 1 mL/g-100 mL/g.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114213305A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
| CN114315681A (en) * | 2021-12-31 | 2022-04-12 | 江苏同禾药业有限公司 | High-yield preparation method of brivaracetam |
| CN114480315A (en) * | 2022-02-16 | 2022-05-13 | 成都栩哲医药科技有限公司 | Baeyer-Villiger monooxygenase and application thereof in brivaracetam synthesis |
| CN115028528A (en) * | 2022-08-04 | 2022-09-09 | 东莞理工学院 | A kind of method for synthesizing 4-bromovaleric acid with γ-valerolactone |
| CN116023319A (en) * | 2021-10-25 | 2023-04-28 | 英格尔医药科技(上海)有限公司 | Method for preparing brivaracetam |
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| CN106748748A (en) * | 2015-11-10 | 2017-05-31 | 成都国弘医药有限公司 | A kind of Preparation Method And Their Intermediate of Bu Waxitan |
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| CN106748748A (en) * | 2015-11-10 | 2017-05-31 | 成都国弘医药有限公司 | A kind of Preparation Method And Their Intermediate of Bu Waxitan |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116023319A (en) * | 2021-10-25 | 2023-04-28 | 英格尔医药科技(上海)有限公司 | Method for preparing brivaracetam |
| CN114213305A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
| CN114213305B (en) * | 2021-12-29 | 2023-08-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
| CN114315681A (en) * | 2021-12-31 | 2022-04-12 | 江苏同禾药业有限公司 | High-yield preparation method of brivaracetam |
| CN114480315A (en) * | 2022-02-16 | 2022-05-13 | 成都栩哲医药科技有限公司 | Baeyer-Villiger monooxygenase and application thereof in brivaracetam synthesis |
| CN114480315B (en) * | 2022-02-16 | 2023-09-19 | 四川奥邦古得药业有限公司 | A Baeyer-Villiger monooxygenase and its application in the synthesis of brivaracetam |
| CN115028528A (en) * | 2022-08-04 | 2022-09-09 | 东莞理工学院 | A kind of method for synthesizing 4-bromovaleric acid with γ-valerolactone |
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