CN114751849B - Preparation method of brivaracetam and intermediate compound - Google Patents
Preparation method of brivaracetam and intermediate compound Download PDFInfo
- Publication number
- CN114751849B CN114751849B CN202210441314.XA CN202210441314A CN114751849B CN 114751849 B CN114751849 B CN 114751849B CN 202210441314 A CN202210441314 A CN 202210441314A CN 114751849 B CN114751849 B CN 114751849B
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- propyl
- compound
- brivaracetam
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 45
- 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 40
- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 32
- NVTUTJMZAZZKAZ-ZCFIWIBFSA-N (4r)-4-propyloxolan-2-one Chemical compound CCC[C@H]1COC(=O)C1 NVTUTJMZAZZKAZ-ZCFIWIBFSA-N 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- PIZSVWRKUALQAY-UHFFFAOYSA-N 3-propylcyclobutan-1-one Chemical compound CCCC1CC(=O)C1 PIZSVWRKUALQAY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006220 Baeyer-Villiger oxidation reaction Methods 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- HNNJFUDLLWOVKZ-UHFFFAOYSA-N 2-aminobutanamide Chemical compound CCC(N)C(N)=O HNNJFUDLLWOVKZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000001590 oxidative effect Effects 0.000 claims abstract 5
- 238000006243 chemical reaction Methods 0.000 claims description 53
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 18
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- 229940078916 carbamide peroxide Drugs 0.000 claims description 3
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 229910052751 metal Inorganic materials 0.000 description 16
- 239000002184 metal Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 229940125782 compound 2 Drugs 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000000926 separation method Methods 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- -1 3, 5-diisopropylphenyl group Chemical group 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 101150003085 Pdcl gene Proteins 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 class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000000547 structure data Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 229910052706 scandium Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- IIEJGTQVBJHMDL-UHFFFAOYSA-N 2-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-[2-oxo-2-[3-(sulfamoylamino)pyrrolidin-1-yl]ethyl]-1,3,4-oxadiazole Chemical compound C1CN(CC1NS(=O)(=O)N)C(=O)CC2=NN=C(O2)C3=CN=C(N=C3)NC4CC5=CC=CC=C5C4 IIEJGTQVBJHMDL-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-LHHVKLHASA-N Quinidine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 101710084141 Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 1
- 229910001544 silver hexafluoroantimonate(V) Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
- B01J2531/35—Scandium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an intermediate compound for synthesizing brivaracetam, wherein the intermediate compound is (R) -4-propyl-dihydrofuran-2-one, and the preparation method comprises the following steps: subjecting 3-propylcyclobutanone to an asymmetric Baeyer-Villiger oxidation reaction in the presence of a catalyst and optionally an oxidant to give (R) -4-propyl-dihydrofuran-2-one. The invention further discloses a preparation method of the brivaracetam, which comprises the steps of preparing an intermediate compound (R) -4-propyl-dihydrofuran-2-one by the preparation method of the intermediate compound, and then reacting the intermediate compound with L-2-aminobutanamide to obtain the brivaracetam. The method has the advantages of simple route, short steps, low cost, safety, and high product yield and chiral purity.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a preparation method of brivaracetam and an intermediate compound.
Background
Brivaracetam (Brivaracetam) is a third generation antiepileptic drug, belongs to a novel synaptic vesicle protein 2A (SV 2A) high affinity ligand, and has a certain inhibition effect on voltage-dependent sodium ion channels. In 2016, brivaracetam was FDA approved for the treatment of seizures, which had a better therapeutic effect on systemic seizures.
The structural formula of brivaracetam is as follows:
the prior art discloses a plurality of brivaracetam synthesis methods, and the flow is summarized as follows:
1. technical route one: patent CN1882535a discloses a synthetic preparation method of brivaracetam, the synthetic route is as follows:
after the brivaracetam racemate is synthesized by the route, the brivaracetam racemate is purified and separated by utilizing a chromatographic column, so that the optical pure brivaracetam is obtained. Disadvantages of this route are: at least half of diastereoisomers need to be discarded, the atom economy is poor, and because the chromatographic column is high in price and limited in sample injection amount, the physical properties of all optical isomers are similar, so that the separation and purification effect is poor by adopting the chromatographic column, the batch processing capacity is small, the industrial amplification cost is high, and the low-cost mass production is difficult to realize.
2. Technical route II: benoit M. (J.Med. Chem.2004,47, 530-549) reported another synthetic method of brivaracetam, which was technically routed as follows:
this route also requires optical isomer resolution using chiral chromatography columns. Disadvantages of this route are: at least half of the diastereoisomers need to be discarded, the atom economy is poor, the purity of the brivaracetam racemate obtained by synthesis is low, the brivaracetam racemate can be recrystallized after coarse separation by silica gel, so that the brivaracetam racemate with high purity can be obtained, and then the brivaracetam racemate can be separated by chromatography of a chromatographic column. Similar to the first technical route, the second technical route has small batch processing capacity and high industrial amplification cost, and is difficult to realize low-cost mass production due to high price of the chromatographic column and limited separation effect.
3. Technical route three: the Shuoshi paper of China institute of pharmaceutical industry Zhou Chao, the synthesis research of antiepileptic drug brivaracetam, discloses a method for synthesizing and preparing brivaracetam, which comprises the following synthetic route:
however, this route has the following disadvantages: 1) The steps are complicated; the oxazolidone is used as chiral induction group, which has higher price and higher economic cost, and the oxazolidone is subjected to assembly and removal steps; 2) The second step requires reaction conditions of-70 ℃, the reaction conditions are severe, and large-scale production is difficult to realize; 3) Thirdly, hydrogen peroxide is used as peroxide, so that explosion risk exists; 4) And in the fourth step, dimethyl sulfide borane is used, so that the explosion risk exists, the pungent smell exists, and the safety and environmental protection risks exist.
As above, the prior art synthetic methods for preparing brivaracetam have the following general drawbacks:
1) After the racemate is synthesized, column chromatography separation is needed: this route requires discarding at least half of the diastereoisomers, with poor atomic economy; the separation difficulty of column chromatography is high, and the industrial scale-up production cost is high.
2) Oxazolidinone is used as chiral induction group: complicated steps and harsh reaction conditions; oxazolidinones are expensive and undergo assembly and removal steps at high cost.
3) The enzyme catalysis method is adopted: the chiral purity of the prepared final product is too low to meet the requirement of medicine.
4) The reaction conditions are harsh, and the safety is low.
Therefore, the development of the preparation method of the brivaracetam, which has the advantages of simple route, simple and convenient operation, low cost, safety and high purity of the prepared product, has important significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel preparation method of brivaracetam, which has the advantages of simple route, short steps, low cost, safety and high purity of the prepared product.
To this end, the first aspect of the present invention provides a process for the preparation of an intermediate compound for the synthesis of brivaracetam, said intermediate compound being (R) -4-propyl-dihydrofuran-2-one, said process comprising:
subjecting 3-propylcyclobutanone to an asymmetric Baeyer-Villiger oxidation reaction in the presence of a catalyst and optionally an oxidizing agent to provide (R) -4-propyl-dihydrofuran-2-one having the following formula:
according to a preferred embodiment of the present invention, the catalyst is selected from at least one of the compounds represented by the following formulas 1 and 2; or the catalyst is a complex of a compound shown in the following formula 3 or formula 4 and a metal, wherein the metal is at least one selected from IB, IIB, IIIB, IVB, VA, VIA and VIII group metal elements, preferably at least one selected from Sc, pd, ag, sb, rh, ru, mo, au, zn, cu and Fe;
wherein R in formula 1 1 Aryl having 1 to 4 benzene rings, such as phenyl, naphthyl, anthryl, phenanthryl, preferably phenyl or phenanthryl;
r in 2 2 Is phenyl or C 1 -C 6 Preferably a 3, 5-dialkylphenyl group, such as 3, 5-diisopropylphenyl group;
r in 3 3 Is phenyl or C 1 -C 6 Phenyl substituted by alkyl; preferably a 2,4, 6-trialkylphenyl group such as 2,4, 6-triisopropylphenyl group;
r in 4 4 And R is 5 Each independently selected from C 1 -C 6 And R is an alkyl group of 4 And R is 5 Optionally forming a five-membered ring or a six-membered ring.
According to some embodiments of the invention, the metal is selected from at least one of IB, IIIB, VA and group VIII metal elements, preferably from at least one of Sc, pd, ag, sb.
According to some preferred embodiments of the present invention, the five-or six-membered ring in formula 4 is C 1 -C 3 An alkyl-substituted five-membered ring or six-membered ring.
According to some preferred embodiments of the present invention, at least one carbon is passed between any carbon atoms on the five-or six-membered ring in formula 4Bridged, bridged carbon atoms optionally being C 1 -C 3 Alkyl substitution of (a). In some preferred embodiments, the ortho carbon atoms on the five-or six-membered ring in formula 4 are bridged by at least one carbon, for example, one carbon between the 2,3 carbon atoms. In other preferred embodiments, meta carbon atoms on the five-or six-membered ring in formula 4 are bridged by at least one carbon, for example one carbon between carbon atoms in the 3,5 position.
According to some preferred embodiments of the present invention, the compound represented by formula 4 has a structure represented by formula 5 below:
wherein R is 6 Is C 1 -C 3 Preferably isopropyl.
According to some preferred embodiments of the present invention, the compound of formula 4 has a structure as shown in formula 6 below:
wherein R is 7 Is H or C 1 -C 3 Alkyl radicals of (R) -C 1 -C 3 Such as (R) -methyl or (R) -isopropyl.
According to some embodiments of the invention, the compound of formula 1 is selected from at least one of the following compounds C1 and C2:
according to some embodiments of the invention, the compound represented by formula 2 is selected from at least one of the following compounds C3 and C4:
according to some embodiments of the invention, the compound represented by formula 3 is selected from at least one of the following compounds L1 and L2:
according to some embodiments of the invention, the compound represented by formula 4 is selected from at least one of the following compounds L3, L4, L5, L6 and L7:
according to some embodiments of the present invention, the complex of the compound represented by formula 3 or formula 4 and a metal is prepared by a method comprising the steps of:
the complex is obtained by contact reaction of a compound represented by formula 3 or formula 4 and a salt of the metal in a solvent, and it is understood that the compound represented by formula 3 or formula 4 is a ligand compound.
According to some embodiments of the invention, the salt of the metal is selected from at least one of a chloride, fluoride or trifluoromethane sulfonate of the metal. It should be noted that the metal salts described in the present invention are not limited to single metal salts, but include salts composed of at least two metal ions, such as double salts, and specific examples are AgSbF 6 Etc.
According to some preferred embodiments of the invention, the salt of the metal is selected from Sc (OTf) 3 ,PdCl 2 ,(PhCN) 2 PdCl 2 And AgSbF 6 At least one of them.
Preferably, the ratio of the compound represented by the formula 3 or the formula 4 to the metal salt is (1 to 1.2): 1 by weight.
Preferably, the temperature of the contact reaction is-10 to 40 ℃.
Preferably, the contact reaction time is 1 to 12 hours.
According to some embodiments of the present invention, the compound represented by formula 3 or formula 4 and the salt of the metal are subjected to a contact reaction in an organic solvent selected from solvents such as ethyl acetate, tetrahydrofuran, etc., which dissolve the reactants to effectively disperse the contact reaction. The amount of the organic solvent is not particularly limited as long as the reactant is sufficiently dissolved.
According to some embodiments of the invention, the catalyst is used in an amount of 1 to 10 mole% of the amount of 3-propylcyclobutanone in the asymmetric Baeyer-Villiger oxidation reaction.
According to some embodiments of the invention, the oxidizing agent is m-chloroperoxybenzoic acid, hydrogen peroxide or carbamide peroxide.
According to some embodiments of the invention, the oxidizing agent is present in an amount of 100 to 150 mole% of the amount of 3-propylcyclobutanone.
According to some embodiments of the invention, the asymmetric Baeyer-Villiger oxidation reaction is carried out in an organic solvent, preferably selected from at least one of ethyl acetate, tetrahydrofuran, isopropyl ether, toluene, dichloroethane, dichloromethane, chloroform and N, N-dimethylformamide, so as to dissolve the reactants to allow for a sufficient contact reaction. The amount of the organic solvent is not particularly limited as long as the reaction product is sufficiently dissolved.
According to some preferred embodiments of the present invention, the preparation method comprises mixing 3-propylcyclobutanone with a catalyst to obtain a mixture, and mixing the obtained mixture with an oxidizing agent to perform a reaction.
According to some preferred embodiments of the invention, the temperature of the asymmetric Baeyer-Villiger oxidation reaction is-40 ℃ to-30 ℃ and/or the time of the asymmetric Baeyer-Villiger oxidation reaction is 8h to 24h.
It will be appreciated that the preparation process also includes operations of quenching, extraction and/or column chromatography separation and purification optionally performed after the reaction. Specifically, quenching methods, extraction solvents and column chromatographic separation methods which are conventional or known in the art can be adopted according to the conditions of reactants and products, and are not described in detail herein.
According to some preferred embodiments of the present invention, the 3-propylcyclobutanone is prepared by a process comprising the steps of:
s1, mixing 1-pentene and trichloroacetyl chloride in the presence of phosphorus oxychloride and a zinc copper reagent for a first reaction, and separating to obtain a compound 5 as follows;
s2, mixing the compound 5 with acid and zinc powder for a second reaction, and separating to obtain 3-propyl cyclobutanone, wherein the acid is preferably acetic acid, trifluoromethanesulfonic acid or a mixture of dilute hydrochloric acid and acetic acid.
It will be appreciated that steps S1, S2 may also include steps for separating the formed product after the reaction is complete, including but not limited to filtration, precipitation, washing, and the like, and any combination thereof.
According to some embodiments of the invention, in step S1, the first reaction is performed in a first organic solvent, preferably selected from at least one of diethyl ether, isopropyl ether, methyl tertiary ether and tetrahydrofuran, provided that the first organic solvent is capable of dissolving the reactants to allow the reaction to proceed sufficiently.
According to some embodiments of the invention, in step S1, the trichloroacetyl chloride is used in a molar ratio to 1-pentene of (0.8 to 1.2): 1.
According to some embodiments of the invention, in step S1, the molar ratio of phosphorus oxychloride to 1-pentene added is (1 to 1.2): 1.
According to some embodiments of the invention, the amount of zinc copper reagent added in the first reaction is (2-4): 1 in a molar ratio to 1-pentene.
According to some embodiments of the invention, in step S1, the temperature of the first reaction is 20 ℃ to 50 ℃.
According to some embodiments of the invention, in step S1, the time of the first reaction is 2h to 12h.
According to some embodiments of the invention, in step S2, the ratio of the amount of zinc powder to the mass of compound 5 is (1-2): 1.
According to some embodiments of the invention, in step S2, the temperature of the second reaction is between 90 ℃ and 180 ℃.
According to some embodiments of the invention, in step S2, the second reaction is performed for a period of time ranging from 3h to 9h.
According to the invention, the intermediate compound is prepared by adopting the preparation method, and the method is simple and convenient, the product yield is high, and the chiral purity is high.
The second aspect of the present invention provides a process for the preparation of brivaracetam, comprising the steps of:
(1) The intermediate compound (R) -4-propyl-dihydrofuran-2-one is prepared by adopting the preparation method of the first aspect of the invention;
(2) Mixing an intermediate compound (R) -4-propyl-dihydrofuran-2-one and L-2-aminobutanamide for reaction to obtain brivaracetam;
according to some embodiments of the invention, in step (2), the mixing reaction is performed in a second organic solvent selected from at least one of toluene, DMSO, N-methylpyrrolidone and DMF.
According to some preferred embodiments of the present invention, the second organic solvent is a mixture of toluene and DMF, preferably the volume ratio of toluene to DMF in the mixture is 1 (0.5-3).
According to some embodiments of the invention, the temperature of the mixing reaction is 100 ℃ to 180 ℃.
According to some embodiments of the invention, the mixing reaction is for a period of time ranging from 12 hours to 48 hours.
According to some preferred embodiments of the present invention, the step (2) further comprises the steps of removing the solvent after the mixing reaction, washing, drying and recrystallizing.
According to some preferred embodiments of the present invention, the solvent used for the recrystallization is a mixture of n-heptane and isopropyl acetate, and the volume ratio of n-heptane to isopropyl acetate in the mixture of n-heptane and isopropyl acetate is 1 (3-8).
In a further aspect the present invention provides an intermediate compound obtainable by a process according to the first aspect of the present invention and brivaracetam obtainable by a process according to the second aspect of the present invention.
In the invention, C 1 -C 6 The alkyl group of (a) includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like.
In the invention, C 1 -C 3 The alkyl group of (a) includes methyl, ethyl, propyl, isopropyl.
According to the preparation method disclosed by the invention, the route is concise, the steps are short, the cost is low, the preparation method is safe, the impurities of the prepared brivaracetam raw material medicine are few, and the chiral purity is high. The method is used for synthesizing (R) -4-propyl-dihydrofuran-2-one through metal-catalyzed asymmetric Baeyer-Villiger oxidation with low cost, economy, high efficiency and environmental protection, and can prepare the brivaracetam bulk drug with high optical purity on the basis, and the brivaracetam bulk drug meeting the medicinal requirement can be prepared only by 4 steps, so that chiral resolution and complicated separation and purification used in the traditional process are avoided, the method is suitable for industrial production, and has remarkable cost advantage.
The method of the invention also has the following advantages:
(1) The application of the asymmetric Baeyer-Villiger oxidation reaction catalyzed by metal in the preparation of (R) -4-propyl-dihydrofuran-2-ketone is provided for the first time.
(2) The method for preparing (R) -4-propyl-dihydrofuran-2-ketone uses a metal catalyst for catalysis, the reaction condition is mild, and the ee value of the obtained daily standard product can reach 99%.
(3) The invention discloses a simple and convenient method for preparing brivaracetam. (R) -4-propyl-dihydrofuran-2-one reacts with L-2-aminobutanamide under proper conditions, and brivaracetam can be prepared by one step.
Drawings
FIG. 1 is a diagram of Compound 1 obtained in example 1 1 H NMR chart.
FIG. 2 is a diagram of Compound 1 obtained in example 1 13 C NMR chart.
FIG. 3 shows (R) -4-propyl-dihydrofuran-2-one obtained in example 2 1 H NMR chart.
FIG. 4 is a diagram of (R) -4-propyl-dihydrofuran-2-one obtained in example 2 13 C NMR chart.
FIG. 5 is an optical purity measurement chart of (R) -4-propyl-dihydrofuran-2-one obtained in example 2, wherein the retention time of (R) -4-propyl-dihydrofuran-2-one was 21.807min and the retention time of the optical isomer thereof was 22.810min.
FIG. 6 is a diagram of brivaracetam prepared in example 6 1 H NMR chart.
FIG. 7 is a diagram of brivaracetam prepared in example 6 13 C NMR chart.
Detailed Description
According to the invention, "optional" may refer to the presence or absence of an additive, as well as to the addition or absence of an additive.
In order that the invention may be more readily understood, the invention will be described in detail below with reference to the following examples and the accompanying drawings, which are provided for illustration only and are not to be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The materials used in the examples, unless otherwise specified, are all commercially available products or conventional products which can be synthesized by known methods.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The data of the embodiment of the invention are obtained by the following method:
1、 1 H-NMR 13 C-NMR spectra were determined on a Varian INOVA-400 instrument after dissolution of the sample in deuterated chloroform;
2. chiral purity of (R) -4-propyl-dihydrofuran-2-one was determined by HPLC (normal phase) using a column of (LIPODEX E25 m.times.0.25 mm).
Example 1
Preparation of Compound 1
Trichloroacetyl chloride (2.24 mL,20 mmol) and phosphorus oxychloride (1.02 mL,11.0 mmol) were dissolved in diethyl ether (10 mL), after which the solution was slowly dropped into a flask containing 1-pentene (1.09 mL,10 mmol), diethyl ether (20 mL) and Zinc Copper reagent (Zinc-coupler, CAS#:53801-63-1,1.96g,30.0 mmol). The mixture was heated to 40℃and stirred for 2 hours, and then cooled to room temperature naturally and stirred for 8 hours. The solution was then filtered through celite and 80mL of n-hexane was added to the filtrate to precipitate the zinc chloride salt. The clear solution was obtained by filtration, and then washed with water, a saturated sodium hydrogencarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the solvent was distilled off to give a pale yellow oily substance (compound 5) (1.69 g), yield 94%, which was directly subjected to the next reaction.
Compound 5 (1.69 g) was dissolved in 10mL of acetic acid, 2.4g of zinc powder was added, and the mixture was stirred at room temperature for 2 hours, followed by heating to 100℃and reaction for 6 hours. After cooling to room temperature, 20mL of water was added for dilution, followed by extraction with diethyl ether (20 mL). The organic phase was washed with a saturated sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and the solution was subjected to a silica gel flash column to give a colorless oil (compound 1) (0.97 g), yield 92%, which was directly subjected to the next reaction.
Structure data for compound 1 results:
NMR hydrogen spectrum (fig. 1): 1 H NMR(400MHz,Chloroform-d)δ4.42–4.34(m,1H),3.93–3.83(m,1H),2.66–2.45(m,2H),2.22–2.07(m,1H),1.50–1.39(m,2H),1.31(dddd,J＝14.4,7.1,5.9,3.0Hz,2H),0.90(t,J＝7.2Hz,3H)。
NMR carbon spectrum (fig. 2): 13 C NMR(151MHz,Chloroform-d)δ177.31,73.40,35.44,35.17,34.47,20.53,13.91。
example 2
Preparation of Compound 2
Ligand compound L2.39 g and scandium triflate 0.24g were dissolved in 100mL of ethyl acetate, and stirred at 35℃for 1 hour to give catalyst 1Sc (OTf) at a concentration of 0.005M 3 -RaPr 3 Ethyl acetate solution of (a).
To a nitrogen-protected dry reaction flask was added 112mg (1.0 mmol) of compound 1, and 10mL (0.05 mmol) of the catalyst 1 solution prepared as described above. After adding 10mL of ethyl acetate, the temperature was lowered to-20℃and 207mg (1.2 mmol) of m-chloroperoxybenzoic acid was added thereto, and the reaction was stirred at-20℃for an additional 20 hours. Then saturated potassium carbonate solution is added to quench the reaction, and the reaction solution is extracted with dichloromethane for 3 times. Separating by silica gel normal phase column chromatography to obtain pure compound 2 with yield of 83% and chiral purity of 99.8%.
Structure data for compound 2 results:
NMR hydrogen spectrum (fig. 3): 1 H NMR(400MHz,Chloroform-d)δ＝4.42–4.34(m,1H),3.93–3.83(m,1H),2.66–2.45(m,2H),2.22–2.07(m,1H),1.50–1.39(m,2H),1.31(dddd,J＝14.4,7.1,5.9,3.0Hz,2H),0.90(t,J＝7.2Hz,3H)。
NMR carbon spectrum (fig. 4): 13 C NMR(151MHz,Chloroform-d)δ＝208.9,52.7,38.6,23.8,21.5,14.0。
example 3
Preparation of Compound 2
Directional loading (PhCN) 2 PdCl 2 To a bottle of (10 mg,0.025mmol,5.0 mol%) and ligand compound L7 (13 mg,0.0275mmol,5.5 mol%) was added 2mL of dry tetrahydrofuran and stirred at room temperature for 1 hour. AgSbF6 (17 mg,0.05mmol,10 mol%) was added and stirring was continued for 1 hour, and filtration was carried out to give a solution of catalyst 2. To the filtrate was added compound 1 (56 mg,0.5 mmol), and after cooling the reaction solution to-40℃with stirring, carbamide peroxide (61 mg,0.65 mmol) was added, and the mixture was stirred at-40℃for 8 hours. Concentrating under pressure, and separating with column to obtain pure compound 2 with yield of 72% and chiral purity of 98.6%.
Example 4
Preparation of Compound 2
Compound C2 (7.6 mg,10mol%,0.01 mmol) and compound 1 (11.2 mg,0.1 mmol) were dissolved in 1mL of CHCl under nitrogen 3 . The solution was cooled to-40℃with stirring, and 17mg of hydrogen peroxide (30%, 0.15 mmol) was added. Keeping the temperature at-40 ℃ and stirring for 24 hours. After the reaction was completed, the reaction was quenched with sodium sulfite. Dichloromethane extraction, anhydrous magnesium sulfate drying, and vacuum concentration. And obtaining the compound 2 through column chromatography. The yield was 86%, and the chiral purity was 97.8%.
Example 5
After 1.12g (0.01 mol) of compound 1 and 4 (0.56 g,0.001 mol) of compound C were dissolved in 10mL of chloroform, the solvent was cooled to-40 ℃. Quinidine hydride 1,4- (2, 3-naphthyridine) diether (1.56 g,0.002 mol) and hydrogen peroxide (30%, 1.7g,0.015 mol) were added sequentially. After stirring the reaction for 24 hours, the reaction was quenched with sodium thiosulfate. Dichloromethane extraction, anhydrous magnesium sulfate drying, and vacuum concentration. And obtaining the compound 2 through column chromatography. The yield was 93% and the chiral purity was 99.1%.
Example 6
Preparation of Compound 6
After compound 2 was prepared by the method described in example 2, 10g of compound 2 was weighed into a mixed solvent of toluene and DMF (toluene: DMF: 20ml:40 ml), and 10.37g of L-2-aminobutanamide was added at room temperature. Heating to 100deg.C and stirring for 6 hr. Compound 2 reacted completely as monitored by HPLC. Concentrating under reduced pressure, and evaporating to remove solvent to obtain viscous crude product. The crude product was dissolved in 60ml of methylene chloride, and the organic phase was washed with a saturated sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. Via n-heptane: and recrystallizing isopropyl acetate (volume ratio is 1:1) to obtain 12.4g of high-purity brivaracetam (compound 6), wherein the purity of a product liquid phase is up to 99.2%.
Structure data for compound 6 results:
NMR hydrogen spectrum (fig. 6): 1 H NMR(400MHz,Chloroform-d)δ6.20(s,1H),5.36(s,1H),4.44(dd,J＝8.8,6.9Hz,1H),3.49(dd,J＝9.8,7.8Hz,1H),3.01(dd,J＝9.8,7.0Hz,1H),2.59(dd,J＝16.8,8.6Hz,1H),2.34(p,J＝7.7Hz,1H),2.08(dd,J＝16.8,8.0Hz,1H),1.95(dp,J＝14.5,7.4Hz,1H),1.77–1.61(m,2H),1.47–1.38(m,2H),1.36(dd,J＝6.9,4.8Hz,1H),1.34–1.23(m,2H),0.91(td,J＝7.3,2.7Hz,6H)。
NMR carbon spectrum (fig. 7): 13 C NMR(151MHz,Chloroform-d)δ175.70,171.89,55.97,49.53,37.86,36.59,31.85,20.75,20.52,13.99,10.43。
it should be noted that the above-described embodiments are only for explaining the present invention and do not constitute any limitation of the present invention. The invention has been described with reference to exemplary embodiments, but it is understood that the words which have been used are words of description and illustration, rather than words of limitation. Modifications may be made to the invention as defined in the appended claims, and the invention may be modified without departing from the scope and spirit of the invention. Although the invention is described herein with reference to particular means, materials and embodiments, the invention is not intended to be limited to the particulars disclosed herein, as the invention extends to all other means and applications which perform the same function.
Claims (13)
1. A process for the preparation of an intermediate compound for the synthesis of brivaracetam, said intermediate compound being (R) -4-propyl-dihydrofuran-2-one, said process comprising:
subjecting 3-propylcyclobutanone to an asymmetric Baeyer-Villiger oxidation reaction in the presence of a catalyst and an oxidant to provide (R) -4-propyl-dihydrofuran-2-one:
，
the catalyst is selected from compounds shown in the following formula 2;
；
2, 2
Wherein,
r in 2 2 Is C 1 -C 6 Phenyl substituted by alkyl;
the oxidant is m-chloroperoxybenzoic acid, hydrogen peroxide or carbamide peroxide;
the dosage of the catalyst in the preparation method is 1-10mol% of the dosage of the 3-propyl cyclobutanone; the consumption of the oxidant is 100-150mol% of the consumption of the 3-propyl cyclobutanone;
the preparation method comprises the steps of mixing 3-propyl cyclobutanone with a catalyst to obtain a mixture, and mixing the obtained mixture with an oxidant for reaction, wherein the reaction temperature is-40 ℃ to-30 ℃, and the reaction time is 8-24 hours.
2. The method of claim 1, wherein the C1-C6 alkyl substituted phenyl is 3, 5-dialkylphenyl.
3. The preparation method according to claim 2, wherein the compound represented by formula 2 is selected from the following compounds C4:
。
4. a method according to any one of claims 1 to 3, wherein the asymmetric Baeyer-Villiger oxidation reaction is carried out in an organic solvent.
5. The method according to claim 4, wherein the organic solvent is at least one selected from the group consisting of ethyl acetate, tetrahydrofuran, isopropyl ether, toluene, dichloroethane, dichloromethane, chloroform and N, N-dimethylformamide.
6. A process according to any one of claims 1 to 3, wherein the 3-propylcyclobutanone is prepared by a process comprising the steps of:
s1, mixing 1-pentene and trichloroacetyl chloride in the presence of phosphorus oxychloride and a zinc copper reagent for a first reaction, and separating to obtain a compound 5 as follows;
s2, mixing the compound 5 with acid and zinc powder for a second reaction, and separating to obtain 3-propyl cyclobutanone, wherein the acid is acetic acid, trifluoromethanesulfonic acid or a mixture of dilute hydrochloric acid and acetic acid.
7. The production method according to claim 6, wherein in step S1, the first reaction is performed in a first organic solvent selected from at least one of diethyl ether, isopropyl ether, methyl tertiary ether and tetrahydrofuran; and/or the amount of the trichloroacetyl chloride and the 1-pentene is (0.8-1.2) 1 in terms of a molar ratio, and/or the amount of the phosphorus oxychloride added and the 1-pentene is (1-1.2) 1 in terms of a molar ratio, and/or the amount of the zinc copper reagent added is (2-4) 1 in terms of a molar ratio with the 1-pentene.
8. The preparation method according to claim 6, wherein in the step S1, the temperature of the first reaction is 20 ℃ to 50 ℃ and/or the time of the first reaction is 2h to 12h;
and/or in the step S2, the mass ratio of the zinc powder to the compound 5 is (1-2) 1.
9. The method according to claim 8, wherein in step S2, the temperature of the second reaction is 90 ℃ to 180 ℃ and/or the time of the second reaction is 3h to 9h.
10. A process for the preparation of brivaracetam comprising the steps of:
(1) An intermediate compound (R) -4-propyl-dihydrofuran-2-one prepared by the preparation method of any one of claims 1-9;
(2) And mixing the intermediate compound (R) -4-propyl-dihydrofuran-2-ketone and L-2-aminobutanamide for reaction to obtain brivaracetam.
11. The preparation method according to claim 10, wherein in the step (2), the mixing reaction is performed in a second organic solvent selected from at least one of toluene, DMSO, N-methylpyrrolidone and DMF.
12. The preparation method according to claim 11, wherein in the step (2), the second organic solvent is selected from a mixture of toluene and DMF, and the volume ratio of toluene to DMF in the mixture is 1 (0.5-3); the step (2) further comprises the steps of removing a solvent after the mixing reaction, washing, drying and recrystallizing, wherein the solvent used for the recrystallization is a mixture of n-heptane and isopropyl acetate, and the volume ratio of the n-heptane to the isopropyl acetate in the mixture of n-heptane and isopropyl acetate is 1 (3-8).
13. The method according to claim 12, wherein in the step (2), the temperature of the mixing reaction is 100 ℃ to 180 ℃ and/or the time of the mixing reaction is 12h to 48h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210441314.XA CN114751849B (en) | 2022-04-24 | 2022-04-24 | Preparation method of brivaracetam and intermediate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210441314.XA CN114751849B (en) | 2022-04-24 | 2022-04-24 | Preparation method of brivaracetam and intermediate compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114751849A CN114751849A (en) | 2022-07-15 |
| CN114751849B true CN114751849B (en) | 2024-03-22 |
Family
ID=82332343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210441314.XA Active CN114751849B (en) | 2022-04-24 | 2022-04-24 | Preparation method of brivaracetam and intermediate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114751849B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115340510B (en) * | 2022-10-18 | 2023-01-24 | 天津辰欣药物研究有限公司 | Preparation method of brivaracetam intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1449840A1 (en) * | 2003-02-19 | 2004-08-25 | Kyushu University | Method of producing optically active lactone compound |
| CN108929289A (en) * | 2018-06-19 | 2018-12-04 | 上海博氏医药科技有限公司 | A kind of midbody compound and its preparation method and application being used to prepare Bu Waxitan |
| CN113717132A (en) * | 2021-08-31 | 2021-11-30 | 珠海润都制药股份有限公司 | Key intermediate of antiepileptic drug and preparation method thereof |
-
2022
- 2022-04-24 CN CN202210441314.XA patent/CN114751849B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1449840A1 (en) * | 2003-02-19 | 2004-08-25 | Kyushu University | Method of producing optically active lactone compound |
| CN108929289A (en) * | 2018-06-19 | 2018-12-04 | 上海博氏医药科技有限公司 | A kind of midbody compound and its preparation method and application being used to prepare Bu Waxitan |
| CN113717132A (en) * | 2021-08-31 | 2021-11-30 | 珠海润都制药股份有限公司 | Key intermediate of antiepileptic drug and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| Andrei V. Malkov等.Enantioselective Baeyer-Villiger Oxidation Catalyzed by Palladium(II) Complexes with Chiral P,N-Ligands.《J. Org. Chem.》.2008,第73卷3996-4003. * |
| Enantioselective Baeyer-Villiger Oxidation:Desymmetrization of Meso Cyclic Ketones and Kinetic Resolution of Racemic 2-Arylcyclohexanones;Lin Zhou等;《J. Am. Chem. Soc.》;第134卷;17023-17026 * |
| Jirí Zurek等.N1,N10-Ethylene-bridged flavinium salts derived from L-valinol: synthesis and catalytic activity in H2O2 oxidations.《Tetrahedron Letters》.2009,第51卷1083-1086. * |
| Mechanistic Investigation of Chiral Phosphoric Acid Catalyzed Asymmetric Baeyer-Villiger Reaction of 3-Substituted Cyclobutanones with H2O2 as the Oxidant;Senmiao Xu等;《Chem. Eur. J.》;第16卷;3021-3035 * |
| Mingchuan Xu等.Acid-catalyzed ring-expansion of 4-(1-hydroxycyclobutyl)-1,2,3-triazoles.《Org. Chem. Front.》.2022,第9卷1065. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114751849A (en) | 2022-07-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101193880B (en) | Exo- and diastereo- selective syntheses of himbacine analogs | |
| KR102287596B1 (en) | Process for the preparation of a pde4 inhibitor | |
| CN112574163B (en) | Method for synthesizing Brazilin natural product (+) -Brazilin | |
| CN114751849B (en) | Preparation method of brivaracetam and intermediate compound | |
| CN109970755B (en) | Synthesis of substituted salicylaldehyde derivatives | |
| CN110698467B (en) | Synthesis method of englitjing | |
| CN102659494B (en) | Method for asymmetric synthesis of 3,3-disubstituted-2-oxindole compound | |
| CN111574444A (en) | Preparation method of bedaquiline | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN114195818B (en) | 4-arylthio coumarin compound and preparation method thereof | |
| CN106905358B (en) | Preparation of vitamin D3Process for preparing analogue intermediates | |
| Bassolino et al. | Practical and Scalable Synthesis of 7-Azetidin-1-yl-4-(hydroxymethyl) coumarin: An Improved Photoremovable Group | |
| CN115028597B (en) | Method for preparing benzoxazole derivative by TEMPO continuous dehydrocyclization and application | |
| CN112125843B (en) | Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound | |
| CN111875534B (en) | Safe and efficient preparation method of 1, 8-diformylcarbazole | |
| CN116063211B (en) | Preparation method of Belzutifan | |
| CN114478407B (en) | Preparation method and application of chiral homopiperazine and derivatives thereof | |
| CN114213298B (en) | Method for preparing thiosulfonate compound by directly oxidizing thiophenol | |
| CN112142709B (en) | Synthetic method of 6-aryl-2,3,4,5-tetrahydrooxaheptin-3-alcohol derivative | |
| CN112679361B (en) | Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde | |
| CN111662233B (en) | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method | |
| CN112939830B (en) | Nucleophilic reaction method of alkenyl thioether to o-methylene benzoquinone | |
| CN110218210B (en) | Method for synthesizing moxifloxacin chiral side chain intermediate | |
| CN111747873B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN117229172A (en) | Diquinine compound and synthetic method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Jin Shuaijiang Inventor after: Liu Bo Inventor after: Liu Yiyao Inventor after: Zhang Lei Inventor after: Cai Chengshu Inventor after: Wang Ke Inventor after: Yang Renming Inventor after: Wan Yanfei Inventor after: Yang Likai Inventor after: Fan Shide Inventor before: Jin Shuaijiang Inventor before: Zhang Lei Inventor before: Cai Chengshu Inventor before: Wang Ke Inventor before: Yang Renming Inventor before: Wan Yanfei Inventor before: Yang Likai Inventor before: Fan Shide Inventor before: Liu Bo |
|
| CB03 | Change of inventor or designer information | ||
| CB02 | Change of applicant information |
Address after: No. 990 Baicao Road, High tech Zone, Chengdu, Sichuan Province, 611731 Applicant after: Sichuan Aobang Gude Pharmaceutical Co.,Ltd. Address before: 611731 No. 16, Baicao Road, Gaoxin West District, Chengdu, Sichuan Applicant before: Chengdu xuzhe Pharmaceutical Technology Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |