WO2017201846A1 - 一种噁唑烷酮类抗菌药物及其中间体的制备方法 - Google Patents
一种噁唑烷酮类抗菌药物及其中间体的制备方法 Download PDFInfo
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- WO2017201846A1 WO2017201846A1 PCT/CN2016/090282 CN2016090282W WO2017201846A1 WO 2017201846 A1 WO2017201846 A1 WO 2017201846A1 CN 2016090282 W CN2016090282 W CN 2016090282W WO 2017201846 A1 WO2017201846 A1 WO 2017201846A1
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- Prior art keywords
- compound
- oxazolidinone antibacterial
- reagent
- catalyst
- reaction
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 4
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 4
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 51
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 16
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000003242 anti bacterial agent Substances 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical group ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 6
- PCMMSLVJMKQWMQ-UHFFFAOYSA-N 2,4-dibromopyridine Chemical compound BrC1=CC=NC(Br)=C1 PCMMSLVJMKQWMQ-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 238000006276 transfer reaction Methods 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 239000000852 hydrogen donor Substances 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 238000005750 Corey-Bakshi-Shibata reduction reaction Methods 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 3
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- 125000001979 organolithium group Chemical group 0.000 claims description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical class [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 claims description 3
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical group OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- UOPFIWYXBIHPIP-SFTDATJTSA-N n-[(1s,2s)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-SFTDATJTSA-N 0.000 claims 1
- 229910052703 rhodium Inorganic materials 0.000 claims 1
- 239000010948 rhodium Substances 0.000 claims 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 37
- -1 azide compounds Chemical class 0.000 abstract description 5
- 239000002360 explosive Substances 0.000 abstract description 5
- 231100000024 genotoxic Toxicity 0.000 abstract description 4
- 230000001738 genotoxic effect Effects 0.000 abstract description 4
- 230000002009 allergenic effect Effects 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 2
- 150000003841 chloride salts Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940124350 antibacterial drug Drugs 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SLMHHOVQRSSRCV-UHFFFAOYSA-N 2,3-dibromopyridine Chemical compound BrC1=CC=CN=C1Br SLMHHOVQRSSRCV-UHFFFAOYSA-N 0.000 description 1
- KYFVZUBWWBEZJR-UHFFFAOYSA-N 3,3-dihydroxy-2h-isoindol-1-one Chemical class C1=CC=C2C(O)(O)NC(=O)C2=C1 KYFVZUBWWBEZJR-UHFFFAOYSA-N 0.000 description 1
- WEEOKJZZMSQKTR-UHFFFAOYSA-N 3-(2H-1,2-benzoxazin-3-yl)-4-pyridin-3-yl-1,3-oxazolidin-2-one Chemical class C=1C2=CC=CC=C2ONC=1N1C(=O)OCC1C1=CC=CN=C1 WEEOKJZZMSQKTR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- NIFOUKIHNJPUOK-JSGCOSHPSA-N CC1(C)OB(c(cc2OC[C@H]3[C@H](CO)O4)ccc2N3C4=O)OC1(C)C Chemical compound CC1(C)OB(c(cc2OC[C@H]3[C@H](CO)O4)ccc2N3C4=O)OC1(C)C NIFOUKIHNJPUOK-JSGCOSHPSA-N 0.000 description 1
- JKBLWYHIECGMDC-SZMVWBNQSA-N CN(C[C@@H](c(cc1)ncc1-c(cc1OC[C@H]2[C@H](CO)O3)ccc1N2C3=O)O1)C1=O Chemical compound CN(C[C@@H](c(cc1)ncc1-c(cc1OC[C@H]2[C@H](CO)O3)ccc1N2C3=O)O1)C1=O JKBLWYHIECGMDC-SZMVWBNQSA-N 0.000 description 1
- XZMKAVUDMBOGLC-QMMMGPOBSA-N CN(C[C@@H](c(cc1)ncc1[BrH]I)O1)C1=O Chemical compound CN(C[C@@H](c(cc1)ncc1[BrH]I)O1)C1=O XZMKAVUDMBOGLC-QMMMGPOBSA-N 0.000 description 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- FBMXFJQSNVAZQN-UHFFFAOYSA-N ethanamine heptane Chemical compound CCCCCCC.CCN FBMXFJQSNVAZQN-UHFFFAOYSA-N 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- 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
Definitions
- the invention relates to a preparation method of an oxazolidinone antibacterial medicine and an intermediate thereof, and belongs to the field of medicine.
- M is H or an alkali metal, an alkaline earth metal, or a basic amino acid pharmaceutically acceptable salt.
- the above reaction route has several disadvantages: firstly, it is a safety problem, the reaction involves an explosive azide compound, and it is a reaction at a high temperature of 90 ° C; the chloride used in the process is an allergic compound and is also genotoxic. Secondly, the process steps are long and involve 10 steps of reaction. Post-treatment generally uses column chromatography, which is not suitable for industrial large-scale production.
- a key chiral intermediate VII (hereinafter referred to as an oxazolidinone antibacterial intermediate) is involved in this route, and its synthesis efficiency has an important influence on the entire route.
- the invention provides a preparation method of an oxazolidinone antibacterial drug and an intermediate thereof, the preparation method avoids the use of an explosive azide compound, has higher safety, and has a shorter reaction step, and is suitable for industrialization. produce.
- a preparation method of an oxazolidinone antibacterial intermediate comprises the following steps:
- the metal reagent is an organolithium reagent or a Grignard reagent.
- the 2,4-dibromopyridine and the n-butyllithium are first formed into a metal lithium reagent, and then the Weinreb amide II is added to carry out the reaction; when the Grignard reagent is used, the 2,4- directly The dibromopyridine reacts with magnesium to form a Grignard reagent, which is then reacted with Weinreb Amide II.
- the metal reagent is n-butyllithium, and the yield of the reaction is higher when n-butyllithium is used.
- the method of chiral reduction comprises a Noyori asymmetric hydrogen transfer reaction, a CBS reduction or an enzymatic reduction method.
- the chiral reduction method is Noyori asymmetric hydrogen transfer reaction, and the effect of Noyori asymmetric hydrogen transfer reaction is better.
- the catalyst is composed of a ruthenium catalyst and a ligand, the ruthenium catalyst is dichloro(p-methylcumene)ruthenium (II) dimer, and the chiral ligand is (1S). 2S)-(+)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine, at which time the cost is low, the ee value of the product is high, and the reaction is easy to control.
- the hydrogen donor is a formic acid-triethylamine having a molar ratio of 5:2.
- the acid is trifluoroacetic acid or hydrochloric acid; and further preferably, in the step (3), the acid is hydrochloric acid, and the reaction cost with hydrochloric acid is lower, and the product purity is higher.
- the cyclizing reagent consists of N,N'-carbonyldiimidazole and 4-dimethylaminopyridine.
- the solvent for the cyclization reaction is preferably tetrahydrofuran, and when tetrahydrofuran is used as the reaction solvent, the reaction yield can be remarkably improved and the side reaction can be reduced.
- the invention also provides a preparation method of an oxazolidinone antibacterial drug, comprising the following steps:
- (C) compound IX is esterified in the presence of a phosphoric acid monoesterification reagent, and post-treated to obtain the oxazolidinone antibacterial agent;
- M is H or an alkali metal, an alkaline earth metal, or a basic amino acid pharmaceutically acceptable salt.
- the coupling catalyst is a palladium catalyst or a nickel catalyst; and further preferably, in the step (B), the coupling catalyst is tetrakis(triphenylphosphine). Palladium (0).
- the phosphoric acid monoesterification reagent is POCl 3 /Et 3 N or POCl 3 /PO(OEt) 3 ; as a further preferred, in the step (C), the phosphoric acid single The esterification reagent is POCl 3 /Et 3 N.
- the obtained product may be a free acid of an oxazolidinone antibacterial drug or a corresponding pharmaceutically acceptable salt.
- the post-treatment further comprises the step of adding a base to a salt, preferably M is Na, the base is sodium methoxide or sodium isooctanoate; as a further preferred step (7) In the case, the base is sodium isooctanoate.
- the method avoids the explosive azide compound and the allergenic and genotoxic chloride used in the original process, the reaction condition is mild and safe; and the process step is shortened to 7 steps, all products are all By recrystallization purification, post-treatment methods such as column chromatography that cannot be industrially produced are avoided.
- Figure 1 is a nuclear magnetic resonance hydrogen spectrum (rotamer) of compound IV prepared according to Example 1;
- Figure 2 is a high resolution mass spectrum of compound IV prepared according to Example 1;
- Figure 3 is a nuclear magnetic resonance hydrogen spectrum (rotamer) of compound V prepared according to Example 3;
- Figure 4 is a high resolution mass spectrum of Compound V prepared according to Example 3.
- Figure 5 is a nuclear magnetic resonance spectrum of compound VI prepared according to Example 6;
- Figure 6 is a high resolution mass spectrum of compound VI prepared according to Example 6;
- Figure 7 is a nuclear magnetic resonance spectrum of compound VII prepared according to Example 8.
- Figure 8 is a high resolution mass spectrum of Compound VII prepared according to Example 8.
- Figure 9 is a nuclear magnetic resonance spectrum of Compound IX prepared according to Example 9;
- Figure 10 is a high resolution mass spectrum of Compound IX prepared according to Example 9;
- 2,4-Dibromopyridine III (23.69 g, 0.1 mol) was weighed into a reaction flask, and toluene (100 ml) was added thereto and stirred to dissolve. After cooling to -78 ° C, 2.5 M n-butyllithium in n-hexane solution (40 ml, 0.1 mol) was added dropwise, and the addition was completed, and Weinreb amide II (23.23 g, 0.1 mol) was added (CAS No.: 140170-90-7) , continue to react for 1 hour. The reaction was quenched by the addition of 10% ammonium chloride solution (100 mL).
- Weinreb amide II (23.23 g, 0.1 mol) was added dropwise, and the addition was completed, and the reaction was continued for 1 hour.
- the reaction was quenched by the addition of 10% ammonium chloride solution (100 mL).
- the mixture was extracted with methylene chloride, washed with water and dried over anhydrous sodium sulfate.
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Abstract
一种噁唑烷酮类抗菌药物及其中间体的制备方法,该制备方法避免采用易爆的叠氮化合物及易过敏且具有基因毒性的氯化物,避免了无法工业化生产的柱层析纯化方法,反应条件温和安全,工艺步骤短,适合大规模工业化生产。其中,M为H或碱金属、碱土金属、碱性氨基酸可药用盐类。
Description
本发明涉及一种噁唑烷酮类抗菌药物及其中间体的制备方法,属于医药领域。
目前多药耐药菌给世界范围内的临床抗感染治疗带来了严重的挑战,开发全新作用机制的抗菌药物也因此日益迫切。为此,进入新世纪以来,新型的噁唑烷酮类抗菌药物逐渐被开发出来,代表性的如美国法玛西亚普强公司开发的利奈唑胺,该药于2000年经FDA批准在美国上市,这是全球首个上市的噁唑烷酮类抗菌药物。之后,美国Cubist公司开发的磷酸泰地唑胺也于2014年经FDA批准在美国上市。
我们和中科院上海药物所杨玉社课题组联合开发了一种新型噁唑烷酮类抗菌药物,化合物结构如式I所示:
其中,M为H或碱金属、碱土金属、碱性氨基酸可药用盐类。
研究结果显示,式I的新型噁唑烷酮类抗菌药物具有较同类药物更强的抗菌活性,尤其是抗多耐药菌活性,详见专利EP2940024A1中描述。
杨玉社课题组在期刊文献(“Solubility-Driven Optimization of(Pyridin-3-yl)Benzoxazinyloxazolidinones Leading to a Promising Antibacterial Agent”;Guo,Bin;Fan,Houxing;Xin,Qisheng;Chu,Wenjing;Wang,Hui;Huang,Yanqin;Chen,Xiaoyan;Yang,Yushe;Journal of Medicinal Chemistry,2013,56,2642-2650)中报道了式I的新型噁唑烷酮类抗菌药物的合成方法,反应路线如下:
上述反应路线存在几个缺点:首先是安全问题,反应涉及易爆的叠氮化合物,而且是90℃高温下反应;工艺采用的氯化物是易过敏的化合物,同时还具有基因毒性。其次,工艺步骤长,涉及10步反应,后处理普遍采用柱层析,不适合工业化大生产。
该路线中涉及到一个关键的手性中间体VII(以下记为噁唑烷酮类抗菌药物中间体),其合成效率对整条路线具有重要的影响。
发明内容
本发明提供了一种噁唑烷酮类抗菌药物及其中间体的制备方法,该制备方法避免了易爆的叠氮化合物的使用,具有更高的安全性;并且反应步骤缩短,适合工业化大生产。
一种噁唑烷酮类抗菌药物中间体的制备方法,包括以下步骤:
(1)Weinreb酰胺II和2,4-二溴吡啶在金属试剂的作用下发生酰化反应得到化合物IV;
(2)化合物IV在催化剂及氢供体的存在下发生手性还原反应,得到化合物V;
(3)化合物V在酸的作用下进行脱保护反应得到化合物VI;
(4)化合物VI在环化试剂的存在下进行环化反应得到所述的噁唑烷酮类抗菌药物中间体;
本发明中,采用Weinreb酰胺II作为起始原料,以较高的效率得到的用于合成噁唑烷酮类抗菌药物的关键手性中间体,不需要再对氯化物进行叠氮化操作,避免了易爆叠氮化物的产生和使用,操作更加安全,便于进行工业化生产;同时,还避免了易过敏且具有基因毒性的氯化物中间体的使用。
步骤(1)中,作为优选,所述的金属试剂为有机锂试剂或格氏试剂。当使用有机锂试剂进行反应时,先使2,4-二溴吡啶与正丁基锂发生形成金属锂试剂,然后加入Weinreb酰胺II进行反应;当使用格氏试剂时,直接将2,4-二溴吡啶与镁反应形成格氏试剂,然后再与Weinreb酰胺II进行反应。作为进一步的优选,所述的金属试剂为正丁基锂,采用正丁基锂时反应的收率更高。
作为优选,步骤(2)中,手性还原的方法包括Noyori不对称氢转移反应、CBS还原或酶催化还原法。作为进一步的优选,手性还原的方法为Noyori不对称氢转移反应,采用Noyori不对称氢转移反应的效果较好。
此时,所述的催化剂由钌催化剂和配体组成,所述的钌催化剂为二氯(p-甲基异丙苯)钌(II)二聚体,所述的手性配体为(1S,2S)-(+)-N-对甲苯磺酰基-1,2-二苯基乙二胺,此时成本较低,产物的ee值较高,并且反应便于控制。
作为优选,步骤(2)中,所述的氢供体为摩尔比为5:2的甲酸-三乙胺。
作为优选,步骤(3)中,所述的酸为三氟乙酸或盐酸;作为进一步优选,步骤(3)中,所述的酸为盐酸,采用盐酸反应成本更低,产品纯度更高。
作为优选,步骤(4)中,所述的环化试剂由N,N’-羰基二咪唑和4-二甲氨基吡啶组成。
步骤(4)中,环化反应的溶剂优选为四氢呋喃,采用四氢呋喃作为反应溶剂的时候,可以明显提高反应收率,减少副反应。
本发明还提供了一种噁唑烷酮类抗菌药物的制备方法,包括以下步骤:
(A)按照权利要求1~8任一项所述的制备方法制得所述的噁唑烷酮类抗菌药物中间体;
(B)噁唑烷酮类抗菌药物中间体和化合物VIII在偶联催化剂的作用下发生Suzuki偶联反应得到化合物IX;
(C)化合物IX在磷酸单酯化试剂存在下发生酯化反应,经过后处理得到所述的噁唑烷酮类抗菌药物;
其中,M为H或碱金属、碱土金属、碱性氨基酸可药用盐类。
作为优选,步骤(B)中,所述的偶联催化剂为钯催化剂或镍催化剂;作为进一步的优选,步骤(B)中,所述的偶联催化剂为四(三苯基膦)
钯(0)。
作为优选,步骤(C)中,所述的磷酸单酯化试剂为POCl3/Et3N或POCl3/PO(OEt)3;作为进一步的优选,步骤(C)中,所述的磷酸单酯化试剂为POCl3/Et3N。
步骤(C)中,所得到的产物可以为噁唑烷酮类抗菌药物的游离酸,也可以为相应的可药用盐。当需要得到相应的药用盐时,所述的后处理还包括加碱成盐操作,作为优选,M为Na,所述的碱为甲醇钠或异辛酸钠;作为进一步的优选,步骤(7)中,所述的碱为异辛酸钠。
化合物IV和V由于Boc取代基的空间位阻较大,导致单键旋转受阻,从核磁共振氢谱上可以发现,产物为一对旋转异构体(rotamer),原料II也存在相同的旋转异构体现象,参见其合成文献报道(“Conversion of-Amino Acids into Bioactive o-Aminoalkyl Resorcylates and Related Dihydroxyisoindolinones”;Bhavesh H.Patel,Andrew M.Mason,Hetal Patel,R.Charles Coombes,Simak Ali,and Anthony G.M.Barrett;Journal of Organic Chemistry,2011,76,6209-6217)。
同现有技术相比,本方法避免了原工艺中采用的易爆的叠氮化合物及易过敏且具有基因毒性的氯化物,反应条件温和安全;而且工艺步骤缩短至7步反应,所有产品均通过重结晶提纯,避免了柱层析等无法工业化生产的后处理方法。
图1按照实施例1制备的化合物IV核磁共振氢谱(rotamer);
图2按照实施例1制备的化合物IV高分辨质谱;
图3按照实施例3制备的化合物V核磁共振氢谱(rotamer);
图4按照实施例3制备的化合物V高分辨质谱;
图5按照实施例6制备的化合物VI核磁共振氢谱;
图6按照实施例6制备的化合物VI高分辨质谱;
图7按照实施例8制备的化合物VII核磁共振氢谱;
图8按照实施例8制备的化合物VII高分辨质谱;
图9按照实施例9制备的化合物IX核磁共振氢谱;
图10按照实施例9制备的化合物IX高分辨质谱;
图11按照实施例12制备的化合物I(M=Na)核磁共振氢谱;
图12按照实施例12制备的化合物I(M=Na)高分辨质谱。
参照下列实施例说明本发明的特定实施方案。这些实施例是用以阐明本发明,而非以任何方式限制本发明。
实施例1化合物IV的合成(正丁基锂法):
称取2,4-二溴吡啶III(23.69g,0.1mol)于反应瓶中,加入甲苯(100ml)搅拌溶解。冷却到-78℃,滴加2.5M正丁基锂的正己烷溶液(40ml,0.1mol),滴加完毕,加入Weinreb酰胺II(23.23g,0.1mol)(CAS号:140170-90-7),继续反应1小时。加入10%氯化铵溶液(100ml)淬灭反应。分出甲苯层,水洗,无水硫酸钠干燥,浓缩,乙酸乙酯-正庚烷重结晶,得化合物IV 16.83g,收率51%,HPLC纯度98%。
实施例2化合物IV的合成(格氏试剂法)
称取镁屑(2.43g,0.1mol)及1粒碘于反应瓶中,加入四氢呋喃(50ml)搅拌。升温到45℃,先加入5ml配好的2,4-二溴吡啶III(23.69g,0.1mol)的四氢呋喃(总体积150ml)溶液。反应引发后,缓慢滴加剩余溶液,滴加完毕,继续反应1小时。冷却到0℃,滴加Weinreb酰胺II(23.23g,0.1mol),滴加完毕,继续反应1小时。加入10%氯化铵溶液(100ml)淬灭反应。二氯甲烷萃取,水洗,无水硫酸钠干燥,浓缩,乙酸乙酯-正庚烷重结晶,得化合物IV 12.56g,收率38%,HPLC纯度97%。
实施例3化合物V的合成(Noyori不对称氢转移反应)
称取二氯(p-甲基异丙苯)钌(II)二聚体(0.61g,1mmol)和(1S,2S)-(+)-N-对甲苯磺酰基-1,2-二苯基乙二胺(0.73g,2mmol)于反应瓶中,加入N,N-二甲基甲酰胺(5ml)及三乙胺(0.2ml),室温搅拌1小时。再加入甲酸-三乙胺(摩尔比为5:2,43.25g)和甲基叔丁基醚(100ml)搅拌。降温到0℃,加入化合物IV(32.92g,0.1mol),反应4小时。水洗,无水硫酸钠干燥,浓缩,得到油状化合物V粗品35.38g(含部分溶剂,不影响后续反应),HPLC纯度97%,ee值86%,粗品直接投入下一步反应。
实施例4化合物V的合成(CBS还原法)
称取(R)-(+)-2-甲基-CBS-二苯基-噁唑硼烷(1.39g,5mmol)于反应瓶中,加入二氯甲烷(50ml)搅拌溶解。再加入2M硼烷二甲硫醚的四氢呋喃溶液(50ml,0.1mol)。降温到-10℃,滴加化合物IV(32.92g,0.1mol)的二氯甲烷(150ml)溶液,滴加完毕,反应1小时。滴加甲醇(14ml)淬灭反应,水洗,无水硫酸钠干燥,浓缩,得到油状化合物V粗品35.72g,HPLC纯度94%,ee值82%,粗品直接投入下一步反应。
实施例5化合物V的合成(酶催化还原法):
称取化合物IV(32.92g,0.1mol),酮还原酶KRED(4g)和辅酶NADP(0.1g)于反应瓶中。再加入异丙醇(200ml)和磷酸钠缓冲液(取磷酸氢二钠1.09g,磷酸二氢钠0.23g,加水70ml溶解,加磷酸调至pH 7.0,再加水稀释至100ml)搅拌。升温到45℃,反应过夜。浓缩,加入二氯甲
烷(200ml)和水(100ml)搅拌,分出二氯甲烷层,水洗,无水硫酸钠干燥,浓缩,得到油状化合物V粗品34.85g,HPLC纯度97%,ee值85%,粗品直接投入下一步反应。
实施例6化合物VI的合成(三氟乙酸法):
将实施例3所得油状化合物V粗品35.38g置于反应瓶中,加入二氯甲烷(100ml)搅拌溶解。再加入三氟乙酸(50ml),室温反应8小时。浓缩,加入二氯甲烷(100ml)和水(100ml),饱和氢氧化钠溶液调至pH 9.0,分出二氯甲烷层,水洗,浓缩,乙酸乙酯-正庚烷重结晶,得化合物VI 14.76g,两步合并收率64%,HPLC纯度99%,ee值95%。
实施例7化合物VI的合成(盐酸法):
将实施例5所得油状化合物V粗品34.85g置于反应瓶中,加入6M氯化氢异丙醇溶液(100ml)搅拌溶解,室温下反应6小时,析出沉淀。抽滤,固体溶于水(100ml),饱和氢氧化钠溶液调至pH 9.0,二氯甲烷萃取,浓缩,乙酸乙酯-正庚烷重结晶,得化合物VI 15.38g,两步合并收率67%,HPLC纯度99%,ee值97%。
实施例8化合物VII的合成:
称取化合物VI(23.11g,0.1mol),N,N’-羰基二咪唑(24.32g,0.15mol)和4-二甲氨基吡啶(2.44g,0.02mol)于反应瓶中,加四氢呋喃(100ml)溶解,室温下反应3小时,浓缩,加入二氯甲烷(100ml)和1M盐酸(100ml),
分出二氯甲烷层,水洗,浓缩,乙酸乙酯-正庚烷重结晶,得化合物VII 17.25g,收率67%,HPLC纯度99%,ee值100%。
实施例9化合物IX的合成:
称取化合物VII(25.71g,0.1mol),化合物VIII(34.72g,0.1mol)和碳酸铯(65.16g,0.2mol)于反应瓶中,加入二氧六环(180ml)和水(20ml)的混合溶剂搅拌溶解,再加入Pd(PPh3)4(0.51g),回流反应5小时,冷却至室温,抽滤,水洗,丙酮重结晶,得化合物IX 29.43g,收率74%,HPLC纯度为99%(杂质包括6个非对映异构体),ee值100%。
实施例10化合物I(M=H)的合成(POCl3/Et3N法):
称取化合物IX(39.74g,0.1mol)于反应瓶中,加入二氯甲烷(400ml)搅拌溶解。再加入三乙胺(55.75ml,0.4mol)和三氯氧磷(46g,0.3mol),室温反应过夜。滴加水(200ml),抽滤,N,N-二甲基甲酰胺重结晶,得化合物I(M=H)28.20g,收率59%,HPLC纯度为99%(杂质包括6个非对映异构体),ee值100%。
实施例11化合物I(M=H)的合成(POCl3/PO(OEt)3法):
称取化合物IX(39.74g,0.1mol)于反应瓶中,加入磷酸三乙酯(200ml)搅拌溶解。再加入三氯氧磷(46g,0.3mol),室温反应3小时。滴加水(200ml),抽滤,N,N-二甲基甲酰胺重结晶,得化合物I(M=H)25.89g,收率54%,HPLC纯度为99%(杂质包括6个非对映异构体),ee值100%。
实施例12化合物I(M=Na)的合成(异辛酸钠法):
称取化合物I(M=H)(4.77g,0.01mol)和异辛酸钠(6.65g,0.04mol)于反应瓶中,加入水(25ml)搅拌溶解。溶清后,滴加异丙醇(250ml),析出沉淀,抽滤,异丙醇洗涤,得化合物I(M=Na)3.78g,收率73%,HPLC纯度为99.7%(杂质包括6个非对映异构体),ee值100%。
实施例13化合物I(M=Na)的合成(甲醇钠法):
称取化合物I(M=H)(4.77g,0.01mol)于反应瓶中,加入甲醇(100ml)搅拌。室温滴加1M的甲醇钠的甲醇溶液(40ml,0.04mol),析出沉淀,抽滤,甲醇洗涤,得化合物I(M=Na)3.52g,收率68%,HPLC纯度为99.1%(杂质包括6个非对映异构体),ee值100%。
Claims (10)
- 根据权利要求1所述的噁唑烷酮类抗菌药物中间体的制备方法,其特征在于,步骤(1)中,所述的金属试剂为有机锂试剂或格氏试剂。
- 根据权利要求2所述的噁唑烷酮类抗菌药物中间体的制备方法,其特征在于,步骤(1)中,所述的金属试剂为正丁基锂。
- 根据权利要求1所述的噁唑烷酮类抗菌药物中间体的制备方法,其特征在于,步骤(2)中,手性还原的方法包括Noyori不对称氢转移反应、CBS还原或酶催化还原法。
- 根据权利要求4所述的噁唑烷酮类抗菌药物中间体的制备方法, 其特征在于,步骤(2)中,所述的催化剂由钌催化剂和配体组成;所述的钌催化剂为二氯(p-甲基异丙苯)钌(II)二聚体,所述的手性配体为(1S,2S)-(+)-N-对甲苯磺酰基-1,2-二苯基乙二胺;步骤(2)中,所述的氢供体为摩尔比为5:1~2的甲酸-三乙胺。
- 根据权利要求1所述的噁唑烷酮类抗菌药物中间体的制备方法,其特征在于,步骤(3)中,所述的酸为三氟乙酸或盐酸;步骤(4)中,所述的环化试剂由N,N’-羰基二咪唑和4-二甲氨基吡啶组成。
- 根据权利要求7所述的噁唑烷酮类抗菌药物的制备方法,其特征在于,步骤(B)中,所述的偶联催化剂为钯催化剂或镍催化剂。
- 根据权利要求8所述的噁唑烷酮类抗菌药物的制备方法,其特征在于,步骤(B)中,所述的偶联催化剂为四(三苯基膦)钯(0)。
- 根据权利要求7所述的噁唑烷酮类抗菌药物的制备方法,其特征在于,步骤(C)中,所述的磷酸单酯化试剂为POCl3/Et3N或POCl3/PO(OEt)3。
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CN114057713A (zh) * | 2021-12-03 | 2022-02-18 | 广东莱佛士制药技术有限公司 | 一种合成(r)-沙美特罗中间体的方法 |
CN116423599A (zh) * | 2023-05-29 | 2023-07-14 | 德华兔宝宝装饰新材股份有限公司 | 抗菌阻燃木单板及其制备方法 |
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CN105949241B (zh) * | 2016-06-24 | 2018-01-12 | 浙江普洛得邦制药有限公司 | 一种噁唑烷酮类抗菌药物钠盐的晶型a及其制备方法和应用 |
CN106478724B (zh) * | 2016-09-09 | 2018-04-17 | 浙江普洛得邦制药有限公司 | 一种噁唑烷酮类抗菌药物的晶型c及其制备方法和应用 |
CN106632481B (zh) * | 2016-09-09 | 2018-05-29 | 优胜美特制药有限公司 | 一种噁唑烷酮类抗菌药物的晶型a及其制备方法和应用 |
CN106478723B (zh) * | 2016-09-09 | 2018-04-13 | 浙江普洛得邦制药有限公司 | 一种噁唑烷酮类抗菌药物的晶型b及其制备方法和应用 |
CN106749321B (zh) * | 2017-01-17 | 2018-10-09 | 浙江普洛得邦制药有限公司 | 一种噁唑烷酮类抗菌药物钠盐的晶型b及其制备方法和应用 |
CN108785728A (zh) * | 2017-05-05 | 2018-11-13 | 国家纳米科学中心 | 含药物中间体修饰的纳米金的抗菌敷料、其制备方法及应用 |
CN107353305A (zh) * | 2017-07-12 | 2017-11-17 | 浙江普洛得邦制药有限公司 | 一种噁唑烷酮类抗菌药物的三羟甲基氨基甲烷盐及其晶型a、制备方法和应用 |
GB201714736D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
GB201714745D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
GB201714740D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
GB201714734D0 (en) | 2017-09-13 | 2017-10-25 | Atrogi Ab | New compounds and uses |
CN111349059B (zh) * | 2018-12-20 | 2023-03-31 | 中国科学院上海药物研究所 | 一类手性环氧化合物的制备方法 |
CN111471041B (zh) * | 2019-01-23 | 2022-09-20 | 中国科学院上海药物研究所 | 一种噁唑烷酮类抗菌药物中间体的合成方法 |
CN114057712A (zh) * | 2021-12-03 | 2022-02-18 | 广东莱佛士制药技术有限公司 | 一种合成手性苯基噁唑烷-2-酮的方法 |
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