WO2017076285A1 - 一种泰地唑胺的制备方法及其中间体和制备方法 - Google Patents
一种泰地唑胺的制备方法及其中间体和制备方法 Download PDFInfo
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- WO2017076285A1 WO2017076285A1 PCT/CN2016/104311 CN2016104311W WO2017076285A1 WO 2017076285 A1 WO2017076285 A1 WO 2017076285A1 CN 2016104311 W CN2016104311 W CN 2016104311W WO 2017076285 A1 WO2017076285 A1 WO 2017076285A1
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- Prior art keywords
- group
- palladium
- compound
- halogen
- preparation
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 229960003879 tedizolid Drugs 0.000 title abstract description 5
- 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 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- -1 tedizolid compound Chemical class 0.000 claims abstract description 39
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000000460 chlorine Substances 0.000 claims abstract description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 21
- 150000002367 halogens Chemical class 0.000 claims abstract description 21
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000001424 substituent group Chemical group 0.000 claims abstract description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 14
- 238000005859 coupling reaction Methods 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 5
- 238000006243 chemical reaction Methods 0.000 claims description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 22
- 239000003446 ligand Substances 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000010949 copper Substances 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000002009 diols Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- 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
- 235000011056 potassium acetate Nutrition 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[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.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 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 4
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004985 diamines Chemical class 0.000 claims description 4
- 239000012954 diazonium Substances 0.000 claims description 4
- 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 4
- 125000005594 diketone group Chemical group 0.000 claims description 4
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- JGBZTJWQMWZVNX-UHFFFAOYSA-N palladium;tricyclohexylphosphane Chemical compound [Pd].C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 JGBZTJWQMWZVNX-UHFFFAOYSA-N 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 150000001298 alcohols Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 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 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 2
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 claims description 2
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 claims description 2
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 claims 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N CuO Inorganic materials [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 150000003457 sulfones Chemical class 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 abstract 2
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 abstract 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 39
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- 238000003756 stirring Methods 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 239000012065 filter cake Substances 0.000 description 17
- 238000006467 substitution reaction Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 239000012265 solid product Substances 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- 238000012544 monitoring process Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- ARSVSPBHHSDKPC-UHFFFAOYSA-N 5-(2-fluoro-4-iodophenyl)-2-(2-methyltetrazol-5-yl)pyridine Chemical compound FC1=C(C=CC(=C1)I)C=1C=CC(=NC=1)C=1N=NN(N=1)C ARSVSPBHHSDKPC-UHFFFAOYSA-N 0.000 description 8
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- 239000000243 solution Substances 0.000 description 8
- LSYOFPBORRARMF-GSVOUGTGSA-N (5r)-5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical compound OC[C@H]1CNC(=O)O1 LSYOFPBORRARMF-GSVOUGTGSA-N 0.000 description 7
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
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- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- MRQYTJXVULSNIS-UHFFFAOYSA-N 4-bromo-3-fluorophenol Chemical compound OC1=CC=C(Br)C(F)=C1 MRQYTJXVULSNIS-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- 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
- C07F9/65583—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 each of the hetero rings containing nitrogen as ring hetero atom
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- B01J2531/824—Palladium
Definitions
- the invention relates to a preparation method of a novel oxazolidinone antibiotic, terazozinamide or a phosphate thereof, an intermediate compound thereof and a preparation method.
- Tetrazolamide for people including Gram-positive bacteria such as staphylococcus, enterococci and streptococci, anaerobic microorganisms such as bacteriophages and Clostridium, and acid-tolerant microorganisms such as tuberculosis, avian mycobacteria It has potent antibacterial activity with animal pathogens.
- Tedizolid (formerly known as torezolid) was jointly developed by Cubist Pharmaceuticals (a subsidiary of Merck) and Bayer. Antibiotic prodrugs were originally discovered by Dong-A Pharmaceutical East Asia Pharmaceuticals (ST) and used for Gram-positive For the treatment of bacterial infections, Tedizolid is rapidly converted into its active form in plasma, TR 700 (DA 7157).
- WO2005058886A1 discloses 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl]phenyl]-5-(hydroxymethyl)-2-
- the synthesis of oxazolidinone is carried out by using 3-fluoroaniline as a raw material, protected by Cbz, and then reacted with glycidyl butyrate to obtain compound 3, followed by iodide to prepare tin reagent 5, followed by 5-bromo-2-( 2-methyl-2H-tetrazol-5-yl)-pyridine suzuki coupling gives the key intermediate K, the reaction route is as follows:
- the compound of the East Asia Pharmaceuticals has a longer reaction step and a lower overall yield.
- the patent WO2010042887 uses 4-bromo-3-fluoroaniline as the starting material to synthesize borate 10 and then 5-bromo-2-(2- Methyl-2H-tetrazol-5-yl)-pyridine is subjected to suzuki coupling to form intermediate 11 and then reacted with glycidyl butyrate to form oxazolidinone intermediate K.
- the reaction route is as follows:
- CN104496979A discloses a method for preparing medizolamide, and the reaction route is as follows:
- R is hydrogen or a hydroxy protecting group
- one of L and R 1 is a leaving group and the other is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from OH and optionally substituted C 1 a group consisting of -C 6 monohydric and diol, wherein R 2 and R 3 may form a ring
- this route uses Pd to catalyze the synthesis of borate intermediate II, and after separation and purification of borate II, and then with compound I in Pd Suzuki coupling under catalytic conditions affords the compound of formula H. In the route, II must be separated, and then suzuki coupling is carried out, which is cumbersome.
- the object of the present invention is to provide a preparation method of teridazole which is low in production cost, simple in operation, high in yield and purity, and suitable for industrial production, and particularly relates to a novel method for preparing terthazolamide by using novel intermediates.
- the present invention provides a preparation method of the following teridazole compound,
- R is selected from hydrogen, Substituted benzyl group (the substituent is selected from the group consisting of halogen, nitro, C 1 -C 6 alkyl and C 1 -C 6 alkoxy), and R 1 is C 1 -C 6 alkyl or halogen substituted C 1 -C 6 alkyl;
- X is a leaving group (the leaving group includes chlorine, bromine, iodine, a sulfonyloxy group such as trifluoromethanesulfoxy, methanesulfonyloxy, benzenesulfonyloxy, or one or more a substituent-substituted benzenesulfonyloxy group selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; preferably the leaving group is chlorine, bromine or iodine More preferably, the leaving group is bromine or iodine),
- the coupling reaction is carried out under the catalysis of a metal catalyst wherein the substituent of R is as defined above.
- the metal catalyst is a copper catalyst.
- the same catalyst is preferably Cu powder, CuI, CuBr, Cu 2 O, CuO, Cu 2 O, CuSO 4 , Cu(OAc) 2 or Cu(OTf) 2 , more preferably CuI and Cu(OAc) 2 .
- the diamine ligand is preferably:
- the diketone ligand is preferably:
- the phenanthroline ligand is preferably:
- amino acid ligands are preferably:
- the Phos-like ligands are preferably: X-Phos, XantPhos, RuPhos, BrettPhos, SPhos, DavePhos, JohnPhos, tBuXPhos.
- the metal catalyst is a palladium catalyst such as palladium chloride, palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, tetrakis(triphenylene).
- an alkaline environment such as potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, Sodium hydroxide, potassium hydroxide, potassium phosphate or sodium phosphate can promote the progress of the reaction.
- the solvent may be selected from solvents such as aromatic hydrocarbons, ethers, alcohols, ethers, nitriles, and amides, preferably toluene, chlorobenzene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and Methyl sulfoxide (DMSO), dioxane, isopropanol, ethanol or acetonitrile; further preferably N,N-dimethylformamide (DMF) and dioxane.
- the reaction temperature is preferably from 60 to 110 ° C, more preferably from 90 to 110 ° C.
- the protecting group R may optionally be removed (wherein R is not hydrogen, the other definition is the same as above), and a compound of the formula:
- the compound of the above formula can be further phosphorylated to obtain tertidamine phosphate as shown in the following formula.
- the invention also provides a novel tereconazole intermediate, a preparation method of the compound of the following formula,
- X is a leaving group and is as defined above;
- C is a hydroxyl group or an amino group
- C When C is a hydroxyl group, it reacts with a sulfonyl chloride compound (including trifluoroformic acid anhydride, methanesulfonyl chloride, or benzenesulfonyl chloride, etc.) to form a compound having the following formula:
- a sulfonyl chloride compound including trifluoroformic acid anhydride, methanesulfonyl chloride, or benzenesulfonyl chloride, etc.
- X is a leaving group (the leaving group is a sulfonyloxy group such as trifluoromethanesulfoxy group, methanesulfonyloxy group, benzenesulfonyloxy group, or benzene substituted by one or more substituents) a sulfonyloxy group, the substituent being selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy);
- a basic substance can promote the progress of the reaction, such as potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, potassium phosphate or sodium phosphate;
- X is a leaving group, and the leaving group includes chlorine, bromine, and iodine;
- halogen ion a compound of the formula.
- the donor of the halogen ion may be chlorine, bromine or iodine, and iodine may, for example, include an elemental iodine or an iodide salt such as sodium iodide or potassium iodide.
- the invention also provides a novel tereconazole intermediate, a preparation method of the compound of the following formula,
- the coupling reaction is formed under the catalysis of a palladium catalyst
- C is a hydroxyl group or an amino group; one of A and B is a leaving group, and the other is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from OH and C 1 -C 6 mono and A group consisting of a monohydric alcohol or a halogen-substituted C 1 -C 6 mono- and diol, and R 2 and R 3 may form a ring.
- A is a leaving group and B is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from OH and C 1 -C 6 mono- and diol or halogen A group consisting of C 1 -C 6 monohydric and diol, R 2 and R 3 may form a ring.
- B is a leaving group
- A is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from OH and C 1 -C 6 mono- and diol or halogen A group consisting of C 1 -C 6 monohydric and diol, R 2 and R 3 may form a ring.
- the leaving group includes a halogen such as chlorine, bromine, iodine, a sulfonyloxy group such as a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a benzenesulfonyloxy group, or one or more substituents.
- a substituted benzenesulfonyloxy group the substituent being selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; preferably the leaving group is chlorine, bromine, iodine; more preferably The leaving group is bromine or iodine.
- BR 2 R 3 is preferably B(OH) 2 or
- C is hydroxy or amino; preferably B is bromine or iodine, and A is BF 3 , B(OH) 2 or
- the reaction catalyst is a palladium catalyst
- the palladium catalyst is palladium chloride, palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, [1,1'-double (diphenylphosphine)ferrocene]palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride or bis(triphenylphosphine)palladium dichloride.
- the progress of the reaction can be promoted in the presence of a basic substance such as potassium carbonate, sodium carbonate, cesium carbonate, cesium fluoride, potassium acetate, sodium hydroxide, potassium hydroxide, potassium phosphate or sodium phosphate.
- the solvent may be one of water, toluene, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dioxane, isopropanol, ethanol or acetonitrile or In various combinations, it is preferably toluene, water and dioxane, or isopropanol.
- the reaction temperature is preferably from 50 to 120 ° C, more preferably from 70 to 100 ° C.
- C is hydroxy or amino; preferably A is bromine or iodine, and B is BF 3 , B(OH) 2 or
- the reaction is preferably carried out under the catalytic conditions of a palladium catalyst, the solvent is preferably water and dioxane, and the reaction temperature is about 60-80 ° C to prepare a terazozinamide intermediate compound.
- the present invention also provides a novel terizolamide intermediate, a compound of the formula:
- X is a leaving group (the leaving group includes chlorine, bromine, iodine, a sulfonyloxy group such as trifluoromethanesulfoxy, methanesulfonyloxy, benzenesulfonyloxy, or one or more Substituted phenylsulfonyloxy group, said substituent being selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy); said leaving group is preferably bromine or iodine .
- the compound is preferably:
- the present invention provides a novel preparation method of teridazole, which has the advantages of easy availability of raw materials, low cost, high yield of each step, simple and easy operation, environmental protection and economy, and is advantageous for industrial production.
- the preparation method involved in the present invention requires the use of the key intermediate 5-(4-substituted-2-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)pyridine, the middle The use of the body allows the preparation route of the desadizolamide to be carried out.
- Reagents are purchased from commercial sources and used without treatment. Hydrogen proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE 400 at 400 MHz. Mass spectra were recorded using an Agilent HPLC 1260 Infinity and 6120 Duadrupole LC/MS.
- the filtrate is added with 10 g of activated carbon, heated to 70-80 ° C, stirred and decolorized for 1-2 hours, cooled to 40-50 ° C, filtered at this temperature, and the filtrate is reduced.
- the mixture was pressure distilled to 80-100 mL, cooled to 10-15 ° C, and a white solid was precipitated, filtered, and the filter cake was dried at 50 ° C to obtain 54 g of a white solid product, yield 87%.
- HPLC showed a purity of 98.9%.
- the filtrate is added with 10 g of activated carbon, heated to 70-80 ° C, stirred and decolorized for 1-2 hours, cooled to 40-50 ° C, filtered at this temperature, and the filtrate is reduced.
- the mixture was distilled to 60-80 mL, cooled to 0-10 ° C, and a white solid was precipitated, filtered, and the filter cake was dried at 50 ° C to give a white solid product 29.8 g, yield 80%.
- HPLC showed a purity of 99.5%.
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Abstract
本发明涉及下式泰地唑胺化合物的制备方法,式I,其中,R选自氢、式A、式B、苄基或取代基取代的苄基,所述取代基选自卤素、硝基、C1-C6烷基和C1-C6烷氧基组成的组,R1为C1-C6烷基或卤素取代的C1-C6烷基;包括将具有下式结构的化合物式C与具有下式结构的化合物式D,在金属催化剂催化下偶联反应生成,R的取代基定义同上;其中X为离去基团,所述离去基团包括氯、溴、碘,磺酰氧基如三氟甲磺氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组。
Description
本申请要求于2015年11月3日提交中国专利局、申请号为201510739910.6发明名称为“一种泰地唑胺的制备方法及其中间体”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本发明涉及一种新噁唑烷酮类抗菌素泰地唑胺或其磷酸盐的制备方法及其中间体化合物和制备方法。
磷酸泰地唑胺,对包括革兰氏阳性菌如葡萄球菌、肠道球菌和链球菌,厌氧微生物如类菌体和梭菌体以及耐酸微生物如结核分支菌、鸟分支菌在内的人和动物病原体具有有力的抗菌活性。由Cubist Pharmaceuticals公司(Merck公司的子公司)和拜耳共同开发了tedizolid(以前称为torezolid),最初由Dong-A Pharmaceutical东亚制药(东亚ST)发现了抗菌药物前体,用于对革兰氏阳性菌感染的治疗,Tedizolid在血浆中迅速转化成其活性形式,TR 700(DA 7157)。
WO2005058886A1公开了3-[3-氟-4-[6-(2-甲基-2H-四唑-5-基)-3-吡啶基]苯基]-5-(羟基甲基)-2-噁唑烷酮的合成,使用3-氟苯胺为原料,经过Cbz保护,再与缩水甘油丁酸酯反应得到化合物3,碘代后再制备成锡试剂5,之后与5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶suzuki偶联得到关键中间体K,反应路线如下:
该东亚制药原研的化合物的反应步骤较长,总收率不高。成本方面,需要使用比较昂贵的试剂如CF3COOAg,而且路线中两次使用Pd催化剂分别用于制备中间体5和K,条件苛刻不易于放大生产。
后来原研许可商Trius Therapeutics公司对原研化合物路线进行了改进,其专利WO2010042887采用以4-溴-3-氟苯胺为起始原料,合成硼酸酯10,再与5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶进行suzuki偶联生成中间体11,然后再与缩水甘油丁酸酯反应生成噁唑烷酮中间体K,反应路线如下:
相对东亚制药的专利方法,该路线步骤短,总收率有所提高,但反应条件比较苛刻,需要使用丁基锂并在超低温(-65℃)下进行;并且n-BuLi和LiHMDS的使用需要严格的无水条件。
另外CN104496979A公开了一种制备泰地唑胺的方法,反应路线如下:
其中,R为氢或羟基保护基;L和R1中一个为离去基团,另一个为BF3或BR2R3,其中R2和R3独立的选自由OH和任意取代的C1-C6一元和二元醇组成的组,其中R2和R3可以成环;该路线采用Pd催化合成硼酸酯中间体II,分离纯化出硼酸酯II后,再与化合物I在Pd催化条件下进行suzuki偶联得到式H所示化合物。路线中须分离出II,再进行suzuki偶联,操作繁琐。
目前关于泰地唑胺中间体的现有方法,均操作复杂,反应时间长,总收率低,纯度较低。
发明内容
本发明目的是提供一种生产成本低,操作简单,收率和纯度较高,适合工业化生产的泰地唑胺制备方法,具体涉及利用新颖中间体用于制备泰地唑胺的新型方法。
为实现上述目的,本发明提供了一种下式泰地唑胺化合物的制备方法,
包括将具有下式结构的化合物,
其中X为离去基团(所述离去基团包括氯、溴、碘,磺酰氧基如三氟甲磺氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组;优选离去基团为氯、溴或碘;更优选离去基团为溴或碘),
与具有下式结构的化合物,
在金属催化剂催化下偶联反应生成,其中R的取代基定义同上。
在本发明的优选实施方式中,金属催化剂为铜催化剂。所述同催化剂优选Cu粉、CuI、CuBr、Cu2O、CuO、Cu2O、CuSO4、Cu(OAc)2或Cu(OTf)2,更优选CuI和Cu(OAc)2。
除了单独使用铜催化剂,在某些情况下,也需要在配体的配合下进行反应,可以使用二胺类配体、二酮类配体、邻菲罗啉类配体、氨基酸类配体或Phos类配体。二胺类配体优选为:
二酮类配体优选为:
邻菲罗啉类配体优选为:
氨基酸类配体优选为:
Phos类配体优选为:X-Phos、XantPhos、RuPhos、BrettPhos、SPhos、DavePhos、JohnPhos、tBuXPhos。
在本发明的另一些实施方式中,金属催化剂为钯催化剂,比如氯化钯、醋酸钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、四(三苯基膦)钯、[1,1’-双(二苯基磷)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,优选三(二亚苄基丙酮)二钯、氯化钯或醋酸钯。
通常地,在碱性环境下(如醋酸钾、碳酸钠、碳酸钾、碳酸铯、氟化铯、
氢氧化钠、氢氧化钾、磷酸钾或磷酸钠等)能够促进反应的进行。溶剂可以选自芳香烃、醚类、醇类、醚类、腈类及酰胺类等溶剂,优选为甲苯、氯苯、四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、二氧六环、异丙醇、乙醇或乙腈;进一步优选N,N-二甲基甲酰胺(DMF)和二氧六环。反应温度优选为60-110℃,更优选90-110℃。
上式所示化合物可以进一步磷酸化,得到如下式所示的磷酸泰地唑胺,
本发明还提供了新的泰地唑胺中间体,即下式化合物的制备方法,
其中X为离去基团,定义同上;
包括将具有下式结构的化合物
其中,C为羟基或氨基;
1)当C为羟基时,与磺酰氯类化合物(包括三氟甲酸酸酐、甲磺酰氯、或苯磺酰氯等)反应即可生成具有下式结构的化合物:
其中X为离去基团(所述离去基团为磺酰氧基如三氟甲磺氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组);
在这种情况下,加入碱性物质可促进反应的进行,如碳酸钾、碳酸钠、碳酸铯、氟化铯、醋酸钾、氢氧化钠、氢氧化钾、磷酸钾或磷酸钠等;
2)当C为氨基时,在亚硝酸钠存在下反应生成重氮盐化合物,再经卤素离子取代形成具有下式结构的化合物:
其中X为离去基团,所述离去基团包括氯、溴、碘;
在这种情况下,在酸性环境下如醋酸、甲磺酸、盐酸、硫酸、或樟脑磺酸的存在下,与亚硝酸钠反应形成重氮盐,形成的重氮盐被卤素离子取代形成上式所示化合物。卤素离子的供体可以是氯、溴或碘,以碘为例可以包括碘单质或碘盐例如碘化钠、或碘化钾等。
本发明还提供了一种新的泰地唑胺中间体,即下式化合物的制备方法,
包括将具有下式结构的化合物
与具有下式结构的化合物
在钯催化剂催化下偶联反应生成,
其中,C为羟基或氨基;A和B中一个为离去基团,另一个为BF3或BR2R3,其中R2和R3独立的选自由OH和C1-C6一元和二元醇或卤素取代的C1-C6一元和二元醇组成的组,R2和R3可以成环。
在一个实施方式中,优选A为离去基团,B为BF3或BR2R3,其中R2和R3独立的选自由OH和C1-C6一元和二元醇或卤素取代的C1-C6一元和二元醇组成的组,R2和R3可以成环。
在另一个实施方式中,优选B为离去基团,A为BF3或BR2R3,其中R2和R3独立的选自由OH和C1-C6一元和二元醇或卤素取代的C1-C6一元和二元醇组成的组,R2和R3可以成环。
其中,所述离去基团包括卤素如氯、溴、碘,磺酰氧基如三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组;优选离去基团为氯、溴、碘;更优选离去基团为溴或碘。
在具体实施方式中,反应催化剂为钯催化剂,所述钯催化剂为氯化钯、醋酸钯、双(二亚苄基丙酮)钯、四(三苯基膦)钯、[1,1’-双(二苯基磷)二茂铁]二氯化钯、双(三环己基膦)二氯化钯或双(三苯基膦)二氯化钯等。
在碱性物质存在条件下可以促进反应的进行,如碳酸钾、碳酸钠、碳酸铯、氟化铯、醋酸钾、氢氧化钠、氢氧化钾、磷酸钾或磷酸钠。溶剂可以是水、甲苯、四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、二氧六环、异丙醇、乙醇或乙腈等一种或多种组合,优选为甲苯、水和二氧六环、或异丙醇。反应温度优选为50-120℃,更优选为70-100℃。
本发明还提供了新的泰地唑胺中间体,即结构式如下的化合物:
或结构式如下的化合物:
其中X为离去基团(所述离去基团包括氯、溴、碘,磺酰氧基如三氟甲磺氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组);所述离去基团优选溴或碘。所述化合物优选为:
本发明有益的技术效果:
相比于现有技术,本发明提供了一种新型的泰地唑胺制备方法,具有原料易得、成本低、各步收率高、工艺简洁易操作和环保经济等优点,利于工业化生产。其中,本发明专利涉及的制备方法需要使用到关键中间体5-(4-取代-2-氟苯基)-2-(2-甲基-2H-四唑-5-基)吡啶,该中间体的使用使得泰地唑胺的制备路线得以实施。
实施例
为了使本发明所解决的技术问题、技术方案及有益效果更佳清楚明白,以下结合具体实施例,对本发明作进一步的说明。所给出的具体实施例为本发明的优选实施例。
实验和数据分析
试剂通过商业来源购买,未经处理直接使用。氢质子核磁共振谱通过Bruker AVANCE 400在400MHz下获得。质谱使用Agilent HPLC 1260Infinity及6120Duadrupole LC/MS记录。
实施例1:2-(2-甲基-2H-四唑-5-基)-5-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)吡啶的制备
在装有搅拌和温度计的三口烧瓶中加入5-溴-2-(2-甲基-2H-四唑-5-基)吡啶(20.0g,1eq),频那醇硼酸酯(42.3g,2.0eq),醋酸钾(24.5g,3.0eq)及甲苯(400mL),N2置换后,加入Pd(dppf)Cl2(0.6g,3%w/w),再次N2置换后,于80-85℃下搅拌反应12小时,HPLC监控显示反应完全。反应液冷却至40-50℃,在此温度下抽滤,滤液加入5g活性炭,加热至70-80℃搅拌脱色1-2小时,冷却至40-50℃,在此温度下抽滤,滤液减压蒸馏至40-60mL,冷却至10-15℃,白色固体析出,过滤,滤饼放置于50℃下烘干,得到白色固体产品19.5g,收率81.5%。HPLC显示纯度为98.5%。LCMS[M+H]=288.1,NMR(CDCl3,400MHz):9.15(t,1H),8.22(m,2H),4.44(s,3H),1.25(s,12H)。
实施例2:3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯胺的制备
在装有搅拌和温度计的三口烧瓶中加入2-(2-甲基-2H-四唑-5-基)-5-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)吡啶(50g,1eq),4-溴-3-氟苯胺(36.4g,1.1eq),Na2CO3(36.9g,2.0eq),水(300mL)及二氧六环(1000mL),N2置换后,加入Pd(dppf)Cl2(1.5g,3%w/w),再次N2置换后,于70-80℃下搅拌反应12小时,HPLC监控显示反应完全。减压蒸馏去除大部分二氧六环,加入500mL水,室温搅拌2-3小时后,过滤,滤饼用乙醇(100mL)打浆,过滤,滤饼放置于50℃下烘干,得到灰白色固体产品
42.3g,收率90%。HPLC显示纯度99.1%。LCMS[M+H]=271.0,NMR(DMSO-d6,400MHz):9.01(t,1H),8.54(s,2H),8.18(m,2H),7.75(t,1H),7.59(d,1H),7.29(d,1H),4.41(s,3H)。
实施例3:5-(2-氟-4-碘苯基)-2-(2-甲基-2H-四唑-5-基)吡啶的制备
在装有搅拌和温度计的三口烧瓶中加入3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯胺(30.0g,1eq)及醋酸(600mL)。室温搅拌溶解后,依次加入樟脑磺酸(30.9g,1.2eq),碘化钾(36.9g,2.0eq)及亚硝酸钠(9.2g,1.2eq),加完之后于室温下搅拌16小时。HPLC监控显示反应完全。减压蒸馏蒸出大部分醋酸,加入300mL水及500mL二氯甲烷,搅拌后分液,二氯甲烷层水洗后,减压蒸馏去除溶剂,得到棕黄色固体产品20.8g,收率49%。HPLC显示纯度96.7%。LCMS[M+H]=381.9,NMR(DMSO-d6,400MHz):8.85(s,1H),8.28(d,1H),8.01(d,1H),7.65(t,1H),7.56(dd,1H),7.19(d,1H),4.42(s,3H)。
实施例4:(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌和温度计的三口烧瓶中加入5-(2-氟-4-碘苯基)-2-(2-甲基-2H-四唑-5-基)吡啶(50.0g,1eq),(R)-5-(羟甲基)噁唑烷-2-酮(23.0g,1.5eq),环己二胺(1.5g,0.1eq),碘化亚铜(1.3g,0.05eq),碳酸钾(36.3g,2.0eq)及二氧六环(500mL),N2置换后,于100-110℃下搅拌反应16小时,
HPLC显示反应完全。减压蒸馏除去大部分溶剂,残留物加入1000mL水,加热回流1-2小时,冷却至70℃,抽滤,滤饼用DMF(150mL)打浆2小时,过滤,滤饼用水(300mL)重打浆,过滤,滤饼放置于65℃下烘干,得到灰白色固体产品38.5g,收率79.2%。HPLC显示纯度97.9%。LCMS[M+H]=371.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
实施例5:3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯酚的制备
在装有搅拌和温度计的三口烧瓶中加入2-(2-甲基-2H-四唑-5-基)-5-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)吡啶(25g,1eq),4-溴-3-氟苯酚(19.9g,1.2eq),Na2CO3(18.5g,2.0eq),水(120mL)及二氧六环(600mL),N2置换后,加入Pd(dppf)Cl2(0.75g,3%w/w),再次N2置换后,于70-80℃下搅拌反应12小时,HPLC监控显示反应完全。减压蒸馏去除大部分二氧六环,加入500mL水,室温搅拌2-3小时后,过滤,滤饼用异丙醇醇(70mL)打浆,过滤,滤饼放置于50℃下烘干,得到白色固体产品18.2g,收率77%。HPLC显示纯度99.5%。LCMS[M+H]=272.0,NMR(DMSO-d6,400MHz):10.20(s,1H),9.11(s,1H),8.54(d,1H),8.18(d,1H),7.75(t,1H),7.59(d,1H),7.29(d,1H),4.39(s,3H)。
实施例6:3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基三氟甲烷磺酸酯的制备
在装有搅拌和温度计的三口烧瓶中加入3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯酚(15g,1eq),三氟甲烷磺酸酐(23.4g,1.5eq),吡啶(6.6g,1.5eq),及四氢呋喃(150mL),N2置换后,加热回流搅拌反应5小时,HPLC监控显示反应完全。减压蒸馏去除大部分四氢呋喃,加入100mL乙酸乙酯及100mL水,室温搅拌后,分液,有机相干燥后,蒸馏去除溶剂,得到白色固体产品20.0g,收率90%。HPLC显示纯度96.3%。LCMS[M+H]=403.9,NMR(DMSO-d6,400MHz):9.12(s,1H),8.44(d,1H),8.08(d,1H),7.85(t,1H),7.67(d,1H),7.28(d,1H),4.33(s,3H)。
实施例7:(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌和温度计的三口烧瓶中加入3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基三氟甲烷磺酸酯(10.0g,1eq),(R)-5-(羟甲基)噁唑烷-2-酮(3.8g,1.3eq),Pd(dppf)Cl2(300mg,3%w/w),XantPhos(300mg,3%w/w),碳酸钾(6.9g,2.0eq)及二氧六环(80mL),N2置换后,于100-110℃下搅拌反应16小时,HPLC显示反应完全。减压蒸馏除去大部分溶剂,残留物加入100mL水,加热回流1-2小时,冷却至70℃,抽滤,滤饼用DMF(50mL)打浆2小时,过滤,滤饼用水(150mL)重打浆,过滤,滤饼放置于65℃下烘干,得到灰白色固体产品6.1g,收率66%。HPLC显示纯度96.9%。LCMS[M+H]=371.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
实施例8:磷酸泰地唑胺的制备
在装有搅拌和温度计的三口烧瓶中加入(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(10.0g,1eq)及四氢呋喃(200mL),N2置换后,冷却至0℃,滴加三乙胺(8.2g,3eq)。搅拌下控温0-10℃滴加三氯氧磷(12.4g,3eq),滴加完毕反应慢慢升至室温,反应20小时,HPLC显示反应完全。将反应液慢慢滴入100mL冰水中,搅拌过夜,过滤,50mL水洗后,得滤饼。滤饼于65℃下烘20小时得到白色固体粗品,粗品用40mL甲醇打浆,过滤,滤饼放置于65℃下烘干,得到白色固体纯品6.8g,收率56%。HPLC显示纯度99.7%。LCMS[M+H]=451.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
实施例9:3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)苯胺的制备
在装有搅拌和温度计的三口烧瓶中加入4-溴-3-氟苯胺(50.0g,1eq),频那醇硼酸酯(100.2g,1.5eq),醋酸钾(77.5g,3.0eq)及甲苯(500mL),N2置换后,加入Pd(dppf)Cl2(1.5g,3%w/w),再次N2置换后,于80-85℃下搅拌反应8小时,HPLC监控显示反应完全。反应液冷却至40-50℃,在此温度下抽滤,滤液加入10g活性炭,加热至70-80℃搅拌脱色1-2小时,冷却至40-50℃,在此温度下抽滤,滤液减压蒸馏至80-100mL,冷却至10-15℃,白色固体析出,过滤,滤饼放置于50℃下烘干,得到白色固体产品54g,收率87%。HPLC显示纯度为98.9%。LCMS[M+H]=238.1,NMR(DMSO-d6,
400MHz):7.51(d,1H),7.02(s,1H),6.87(d,1H),6.51(s,2H),1.25(s,12H)。
实施例10:3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯胺的制备
在装有搅拌和温度计的三口烧瓶中加入3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)苯胺(15g,1eq),5-溴-2-(2-甲基-2H-四唑-5-基)吡啶(18.2g,1.2eq),Na2CO3(13.4g,2.0eq),水(60mL)及二氧六环(300mL),N2置换后,加入Pd(dppf)Cl2(450mg,3%w/w),再次N2置换后,于70-80℃下搅拌反应12小时,HPLC监控显示反应完全。减压蒸馏去除大部分二氧六环,加入150mL水,室温搅拌2-3小时后,过滤,滤饼用乙醇(80mL)打浆,过滤,滤饼放置于50℃下烘干,得到灰白色固体产品14.8g,收率87%。HPLC显示纯度98.3%。LCMS[M+H]=271.0,NMR(DMSO-d6,400MHz):9.01(t,1H),8.54(s,2H),8.18(m,2H),7.75(t,1H),7.59(d,1H),7.29(d,1H),4.41(s,3H)。
实施例11:3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)苯酚的制备
在装有搅拌和温度计的三口烧瓶中加入4-溴-3-氟苯酚(30.0g,1eq),频那醇硼酸酯(59.8g,1.5eq),醋酸钾(46.3g,3.0eq)及甲苯(300mL),N2置换后,加入Pd(dppf)Cl2(0.9g,3%w/w),再次N2置换后,于80-85℃下搅拌反应8小时,HPLC监控显示反应完全。反应液冷却至40-50℃,在此温度下抽滤,滤液加入10g活性炭,加热至70-80℃搅拌脱色1-2小时,冷却至40-50℃,在此温度下抽滤,滤液减压蒸馏至60-80mL,冷却至0-10℃,白色固体析出,过滤,滤饼放置于50℃下烘干,得到白色固体产品29.8g,
收率80%。HPLC显示纯度为99.5%。LCMS[M+H]=239.0,NMR(DMSO-d6,400MHz):10.50(s,1H),7.65(d,1H),7.42(s,1H),7.01(d,1H),1.26(s,12H)。
实施例12:3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯酚的制备
在装有搅拌和温度计的三口烧瓶中加入3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代硼戊环-2-基)苯酚(18.0g,1eq),5-溴-2-(2-甲基-2H-四唑-5-基)吡啶(21.8g,1.2eq),Na2CO3(16.0g,2.0eq),水(54mL)及二氧六环(270mL),N2置换后,加入Pd(dppf)Cl2(540mg,3%w/w),再次N2置换后,于70-80℃下搅拌反应12小时,HPLC监控显示反应完全。减压蒸馏去除大部分二氧六环,加入300mL水,室温搅拌2-3小时后,过滤,滤饼用异丙醇醇(90mL)打浆,过滤,滤饼放置于50℃下烘干,得到白色固体产品16.0g,收率78%。HPLC显示纯度98.9%。LCMS[M+H]=272.0,NMR(DMSO-d6,400MHz):10.20(s,1H),9.11(s,1H),8.54(d,1H),8.18(d,1H),7.75(t,1H),7.59(d,1H),7.29(d,1H),4.39(s,3H)。
实施例13:(R)-2-((苄氧基)甲基)环氧乙烷的制备
在装有搅拌和温度计的三口烧瓶中加入苄醇(50g,1eq),氢氧化钾水溶液300mL(50%w/w),TBAB(14.9g,0.1eq)及二氯甲烷(300mL),冷却至0-10℃,缓慢滴加环氧氯丙烷(64.2g,1.5eq),滴加完毕,升至室温反应16小时,HPLC监控显示反应完全。停止搅拌,分液,水相用二氯甲烷300mL萃取一次,合并有机相,未经提纯直接用于下一步反应。
实施例14:(R)-1-氨基-3-(苄氧基)异丙醇的制备
在装有搅拌的氢化瓶中加入(R)-2-((苄氧基)甲基)环氧乙烷的二氯甲烷溶液及100mL氨水,密封后,加热至35℃,搅拌反应16小时,HPLC监控显示反应完全。停止搅拌,加入300mL水,搅拌后分液,有机相用0.1M的HCl溶液(100mL)洗涤,分去二氯甲烷,水相用NaOH调pH=9-10,二氯甲烷萃取(300mL),浓缩二氯甲烷得到无色液体产品55.0g,两步收率66%。HPLC显示纯度98.4%。LCMS[M+H]=182.0,NMR(DMSO-d6,400MHz):7.42-7.25(m,5H),5.11(s,2H),4.54(s,2H),3.68(m,1H),3.50-3.34(m,2H),3.12-3.06(br,1H),3.00-2.89(m,2H)。
实施例15:(R)-5-((苄氧基)甲基)噁唑烷-2-酮的制备
在装有搅拌的三口瓶中加入(R)-1-氨基-3-(苄氧基)异丙醇(20g,1eq)及四氢呋喃(200mL),加热至35℃,加入CDI(26.8g,1.5eq),保温搅拌反应16小时,HPLC监控显示反应完全。停止搅拌,浓缩四氢呋喃溶液后,加入乙酸乙酯200mL及1M盐酸100mL,搅拌后分液,有机相用水洗涤后,浓缩乙酸乙酯得到无色液体产品21.0g,收率92%。HPLC显示纯度99.0%。LCMS[M+H]=208.0,NMR(DMSO-d6,400MHz):8.05(s,1H),7.44-7.22(m,5H),4.56(s,2H),4.28-4.20(m,1H),3.77-3.69(m,1H),3.42-3.29(m,2H),3.11-3.06(m,1H)。
实施例16:(R)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌的三口瓶中加入(R)-5-((苄氧基)甲基)噁唑烷-2-酮(15g,1eq),四氢呋喃(150mL)及Pd/C(1.5g,10%w/w),氢气置换后,加热至45℃,保温搅拌反应3小时,HPLC监控显示反应完全。停止搅拌,过滤去
除Pd/C后,浓缩四氢呋喃得到无色油状产品8.4g,收率99%。HPLC显示纯度98.6%。LCMS[M+H]=117.9,NMR(DMSO-d6,400MHz):7.92(s,1H),4.68-4.60(m,1H),3.97-3.90(m,1H),3.70(br,1H),3.62-3.55(m,2H),3.11-3.06(m,1H)。
实施例17:(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌和温度计的三口烧瓶中加入5-(2-氟-4-碘苯基)-2-(2-甲基-2H-四唑-5-基)吡啶(50.0g,1eq),(R)-5-(羟甲基)噁唑烷-2-酮(23.0g,1.5eq),环己二胺(1.5g,0.1eq),硫酸铜(1.05g,0.05eq),碳酸钾(36.3g,2.0eq)及二氧六环(500mL),N2置换后,于100-110℃下搅拌反应16小时,HPLC显示反应完全。减压蒸馏除去大部分溶剂,残留物加入1000mL水,加热回流1-2小时,冷却至70℃,抽滤,滤饼用DMF(150mL)打浆2小时,过滤,滤饼用水(300mL)重打浆,过滤,滤饼放置于65℃下烘干,得到灰白色固体产品36.3g,收率74.7%。HPLC显示纯度98.3%。LCMS[M+H]=371.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
实施例18:(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌和温度计的三口烧瓶中加入5-(2-氟-4-碘苯基)-2-(2-甲基-2H-四唑-5-基)吡啶(50.0g,1eq),(R)-5-(羟甲基)噁唑烷-2-酮(23.0g,1.5eq),环己二胺(1.5g,0.1eq),Cu(OAc)2(1.19g,0.05eq),碳酸钾(36.3g,2.0eq)及二氧六环(500mL),N2置换后,于100-110℃下搅拌反应16小时,HPLC显示反应完全。减压蒸馏除去大部分溶剂,残留物加入1000mL水,加热回流1-2小时,冷却至70℃,抽滤,滤饼用DMF(150mL)打浆2小时,过滤,滤饼用水(300mL)重打浆,过滤,滤饼放置于65℃下烘干,得到灰白色固体产品39.9g,收率82.1%。HPLC显示纯度97.8%。LCMS[M+H]=371.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
实施例19:(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌和温度计的三口烧瓶中加入5-(2-氟-4-碘苯基)-2-(2-甲基-2H-四唑-5-基)吡啶(50.0g,1eq),(R)-5-(羟甲基)噁唑烷-2-酮(23.0g,1.5eq),环己二胺(1.5g,0.1eq),三(二亚苄基丙酮)二钯(1.5g,3%w/w),碳酸钾(36.3g,2.0eq)及二氧六环(500mL),N2置换后,于100-110℃下搅拌反应16小时,HPLC显示反应完全。减压蒸馏除去大部分溶剂,残留物加入1000mL水,加热回流1-2小时,冷却至70℃,抽滤,滤饼用DMF(150mL)打浆2小时,过滤,滤饼用水(300mL)重打浆,过滤,滤饼放置于65℃下
烘干,得到灰白色固体产品36.7g,收率75.5%。HPLC显示纯度98.0%。LCMS[M+H]=371.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
实施例20:(R)-3-(3-氟-4-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
在装有搅拌和温度计的三口烧瓶中加入5-(2-氟-4-碘苯基)-2-(2-甲基-2H-四唑-5-基)吡啶(50.0g,1eq),(R)-5-(羟甲基)噁唑烷-2-酮(23.0g,1.5eq),环己二胺(1.5g,0.1eq),碘化亚铜(1.3g,0.05eq),碳酸钾(36.3g,2.0eq)及DMF(500mL),N2置换后,于100-110℃下搅拌反应16小时,HPLC显示反应完全。减压蒸馏除去大部分溶剂,残留物加入1000mL水,加热回流1-2小时,冷却至70℃,抽滤,滤饼用DMF(150mL)打浆2小时,过滤,滤饼用水(300mL)重打浆,过滤,滤饼放置于65℃下烘干,得到灰白色固体产品36.9g,收率76.0%。HPLC显示纯度99.5%。LCMS[M+H]=371.1,NMR(DMSO-d6,400MHz):8.95(s,1H),8.24(d,1H),8.10(d,1H),7.78(t,1H),7.45(dd,1H),7.10(d,1H),4.62(m,1H),4.42(s,3H),3.84(m,1H),3.42-3.35(m,2H),3.01(m,1H)。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明保护的范围之内。
Claims (10)
- 根据权利要求1所述的制备方法,其特征在于:所述金属催化剂为铜催化剂或钯催化剂;其中,铜催化剂优选选自CuI、CuBr、CuCl、CuO、Cu2O、 CuSO4、Cu(OAc)2、Cu(OTf)2或Cu粉,更优选CuI或Cu(OAc)2;钯催化剂优选选自氯化钯、醋酸钯、双(二亚苄基丙酮)钯、四(三苯基膦)钯、三(二亚苄基丙酮)二钯、[1,1’-双(二苯基磷)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,更优选三(二亚苄基丙酮)二钯、氯化钯或醋酸钯。
- 根据权利要求1或2所述的制备方法,其特征在于:所述偶联反应在碱性物质作为促进剂作用下反应;所述碱性物质优选选自碳酸钾、碳酸钠、碳酸铯、氟化铯、醋酸钾、氢氧化钠、氢氧化钾、磷酸钾或磷酸钠。
- 根据权利要求1-3中任一项所述的制备方法,其特征在于:所述偶联反应的反应溶剂为甲苯、氯苯、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氧六环、异丙醇、乙醇或乙腈,优选N,N-二甲基甲酰胺或二氧六环;反应温度为60-110℃,优选90-110℃。
- 一种下式化合物的制备方法,其中X为离去基团,所述离去基团包括氯、溴、碘,磺酰氧基如三氟甲磺氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组;包括将具有下式结构的化合物其中,C为羟基或氨基;1)当C为羟基时,与磺酰氯类化合物反应生成具有下式结构的化合物:其中X为离去基团,所述离去基团为磺酰氧基如三氟甲磺氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组;或2)当C为氨基时,在亚硝酸钠存在下反应生成重氮盐化合物,再经卤素离子取代形成具有下式结构的化合物:其中X为离去基团,所述离去基团包括氯、溴、碘。
- 一种下式化合物的制备方法,包括将具有下式结构的化合物与具有下式结构的化合物在钯催化剂催化下偶联反应生成,其中,C为羟基或氨基;A和B中一个为离去基团,另一个为BF3或BR2R3,其中R2和R3独立的选自由OH和C1-C6一元和二元醇或卤素取代的C1-C6一元和二元醇组成的组,其中R2和R3可以成环;优选B为离去基团,A为BF3或BR2R3,其中R2和R3独立的选自由OH和C1-C6一元和二元醇或卤素取代的C1-C6一元和二元醇组成的组,其中R2和R3可以成环;或优选A为离去基团,B为BF3或BR2R3,其中R2和R3独立的选自由OH和C1-C6一元和二元醇或卤素取代的C1-C6一元和二元醇组成的组,其中R2和R3可以成环;所述离去基团包括卤素如氯、溴、碘,磺酰氧基如三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基,或被一个或多个取代基取代的苯磺酰氧基,所述取代基选自卤素、C1-C6烷基和C1-C6烷氧基组成的组;优选离去基团为氯、溴、碘,更优选离去基团为溴或碘;
- 根据权利要求7所述的制备方法,其特征在于:所述钯催化剂为氯化钯、醋酸钯、双(二亚苄基丙酮)钯、四(三苯基膦)钯、[1,1’-双(二苯基磷)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。
- 根据权利要求7或8所述的制备方法,其特征在于:所述偶联反应的反应溶剂为水、甲苯、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氧六环、异丙醇、乙醇或乙腈中的一种或其任意组合,优选为甲苯、水和二氧六环、或异丙醇;反应温度为50-120℃,优选70-100℃。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004056818A1 (en) * | 2002-12-19 | 2004-07-08 | Astrazeneca Ab | Oxazolidinone derivatives as antibacterial |
WO2005058886A1 (en) * | 2003-12-18 | 2005-06-30 | Dong-A Pharm.Co.,Ltd. | Novel oxazolidinone derivatives |
WO2010042887A2 (en) * | 2008-10-10 | 2010-04-15 | Trius Therapeutics | Methods for preparing oxazolidinones and compositions containing them |
CN104327119A (zh) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | 磷酸泰地唑胺的制备方法 |
CN104496979A (zh) * | 2014-09-17 | 2015-04-08 | 博瑞生物医药技术(苏州)有限公司 | 一种噁唑烷酮类化合物及其中间体的制备方法 |
CN104892592A (zh) * | 2015-03-30 | 2015-09-09 | 成都惟新医药科技有限公司 | 一种泰地唑胺的制备方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6403804B1 (en) * | 1998-12-07 | 2002-06-11 | Takasago International Corporation | Process for preparing optically active oxazolidinone derivative |
US7910747B2 (en) * | 2006-07-06 | 2011-03-22 | Bristol-Myers Squibb Company | Phosphonate and phosphinate pyrazolylamide glucokinase activators |
CN102850288A (zh) * | 2011-06-28 | 2013-01-02 | 袁建勇 | 一种利奈唑胺的制备方法 |
US8889671B2 (en) * | 2013-01-23 | 2014-11-18 | Astrazeneca Ab | Compounds and methods for treating bacterial infections |
CN103304594B (zh) * | 2013-06-18 | 2015-07-08 | 上海科利生物医药有限公司 | 一种L-α-甘油磷酸胆碱的制备方法 |
-
2015
- 2015-11-03 CN CN201510739910.6A patent/CN106632298B/zh active Active
-
2016
- 2016-11-02 US US15/772,521 patent/US10385079B2/en active Active
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- 2016-11-02 WO PCT/CN2016/104360 patent/WO2017076293A1/zh active Application Filing
- 2016-11-02 US US15/771,449 patent/US10590154B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004056818A1 (en) * | 2002-12-19 | 2004-07-08 | Astrazeneca Ab | Oxazolidinone derivatives as antibacterial |
WO2005058886A1 (en) * | 2003-12-18 | 2005-06-30 | Dong-A Pharm.Co.,Ltd. | Novel oxazolidinone derivatives |
WO2010042887A2 (en) * | 2008-10-10 | 2010-04-15 | Trius Therapeutics | Methods for preparing oxazolidinones and compositions containing them |
CN104496979A (zh) * | 2014-09-17 | 2015-04-08 | 博瑞生物医药技术(苏州)有限公司 | 一种噁唑烷酮类化合物及其中间体的制备方法 |
CN104327119A (zh) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | 磷酸泰地唑胺的制备方法 |
CN104892592A (zh) * | 2015-03-30 | 2015-09-09 | 成都惟新医药科技有限公司 | 一种泰地唑胺的制备方法 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3372596A4 * |
Cited By (2)
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 |
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