WO2016058467A1 - Method for preparing tedizolid phosphate - Google Patents
Method for preparing tedizolid phosphate Download PDFInfo
- Publication number
- WO2016058467A1 WO2016058467A1 PCT/CN2015/089734 CN2015089734W WO2016058467A1 WO 2016058467 A1 WO2016058467 A1 WO 2016058467A1 CN 2015089734 W CN2015089734 W CN 2015089734W WO 2016058467 A1 WO2016058467 A1 WO 2016058467A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phosphate
- compound
- preparing
- pyridine
- methyltetrazol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title abstract description 8
- 229960003947 tedizolid phosphate Drugs 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 238000005859 coupling reaction Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 14
- 239000010452 phosphate Substances 0.000 claims description 14
- LTGUFDNBCBUPKG-UHFFFAOYSA-N [6-(2-methyltetrazol-5-yl)pyridin-3-yl]boronic acid Chemical compound CN1N=NC(C=2N=CC(=CC=2)B(O)O)=N1 LTGUFDNBCBUPKG-UHFFFAOYSA-N 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- -1 alkyl methanol phosphate Chemical compound 0.000 claims description 9
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims 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 claims 2
- ORRBGDVWXDAQNJ-SSDOTTSWSA-N [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl dihydrogen phosphate Chemical compound P(=O)(O)(O)OC[C@H]1CN(C(O1)=O)C1=CC(=C(C=C1)I)F ORRBGDVWXDAQNJ-SSDOTTSWSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- JANKGNBDRWYWSN-UHFFFAOYSA-N 5-bromo-2-(2-methyltetrazol-5-yl)pyridine Chemical compound CN1N=NC(C=2N=CC(Br)=CC=2)=N1 JANKGNBDRWYWSN-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- NOQXXYIGRPAZJC-SECBINFHSA-N [(2r)-oxiran-2-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@@H]1OC1 NOQXXYIGRPAZJC-SECBINFHSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229940056137 sivextro Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 2
- DIDJTOBWBNSVKL-SSDOTTSWSA-N (5r)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical compound O=C1O[C@@H](CO)CN1C1=CC=C(I)C(F)=C1 DIDJTOBWBNSVKL-SSDOTTSWSA-N 0.000 description 1
- WOTMUQRPKDDBEH-UHFFFAOYSA-N 1-bromo-2-fluoro-4-isocyanatobenzene Chemical compound FC1=CC(N=C=O)=CC=C1Br WOTMUQRPKDDBEH-UHFFFAOYSA-N 0.000 description 1
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 1
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
- MXAPIVPDZNDDQL-UHFFFAOYSA-N 5-bromo-2-(1-methyltetrazol-5-yl)pyridine Chemical compound CN1N=NN=C1C1=CC=C(Br)C=N1 MXAPIVPDZNDDQL-UHFFFAOYSA-N 0.000 description 1
- DMSHUVBQFSNBBL-UHFFFAOYSA-N 5-bromopyridine-2-carbonitrile Chemical compound BrC1=CC=C(C#N)N=C1 DMSHUVBQFSNBBL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- QCGUSIANLFXSGE-UHFFFAOYSA-N C[n]1nnc(-c(cc2)ncc2-c(c(F)c2)ccc2N(CC(COP(O)(O)=O)O2)C2=O)n1 Chemical compound C[n]1nnc(-c(cc2)ncc2-c(c(F)c2)ccc2N(CC(COP(O)(O)=O)O2)C2=O)n1 QCGUSIANLFXSGE-UHFFFAOYSA-N 0.000 description 1
- IZDIPYVECWGPBU-UHFFFAOYSA-N C[n]1nnc(-c2ncc(B(OC)OC)cc2)n1 Chemical compound C[n]1nnc(-c2ncc(B(OC)OC)cc2)n1 IZDIPYVECWGPBU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 0 O=*CC(CN1c(cc2F)ccc2I)OC1=O Chemical compound O=*CC(CN1c(cc2F)ccc2I)OC1=O 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- OYLGJCQECKOTOL-UHFFFAOYSA-L barium fluoride Chemical compound [F-].[F-].[Ba+2] OYLGJCQECKOTOL-UHFFFAOYSA-L 0.000 description 1
- 229910001632 barium fluoride Inorganic materials 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 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
- 229960003907 linezolid Drugs 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Definitions
- the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of a novel oxazolidinone antibiotic phosphotidazole.
- Tedizolid phosphate is an oxazolidinone antibiotic developed by Cubist Pharmaceuticals. Tedizolid phosphate was approved by the US FDA in June 2014 and is marketed under the trade name Sivextro. This drug is the first second-generation oxazolidinone antibiotic to be approved by the FDA. Compared with the first-generation product linezolid, Sivextro has 2-8 times higher inhibitory activity against some bacteria, and the safety is also somewhat Improved. Since the compound Tedizolid does not yet have a standard Chinese translation, the applicant hereby transliterates it as "tedizamide.”
- Tedizolid phosphate is ⁇ (5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazole-5-yl)pyridine-3- Phenyl]-2-oxazol-5-yl ⁇ methanol phosphate (I), the structural formula is:
- 2-(2-methyltetrazol-5-yl)-5-bromopyridine (Intermediate A) is an azide via 2-cyano-5-bromopyridine
- the reaction produces a tetrazolyl derivative, and the methylation reagent such as methyl iodide or dimethyl sulfate is used to methylate the tetrazole ring to obtain 2-(2-methyltetrazole-5- a mixture of 5-bromopyridine (intermediate A) and 2-(1-methyltetrazol-5-yl)-5-bromopyridine (by-product), which is isolated by column chromatography or recrystallization.
- the methylation reagent such as methyl iodide or dimethyl sulfate
- the intermediate B or B' is an organotin reagent or an organoboron reagent prepared by R-3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinemethanol, which is passed through The Stille or Suzuki coupling reaction allows coupling to Intermediate A.
- the existing preparation methods have weaknesses such as long preparation steps, difficult to obtain raw materials, and high cost; the preparation and use of organotin reagents have high requirements on equipment and environment, and there are hidden dangers of environmental pollution. Further, the simultaneous presence of fluorine and iodine of the halogen in the intermediate B or B' structure lowers the selectivity in the formation of the organometallic reagent, increases the side reaction, and makes it difficult to effectively control the product quality.
- the object of the present invention is to provide a preparation method of teridinamine phosphate which is easy to obtain raw materials, simple in process, economical and environmentally friendly, and suitable for industrialization, in view of the defects in the prior art.
- the present invention adopts the following main technical solutions: a preparation method of teridinamine phosphate (I),
- the preparation step comprises the steps of: coupling a compound of the formula II with a compound of the formula III to form teridinamine (I).
- R is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl or pinacol
- the corresponding compound of formula II is 2-(2-methyltetrazol-5-yl).
- Pyridine-5-boric acid dimethyl 2-(2-methyltetrazol-5-yl)pyridine-5-borate, 2-(2-methyltetrazol-5-yl)pyridine-5-borate Ethyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-borate dipropyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-borate diisopropyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid diphenyl ester or 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid pinamate.
- the halogen X in the compound of the formula III is bromine or iodine, and the corresponding compound of the formula III is, in turn, R-3-(3-fluoro-4-bromo-phenyl)-2-oxo-5-oxazolidinylalkylmethanol Phosphate or R-3-(3-fluoro-4-iodo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate.
- the molar ratio of the compound of the formula II to the compound of formula III in the coupling reaction is from 1:0.5 to 1.5, preferably from 1:0.9 to 1.1.
- the catalyst for the coupling reaction is palladium chloride, palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride or bis(triphenylphosphine)palladium dichloride, preferably tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride.
- the base promoter of the coupling reaction is potassium carbonate, sodium carbonate, barium carbonate, barium fluoride, potassium acetate or potassium phosphate, preferably barium carbonate or potassium phosphate.
- the solvent for the coupling reaction is acetonitrile, 1,4-dioxane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably 1,4-dioxane or toluene.
- the temperature of the coupling reaction is from 50 to 150 ° C, preferably from 80 to 130 ° C.
- the preparation method of the teridinamine phosphate (I) according to the invention has the characteristics of easy availability of raw materials, simple process and environmental protection economy, thereby facilitating the industrial production of the raw material drug and promoting its economic technology. development of.
- Embodiment 1 is a diagrammatic representation of Embodiment 1:
- Embodiment 2 is a diagrammatic representation of Embodiment 1:
- Embodiment 3 is a diagrammatic representation of Embodiment 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Disclosed is a method for preparing tedizolid phosphate (I), and the preparation step thereof comprises producing the tedizolid phosphate (I) by means of a coupling reaction of a compound of formula II and a compound of formula III. The preparation method uses easily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.
Description
本发明属于有机合成路线设计及其原料药和中间体制备技术领域,特别涉及一种新的噁唑烷酮类抗菌素磷酸泰地唑胺的制备方法。The invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of a novel oxazolidinone antibiotic phosphotidazole.
Tedizolid phosphate是由卡毕斯特(Cubist)制药公司开发的一种噁唑烷酮类抗生素。Tedizolid phosphate于2014年6月获得美国FDA批准在美国上市,商品名为Sivextro。该药是第一个获得FDA批准的二代噁唑烷酮类抗生素,和一代产品利奈唑胺相比,Sivextro对一些细菌的体外抑制活性要高2-8倍,安全性在一定程度上也有所提高。因化合物Tedizolid还不具有标准的中文译名,故本申请人在此将其音译为“泰地唑胺”。Tedizolid phosphate is an oxazolidinone antibiotic developed by Cubist Pharmaceuticals. Tedizolid phosphate was approved by the US FDA in June 2014 and is marketed under the trade name Sivextro. This drug is the first second-generation oxazolidinone antibiotic to be approved by the FDA. Compared with the first-generation product linezolid, Sivextro has 2-8 times higher inhibitory activity against some bacteria, and the safety is also somewhat Improved. Since the compound Tedizolid does not yet have a standard Chinese translation, the applicant hereby transliterates it as "tedizamide."
磷酸泰地唑胺(Tedizolid phosphate)的化学名为:{(5R)-3-[3-氟-4-[6-(2-甲基-2H-四唑-5-yl)吡啶-3-基]苯基]-2-噁唑酮-5基}甲醇磷酸酯(I),其结构式为:The chemical name of Tedizolid phosphate is {(5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazole-5-yl)pyridine-3- Phenyl]-2-oxazol-5-yl}methanol phosphate (I), the structural formula is:
磷酸泰地唑胺的制备方法已有研究报道,PCT专利第WO2005058886号、第WO2010042887号和《European Journal of Medicinal Chemistry》2011年第46期第1027~1039页均报道了磷酸泰地唑胺及其类似物以及相关中间体的合成方法。对比总结这些方法,其合成路线均是由中间体A和中间体B(或中间体B’)通过芳基偶联反应来实现。The preparation method of ticlopamide is reported. PCT Patent No. WO2005058886, WO2010042887 and European Journal of Medicinal Chemistry, No. 46, 2011, pages 1027 to 1039, have reported tertidamine phosphate and its Methods for the synthesis of analogs and related intermediates. These methods are compared and summarized, and their synthetic routes are all achieved by the intermediate coupling reaction of intermediate A and intermediate B (or intermediate B').
其中2-(2-甲基四唑-5-基)-5-溴吡啶(中间体A)是通过2-氰基-5-溴吡啶的叠氮
化反应生成四氮唑基衍生物,再利用碘甲烷或硫酸二甲酯等甲基化试剂,对四氮唑环进行甲基化反应,制得2-(2-甲基四唑-5-基)-5-溴吡啶(中间体A)和2-(1-甲基四唑-5-基)-5-溴吡啶(副产物)的混合物,经柱层析或重结晶分离得到中间体A。Wherein 2-(2-methyltetrazol-5-yl)-5-bromopyridine (Intermediate A) is an azide via 2-cyano-5-bromopyridine
The reaction produces a tetrazolyl derivative, and the methylation reagent such as methyl iodide or dimethyl sulfate is used to methylate the tetrazole ring to obtain 2-(2-methyltetrazole-5- a mixture of 5-bromopyridine (intermediate A) and 2-(1-methyltetrazol-5-yl)-5-bromopyridine (by-product), which is isolated by column chromatography or recrystallization. A.
中间体B或B’是通过R-3-(3-氟-4-碘苯基)-2-氧代-5-噁唑烷基甲醇制成的有机锡试剂或有机硼试剂,该试剂通过Stille或Suzuki偶联反应,实现与中间体A的偶联。The intermediate B or B' is an organotin reagent or an organoboron reagent prepared by R-3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinemethanol, which is passed through The Stille or Suzuki coupling reaction allows coupling to Intermediate A.
由此看出,现有的制备方法存在制备步骤长、原料难以获得以及成本较高等弱点;有机锡试剂的制备和使用对设备和环境要求都比较高,存在环境污染隐患。另外,中间体B或B’结构中卤素的氟和碘的同时存在,降低了有机金属试剂形成时的选择性,使副反应增多,产品质量难以得到有效控制。It can be seen that the existing preparation methods have weaknesses such as long preparation steps, difficult to obtain raw materials, and high cost; the preparation and use of organotin reagents have high requirements on equipment and environment, and there are hidden dangers of environmental pollution. Further, the simultaneous presence of fluorine and iodine of the halogen in the intermediate B or B' structure lowers the selectivity in the formation of the organometallic reagent, increases the side reaction, and makes it difficult to effectively control the product quality.
发明内容Summary of the invention
本发明的目的在于针对现有技术中的缺陷,提供一种具有原料易得、工艺简洁、经济环保且适合工业化的磷酸泰地唑胺的制备方法。The object of the present invention is to provide a preparation method of teridinamine phosphate which is easy to obtain raw materials, simple in process, economical and environmentally friendly, and suitable for industrialization, in view of the defects in the prior art.
为实现上述发明目的,本发明采用了如下主要技术方案:一种磷酸泰地唑胺(I)的制备方法,In order to achieve the above object, the present invention adopts the following main technical solutions: a preparation method of teridinamine phosphate (I),
其制备步骤包括:通过式II化合物与式III化合物进行偶联反应生成磷酸泰地唑胺(I)。The preparation step comprises the steps of: coupling a compound of the formula II with a compound of the formula III to form teridinamine (I).
此外,本发明还提出如下附属技术方案:In addition, the present invention also proposes the following subsidiary technical solutions:
所述式II化合物中R为氢、甲基、乙基、丙基、异丙基、苯基或频哪基,相应的式II化合物依次为2-(2-甲基四唑-5-基)吡啶-5-硼酸、2-(2-甲基四唑-5-基)吡啶-5-硼酸二甲酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二乙酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二丙酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二异丙酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二苯酯或2-(2-甲基四唑-5-基)吡啶-5-硼酸频哪酯。In the compound of formula II, R is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl or pinacol, and the corresponding compound of formula II is 2-(2-methyltetrazol-5-yl). Pyridine-5-boric acid, dimethyl 2-(2-methyltetrazol-5-yl)pyridine-5-borate, 2-(2-methyltetrazol-5-yl)pyridine-5-borate Ethyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-borate dipropyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-borate diisopropyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid diphenyl ester or 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid pinamate.
所述式III化合物中的卤素X为溴或碘,相应的式III化合物依次为R-3-(3-氟-4-溴-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯或R-3-(3-氟-4-碘-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯。The halogen X in the compound of the formula III is bromine or iodine, and the corresponding compound of the formula III is, in turn, R-3-(3-fluoro-4-bromo-phenyl)-2-oxo-5-oxazolidinylalkylmethanol Phosphate or R-3-(3-fluoro-4-iodo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate.
所述偶联反应的原料式II化合物与式III化合物的投料摩尔比为1∶0.5-1.5,优选1∶0.9-1.1。The molar ratio of the compound of the formula II to the compound of formula III in the coupling reaction is from 1:0.5 to 1.5, preferably from 1:0.9 to 1.1.
所述偶联反应的催化剂为氯化钯、醋酸钯、双(二亚苄基丙酮)钯、四(三苯基膦)钯、[1,1′-双(二苯基膦)二茂铁]二氯化钯、双(三环己基膦)二氯化钯或双(三苯基膦)二氯化钯,优选四(三苯基膦)钯或[1,1′-双(二苯基膦)二茂铁]二氯化钯。The catalyst for the coupling reaction is palladium chloride, palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride or bis(triphenylphosphine)palladium dichloride, preferably tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride.
所述偶联反应的碱促进剂为碳酸钾、碳酸钠、碳酸铯、氟化铯、醋酸钾或磷酸钾,优选碳酸铯或磷酸钾。The base promoter of the coupling reaction is potassium carbonate, sodium carbonate, barium carbonate, barium fluoride, potassium acetate or potassium phosphate, preferably barium carbonate or potassium phosphate.
所述偶联反应的溶剂为乙腈、1,4-二氧六环、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜,优选1,4-二氧六环或甲苯。The solvent for the coupling reaction is acetonitrile, 1,4-dioxane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably 1,4-dioxane or toluene.
所述偶联反应的温度为50-150℃,优选80-130℃。The temperature of the coupling reaction is from 50 to 150 ° C, preferably from 80 to 130 ° C.
相比于现有技术,本发明所涉及的磷酸泰地唑胺(I)的制备方法,具有原料易得、工艺简洁和环保经济等特点,故而利于该原料药的工业化生产,促进其经济技术的发展。Compared with the prior art, the preparation method of the teridinamine phosphate (I) according to the invention has the characteristics of easy availability of raw materials, simple process and environmental protection economy, thereby facilitating the industrial production of the raw material drug and promoting its economic technology. development of.
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。The technical solution of the present invention will be further described in detail below in conjunction with several preferred embodiments.
实施例一:Embodiment 1:
氮气氛下,于三颈反应瓶中加入2-(2-甲基四唑-5-基)吡啶-5-硼酸(II)(2.15g,
10.5mmol)、R-3-(3-氟-4-碘-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯(III)(4.17g,10mmol)、四(三苯基膦)钯(0.23g,0.2mmol)、1M磷酸钾溶液15mL以及甲苯30mL,升温至回流,保持回流反应10-12小时,TLC检测反应完成。加入乙酸乙酯30mL,依次用水及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得油状物用正己烷和乙酸乙酯(1∶1,V/V)重结晶,真空干燥得白色固体磷酸泰地唑胺(I)3.82g,收率84.9%,1H NMR(DMSO-d6):d 8.92(s,1H),8.20(m,2H),7.74(t,1H),7.66(dd,1H),7.50(dd,1H),4.95(m,1H),4.46(s,3H),4.21(t,1H),4.05(m,2H),3.91(m,1H),FAB-MS m/z:451[M+H]+。2-(2-methyltetrazol-5-yl)pyridin-5-boronic acid (II) (2.15 g, 10.5 mmol), R-3-(3-fluoro-) was added to a three-necked reaction flask under a nitrogen atmosphere. 4-iodo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate (III) (4.17 g, 10 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol), 1 M phosphoric acid 15 mL of potassium solution and 30 mL of toluene were heated to reflux, and reflux reaction was maintained for 10-12 hours, and the reaction was confirmed by TLC. After adding 30 mL of ethyl acetate, the mixture was washed with EtOAc EtOAc EtOAc. Solid teridazole phosphate (I) 3.82g, yield 84.9%, 1 H NMR (DMSO-d6): d 8.92 (s, 1H), 8.20 (m, 2H), 7.74 (t, 1H), 7.66 ( Dd, 1H), 7.50 (dd, 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (m, 1H), FAB-MS m/z: 451 [M+H] + .
实施例二:Embodiment 2:
氮气氛下,于三颈反应瓶中加入2-(2-甲基四唑-5-基)吡啶-5-硼酸频哪酯(II)(3.01g,10.5mmol)、R-3-(3-氟-4-溴-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯(III)(3.69g,10mmol)、[1,1′-双(二苯基膦)二茂铁]二氯化钯/二氯甲烷复合物(0.15g,0.2mmol)、醋酸钾(1.17g,12mmol)和1,4-二氧六环50mL,升温至110℃,搅拌反应4-5小时,TLC检测反应完成。加入乙酸乙酯50mL,依次用水及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得油状物用正己烷和乙酸乙酯(1∶1,V/V)重结晶,真空干燥得白色固体磷酸泰地唑胺(I)4.02g,收率89.3%。2-(2-Methyltetrazol-5-yl)pyridin-5-boronic acid pinamate (II) (3.01 g, 10.5 mmol), R-3-(3) was added to a three-necked reaction flask under a nitrogen atmosphere. -Fluoro-4-bromo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate (III) (3.69 g, 10 mmol), [1,1'-bis(diphenylphosphine) dioxin Iron] palladium dichloride/dichloromethane complex (0.15 g, 0.2 mmol), potassium acetate (1.17 g, 12 mmol) and 1,4-dioxane 50 mL, heated to 110 ° C, stirred for 4-5 hours , TLC detects the completion of the reaction. After adding 50 mL of ethyl acetate, the mixture was washed with EtOAc EtOAc. Solid teridazole phosphate (I) 4.02 g, yield 89.3%.
实施例三:Embodiment 3:
氮气氛下,于三颈反应瓶中加入2-(2-甲基四唑-5-基)-5-溴-吡啶(IV)(2.4g,10mmol)、双频哪醇基二硼烷(1.27g,5mmol)、1,1’-双(二苯膦基)二茂铁二氯化钯(0.82g,1mmol)、醋酸钾(1.17g,12mmol)和1,4-二氧六环30mL,升温至110℃,搅拌反应4小时。降至室温,仍然在氮气氛下,向体系内加入R-3-(3-氟-4-溴-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯(III)(3.69g,10mmol)、1,4-二氧六环20mL和5M
磷酸钾0.5mL,再次升温至100℃,搅拌反应4小时,TLC检测反应完成。加入乙酸乙酯50mL,过滤,滤液依次用水及饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得油状物用正己烷和乙酸乙酯(1∶1,V/V)重结晶,真空干燥得白色固体磷酸泰地唑胺(I)3.34g,收率74.2%。2-(2-Methyltetrazol-5-yl)-5-bromo-pyridine (IV) (2.4 g, 10 mmol), bis-pinacol diborane (dimer) was added to a three-necked reaction flask under a nitrogen atmosphere. 1.27 g, 5 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.82 g, 1 mmol), potassium acetate (1.17 g, 12 mmol) and 1,4-dioxane 30 mL The temperature was raised to 110 ° C and the reaction was stirred for 4 hours. At room temperature, still under the nitrogen atmosphere, add R-3-(3-fluoro-4-bromo-phenyl)-2-oxo-5-oxazolidine methanol phosphate (III) to the system (3.69 g, 10 mmol), 1,4-dioxane 20 mL and 5M
Potassium phosphate (0.5 mL) was again heated to 100 ° C, and the reaction was stirred for 4 hours, and the reaction was confirmed by TLC. Ethyl acetate (50 mL) was added, and the filtrate was evaporated. EtOAcjjjjjjjjjjjjjj The white solid solution of tertidazole (I) was dried in white form, 3.34 g, yield 74.2%.
实施例四(中间体II的制备):Example 4 (Preparation of Intermediate II):
于三颈反应瓶中将2-(2-甲基四唑-5-基)-5-溴-吡啶(IV)(2.4g,10mmol)溶于无水四氢呋喃25mL中,降温至-55℃,滴加异丙基氯化镁(1M,15ml),滴毕后搅拌反应30分钟。向该反应体系中加入硼酸三甲酯(1.25g,12mmol),继续搅拌反应4-5小时。低温下用饱和氯化铵溶液淬灭反应,并将反应液倾入1N稀盐酸30mL中,室温反应1小时。用乙酸乙酯萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。减压浓缩,所得固体先用石油醚洗涤,再用水重结晶,得到白色固体2-(2-甲基四唑-5-基)吡啶-5-硼酸(II)1.6g,收率78.0%,FAB-MS m/z:206[M+H]+。2-(2-Methyltetrazol-5-yl)-5-bromo-pyridine (IV) (2.4 g, 10 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran in a three-necked reaction flask and cooled to -55 ° C. Isopropylmagnesium chloride (1 M, 15 ml) was added dropwise, and the reaction was stirred for 30 minutes after the dropwise addition. Trimethyl borate (1.25 g, 12 mmol) was added to the reaction system, and the reaction was further stirred for 4-5 hours. The reaction was quenched with a saturated ammonium chloride solution at a low temperature, and the reaction mixture was poured into 30 mL of 1N diluted hydrochloric acid, and reacted at room temperature for 1 hour. The organic layer was combined and washed with brine, dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained solid was washed with petroleum ether and then recrystallized from water to give white solid 2-(2-methyltetrazol-5-yl)pyridin-5-boronic acid (II) 1.6 g, yield 78.0%. FAB-MS m/z: 206 [M+H] + .
实施例五(中间体II的制备):Example 5 (Preparation of Intermediate II):
于三颈反应瓶中加入2-(2-甲基四唑-5-基)-5-溴-吡啶(IV)(2.4g,10mmol)、双频哪醇基二硼烷(1.27g,5mmol)、1,1’-双(二苯膦基)二茂铁二氯化钯(0.82g,1mmol)、醋酸钾(1.17g,12mmol)和1,4-二氧六环50mL,升温至110℃,搅拌反应8-10小时,TLC检测反应结束。用乙酸乙酯萃取三次,合并有机相,盐水洗涤,无水硫酸钠干燥。浓缩,乙酸乙酯和正己烷(1∶4)重结晶,得灰白色固体2-(2-甲基四唑-5-基)吡啶-5-硼酸频哪酯(II)2.48g,收率86.4%,FAB-MS m/z:288[M+H]+。2-(2-Methyltetrazol-5-yl)-5-bromo-pyridine (IV) (2.4 g, 10 mmol), bis-pinacolyl diborane (1.27 g, 5 mmol) was added to a three-necked reaction flask. , 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.82 g, 1 mmol), potassium acetate (1.17 g, 12 mmol) and 1,4-dioxane 50 mL, heated to 110 The reaction was stirred for 8-10 hours at °C, and the reaction was terminated by TLC. It was extracted three times with ethyl acetate. Concentration, ethyl acetate and n-hexane (1:4) were recrystallized to give 2-(2-methyltetrazol-5-yl)pyridin-5-boronic acid (II) 2.48 g as an off-white solid. %, FAB-MS m/z: 288 [M+H] + .
实施例六(中间体III的制备):Example 6 (Preparation of Intermediate III):
氮气保护下,于三颈反应瓶中加入R-缩水甘油对甲苯磺酸酯(TG)(2.28g,10mmol)和N,N-二甲基甲酰胺25mL,搅拌溶解后,加入碳酸铯(0.33g,1mmol)和3-氟-4-溴-苯基异氰酸酯(V)(2.15g,10mmol),加热至100℃,反应1小时后,TLC检测反应结束。减压回收溶剂,残留物用二氯甲烷和水溶解,分出有机相,水相用二氯甲烷萃取2次,减压浓缩,得到的油状物R-3-(3-氟-4-溴-苯基)-2-氧代-5-噁唑烷基甲醇对甲苯磺酸酯(VI),无需进一步纯化处理,直接加入1N盐酸在50℃下反应5小时,用二氯甲烷萃取3次,合并有机相,依次用饱和食盐水和水洗涤,无水硫酸钠干燥,减压浓缩。将浓缩物溶于磷酸三乙酯30mL中,室温下加入三氯氧磷(2.2mL,24mmol),搅拌2-3小时。加入30mL乙酸乙酯,搅拌半小时后,倾入50g冰水中,并在0℃下继续搅拌2小时,有白色固体析出,过滤,滤饼用丙酮洗涤,干燥,得类白色固体R-3-(3-氟-4-溴-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯(III)2.45g,收率66.4%,FAB-MS m/z:369[M+H]+。Under nitrogen protection, R-glycidyl p-toluenesulfonate (TG) (2.28 g, 10 mmol) and N,N-dimethylformamide 25 mL were added to a three-necked reaction flask, stirred and dissolved, and then cesium carbonate (0.33) was added. g, 1 mmol) and 3-fluoro-4-bromo-phenylisocyanate (V) (2.15 g, 10 mmol) were heated to 100 ° C. After 1 hour of reaction, the reaction was terminated by TLC. The solvent was evaporated under reduced pressure. the residue was crystalljjjjjjjjjjjjjjjj -Phenyl)-2-oxo-5-oxazole alkyl methanol p-toluenesulfonate (VI), without further purification, directly added to 1N hydrochloric acid at 50 ° C for 5 hours, extracted with dichloromethane 3 times The organic phase was combined, washed sequentially with brine brine and brine The concentrate was dissolved in 30 mL of triethyl phosphate, and phosphorus oxychloride (2.2 mL, 24 mmol) was added at room temperature, and stirred for 2-3 hours. After adding 30 mL of ethyl acetate and stirring for half an hour, it was poured into 50 g of ice water, and stirring was continued at 0 ° C for 2 hours. A white solid was precipitated, filtered, and the filter cake was washed with acetone and dried to give a white solid. (3-Fluoro-4-bromo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate (III) 2.45 g, yield 66.4%, FAB-MS m/z: 369 [M+H ] + .
实施例六(中间体III的制备):Example 6 (Preparation of Intermediate III):
氮气保护下,于三颈反应瓶中加入R-缩水甘油对甲苯磺酸酯(TG)(2.28g,10mmol)和四氢呋喃50mL,搅拌溶解后,加入碘化锂(0.14g,1mmol)和3-氟-4-碘-苯基异氰酸酯(V)(2.63g,10mmol),加热至回流,反应2小时后,TLC检测反应结束。减压回收溶剂,残留物用二氯甲烷和水溶解,分出有机相,水相用二氯甲烷萃取2次,减压浓缩,得到的油状物R-3-(3-氟-4-碘-苯基)-2-氧代-5-噁唑烷基甲醇对甲苯磺酸酯(VI),无需进一步纯化处理,直接加入1N盐酸在50℃下反应5小时,用二氯甲烷萃取3次,合并有机相,依次用饱和食盐水和水洗涤,无水硫酸钠干燥,减压浓缩。将浓缩物溶于磷酸三乙酯30mL中,室温下加入三氯氧磷(2.2mL,24mmol),搅拌2-3小时。加入30mL乙酸乙酯,搅拌半小时后,倾入50g冰水中,并在0℃下继续搅拌2小时,有白色固体析出,过滤,滤饼用丙酮洗涤,干燥,得类白色固体R-3-(3-氟-4-碘-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯(III)2.65g,收率63.7%,FAB-MS m/z:417[M+H]+。Under a nitrogen atmosphere, R-glycidyl p-toluenesulfonate (TG) (2.28 g, 10 mmol) and tetrahydrofuran 50 mL were added to a three-necked reaction flask, and after stirring and stirring, lithium iodide (0.14 g, 1 mmol) and 3- were added. Fluor-4-iodo-phenylisocyanate (V) (2.63 g, 10 mmol) was heated to reflux. After 2 hours of reaction, the reaction was terminated by TLC. The solvent was evaporated under reduced pressure. the residue was crystalljjjjjjjjjjjjjjjj -Phenyl)-2-oxo-5-oxazole alkyl methanol p-toluenesulfonate (VI), without further purification, directly added to 1N hydrochloric acid at 50 ° C for 5 hours, extracted with dichloromethane 3 times The organic phase was combined, washed sequentially with brine brine and brine The concentrate was dissolved in 30 mL of triethyl phosphate, and phosphorus oxychloride (2.2 mL, 24 mmol) was added at room temperature, and stirred for 2-3 hours. After adding 30 mL of ethyl acetate and stirring for half an hour, it was poured into 50 g of ice water, and stirring was continued at 0 ° C for 2 hours. A white solid was precipitated, filtered, and the filter cake was washed with acetone and dried to give a white solid. (3-Fluoro-4-iodo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate (III) 2.65 g, yield 63.7%, FAB-MS m/z: 417 [M+H ] + .
需要指出的是,上述实施例仅为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发
明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
It should be noted that the above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the contents of the present invention and implement the present invention.
The scope of protection. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.
Claims (8)
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述式II化合物中R为氢、甲基、乙基、丙基、异丙基、苯基或频哪基,相应的式II化合物依次为2-(2-甲基四唑-5-基)吡啶-5-硼酸、2-(2-甲基四唑-5-基)吡啶-5-硼酸二甲酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二乙酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二丙酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二异丙酯、2-(2-甲基四唑-5-基)吡啶-5-硼酸二苯酯或2-(2-甲基四唑-5-基)吡啶-5-硼酸频哪酯。The method for preparing thetazolamide according to claim 1, wherein R in the compound of formula II is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl or pinacol, correspondingly The compound of formula II is 2-(2-methyltetrazol-5-yl)pyridine-5-boronic acid, 2-(2-methyltetrazol-5-yl)pyridin-5-borate dimethyl ester, 2 -(2-methyltetrazol-5-yl)pyridine-5-borate diethyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-borate dipropyl ester, 2-(2- Methyltetrazole-5-yl)pyridine-5-borate diisopropyl ester, 2-(2-methyltetrazol-5-yl)pyridine-5-borate diphenyl ester or 2-(2-methyltetrayl) Imidazol-5-yl)pyridine-5-boronic acid pinamate.
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述式III化合物中的卤素X为溴或碘,相应的式III化合物依次为R-3-(3-氟-4-溴-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯或R-3-(3-氟-4-碘-苯基)-2-氧代-5-噁唑烷基甲醇磷酸酯。The method for preparing tertidamine phosphate according to claim 1, wherein the halogen X in the compound of the formula III is bromine or iodine, and the corresponding compound of the formula III is R-3-(3-fluoro-4). -Bromo-phenyl)-2-oxo-5-oxazole alkyl methanol phosphate or R-3-(3-fluoro-4-iodo-phenyl)-2-oxo-5-oxazolidinyl Methanol phosphate.
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述偶联反应的原料式II化合物与式III化合物的投料摩尔比为1∶0.5-1.5。The method for preparing tertidazole phosphate according to claim 1, characterized in that the molar ratio of the compound of the formula II to the compound of the formula III in the coupling reaction is from 1:0.5 to 1.5.
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述偶联反应的催化剂为氯化钯、醋酸钯、双(二亚苄基丙酮)钯、四(三苯基膦)钯、[1,1′-双(二苯基膦)二茂铁]二氯化钯、双(三环己基膦)二氯化钯或双(三苯基膦)二氯化钯。The method for preparing thetazolamide according to claim 1, wherein the catalyst for the coupling reaction is palladium chloride, palladium acetate, bis(dibenzylideneacetone)palladium or tetrakis(triphenylphosphine). Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride or bis(triphenylphosphine)palladium dichloride.
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述偶联反应的碱促进剂为碳酸钾、碳酸钠、碳酸铯、氟化铯、醋酸钾或磷酸钾。The method for preparing tertidamine phosphate according to claim 1, wherein the alkali promoter of the coupling reaction is potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, potassium acetate or potassium phosphate.
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述偶联反应的溶剂为乙腈、1,4-二氧六环、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基 乙酰胺或二甲亚砜。The method for preparing tertidamine phosphate according to claim 1, wherein the solvent for the coupling reaction is acetonitrile, 1,4-dioxane, toluene, xylene, N,N-dimethyl Formamide, N,N-dimethyl Acetamide or dimethyl sulfoxide.
- 如权利要求1所述磷酸泰地唑胺的制备方法,其特征在于:所述偶联反应的温度为50-150℃。 A method of producing tertimazine phosphate according to claim 1, wherein the temperature of the coupling reaction is from 50 to 150 °C.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410553205.2 | 2014-10-17 | ||
CN201410553205.2A CN104327119A (en) | 2014-10-17 | 2014-10-17 | Preparation method of tedizolid phosphate |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016058467A1 true WO2016058467A1 (en) | 2016-04-21 |
Family
ID=52401934
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2015/089734 WO2016058467A1 (en) | 2014-10-17 | 2015-09-16 | Method for preparing tedizolid phosphate |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN104327119A (en) |
WO (1) | WO2016058467A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112500433A (en) * | 2020-12-23 | 2021-03-16 | 桂林南药股份有限公司 | Preparation method of tedizolid phosphate |
CN113563679A (en) * | 2021-08-31 | 2021-10-29 | 戴科元 | Flame-retardant antibacterial PVC material and preparation method thereof |
CN113979835A (en) * | 2021-11-14 | 2022-01-28 | 重庆医科大学 | Synthetic method of pazopanib trimer impurity intermediate |
US11555033B2 (en) | 2020-06-18 | 2023-01-17 | Akagera Medicines, Inc. | Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016041505A1 (en) * | 2014-09-17 | 2016-03-24 | 正大天晴药业集团股份有限公司 | Tedizolid phosphate, intermediate and preparation method thereof |
CN104496979A (en) * | 2014-09-17 | 2015-04-08 | 博瑞生物医药技术(苏州)有限公司 | Method for preparing oxazolidinone compound and intermediate thereof |
CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
CN105837634B (en) * | 2015-01-30 | 2020-09-04 | 上海创诺制药有限公司 | Tedizolid phosphate crystal and preparation method thereof |
CN104592218B (en) * | 2015-02-13 | 2015-11-04 | 江苏欧信医药化工有限公司 | The synthetic method of a kind of safe ground azoles amine |
CN104892592A (en) * | 2015-03-30 | 2015-09-09 | 成都惟新医药科技有限公司 | Preparation method for tedizolid |
CN106146485B (en) * | 2015-04-01 | 2021-04-30 | 上海迪赛诺化学制药有限公司 | Method for preparing tedizolid and tedizolid crystal obtained by method |
CN106146559B (en) * | 2015-04-10 | 2019-08-09 | 博瑞生物医药(苏州)股份有限公司 | A kind of preparation method of Oxazolidinone derivative |
CN106279282B (en) * | 2015-05-21 | 2019-08-23 | 博瑞生物医药(苏州)股份有限公司 | A kind of purification process of Tedizolid Phosphate |
CN106608884A (en) * | 2015-10-27 | 2017-05-03 | 博瑞生物医药(苏州)股份有限公司 | Tedizolid system intermediate crystal form |
CN106632298B (en) * | 2015-11-03 | 2021-06-01 | 上海科胜药物研发有限公司 | Preparation method and intermediate of tedizolid |
CN105418681A (en) * | 2015-12-15 | 2016-03-23 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of tedizolid phosphate |
CN105753904B (en) * | 2016-04-22 | 2017-12-08 | 南京济群医药科技股份有限公司 | A kind of process for purification of Tedizolid Phosphate |
CN107382995A (en) * | 2017-09-01 | 2017-11-24 | 杭州新博思生物医药有限公司 | One pot process safe ground azoles amine |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005058886A1 (en) * | 2003-12-18 | 2005-06-30 | Dong-A Pharm.Co.,Ltd. | Novel oxazolidinone derivatives |
WO2006038100A1 (en) * | 2004-10-08 | 2006-04-13 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
WO2009020616A1 (en) * | 2007-08-06 | 2009-02-12 | Micurx Pharmaceuticals, Inc. | Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections |
WO2010042887A2 (en) * | 2008-10-10 | 2010-04-15 | Trius Therapeutics | Methods for preparing oxazolidinones and compositions containing them |
CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2011136537A (en) * | 2009-02-03 | 2013-03-10 | Траюс Терапьютикс | CRYSTAL FORM (R) -3- (4- (2-Methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyl oxazolidine-2-one phosphorus phosphate |
-
2014
- 2014-10-17 CN CN201410553205.2A patent/CN104327119A/en active Pending
-
2015
- 2015-09-16 WO PCT/CN2015/089734 patent/WO2016058467A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005058886A1 (en) * | 2003-12-18 | 2005-06-30 | Dong-A Pharm.Co.,Ltd. | Novel oxazolidinone derivatives |
WO2006038100A1 (en) * | 2004-10-08 | 2006-04-13 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
WO2009020616A1 (en) * | 2007-08-06 | 2009-02-12 | Micurx Pharmaceuticals, Inc. | Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections |
WO2010042887A2 (en) * | 2008-10-10 | 2010-04-15 | Trius Therapeutics | Methods for preparing oxazolidinones and compositions containing them |
CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
Non-Patent Citations (1)
Title |
---|
WEON BIN INI ET AL.: "Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, 18 January 2011 (2011-01-18), XP028185750, DOI: doi:10.1016/j.ejmech.2011.01.014 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11555033B2 (en) | 2020-06-18 | 2023-01-17 | Akagera Medicines, Inc. | Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof |
US11566023B2 (en) | 2020-06-18 | 2023-01-31 | Akagera Medicines, Inc. | Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof |
CN112500433A (en) * | 2020-12-23 | 2021-03-16 | 桂林南药股份有限公司 | Preparation method of tedizolid phosphate |
CN113563679A (en) * | 2021-08-31 | 2021-10-29 | 戴科元 | Flame-retardant antibacterial PVC material and preparation method thereof |
CN113979835A (en) * | 2021-11-14 | 2022-01-28 | 重庆医科大学 | Synthetic method of pazopanib trimer impurity intermediate |
CN113979835B (en) * | 2021-11-14 | 2023-09-26 | 重庆医科大学 | Synthesis method of pazopanib trimer impurity intermediate |
Also Published As
Publication number | Publication date |
---|---|
CN104327119A (en) | 2015-02-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2016058467A1 (en) | Method for preparing tedizolid phosphate | |
CN104496979A (en) | Method for preparing oxazolidinone compound and intermediate thereof | |
US20170247352A1 (en) | Method for preparing alectinib | |
TW201831461A (en) | Process for preparing apalutamide | |
CN107176955A (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
CN106674264A (en) | Synthetic method for (2,2,2-trifluoroethoxyl) phenylboronic acid compounds | |
CN104610359A (en) | Key intermediate for preparing tedizolid phosphate, and preparation method of key intermediate | |
CN103896940B (en) | A kind of synthetic method of Eliquis | |
CN103374039A (en) | Synthesis method of tenofovir | |
WO2007105657A1 (en) | Method of synthesizing oligomer compound with cross-coupling reaction | |
CN103073525B (en) | Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide | |
CN103421050A (en) | Ferrocene dicarboxylate compounds and synthetic method thereof | |
WO2016041505A1 (en) | Tedizolid phosphate, intermediate and preparation method thereof | |
CN101531680B (en) | Method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine | |
CN104496940A (en) | Method for preparing BCR-ABL inhibitor intermediate | |
CN104003943A (en) | Preparation method for ticagrelor intermediate | |
CN104496913B (en) | A method of preparing 5- substitution -2,4- dimethyl sulphur-based pyrimidines | |
CN103772433A (en) | Synthetic method of chemiluminescence reagent AMPPD for immunization analysis | |
CN102531985B (en) | Method for preparing ezetimibe key intermediate | |
CN105801482A (en) | Method for preparing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester | |
CN104926674A (en) | (Z)-3-dimethylamino-2-phenoxy-alpha, beta-unsaturated amide and preparation method thereof | |
CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
CN105777631B (en) | A kind of synthetic method of the bromo- 8- difluoro-methoxies -1,4- dihydroquinoline -3- carboxylic acid, ethyl esters of 1- cyclopropyl -4- oxos -7- | |
CN113045475A (en) | Preparation method of 5-bromo-7-methylindole | |
CN105102417A (en) | Method for producing 4-halosenecioic acid derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15849995 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 23.06.17) |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 15849995 Country of ref document: EP Kind code of ref document: A1 |