CN116478090A - 一种替沃扎尼关键中间体的制备方法 - Google Patents
一种替沃扎尼关键中间体的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 title description 17
- 229960000940 tivozanib Drugs 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000012442 inert solvent Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
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- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- 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 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 7
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000001119 stannous chloride Substances 0.000 claims description 7
- 235000011150 stannous chloride Nutrition 0.000 claims description 7
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000012445 acidic reagent Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- -1 2-chloro-4- ((6, 7-dimethoxy quinoline-4-yl) oxy) -nitrobenzene Chemical compound 0.000 abstract description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 9
- MSAYDMJFSCQXQL-UHFFFAOYSA-N 2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyaniline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C(Cl)=C1 MSAYDMJFSCQXQL-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005755 formation reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- DKTRZBWXGOPYIX-UHFFFAOYSA-N 3-chloro-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C(Cl)=C1 DKTRZBWXGOPYIX-UHFFFAOYSA-N 0.000 abstract description 3
- WRVHQEYBCDPZEU-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinoline Chemical compound C1=CC(Cl)=C2C=C(OC)C(OC)=CC2=N1 WRVHQEYBCDPZEU-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RQXMKRRBJITKRN-UHFFFAOYSA-N 1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea;hydrate;hydrochloride Chemical compound O.Cl.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 RQXMKRRBJITKRN-UHFFFAOYSA-N 0.000 description 8
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 229960003787 sorafenib Drugs 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
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- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 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
- 229940124674 VEGF-R inhibitor Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940125449 fotivda Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/88—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/247—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种替沃扎尼关键中间体式Ⅰ化合物2‑氯‑4‑((6,7‑二甲氧基喹啉‑4‑基)氧)‑苯胺的制备方法,以式Ⅵ化合物4‑氯‑6,7‑二甲氧基喹啉和式III化合物3‑氯‑4‑硝基苯酚为原料,经过威廉姆森成醚反应得到式Ⅱ化合物2‑氯‑4‑((6,7‑二甲氧基喹啉‑4‑基)氧)‑硝基苯,再经还原反应得到式Ⅰ化合物2‑氯‑4‑((6,7‑二甲氧基喹啉‑4‑基)氧)‑苯胺。该方法反应活性强,原料易得成本低廉,反应条件温和,产品易纯化,且收率高,适宜工业化大生产。
Description
技术领域
本发明属于药物化学领域,具体涉及一种替沃扎尼关键中间体的制备方法。
背景技术
替沃扎尼,即化学名为N-[2-氯-4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基]-N'-(5-甲基-3-异恶唑基)脲,是一种有效的,选择性VEGFR抑制剂,作用于VEGFR1/2/3时,IC50分别为0.21nM/0.16nM/0Chemicalbook.24nM,也抑制PDGFR和c-Kit,作用于FGFR-1,Flt3,c-MetEGFR和IGF-1R活性较弱。由AVEO Oncology研发,FDA已于2021年3月批准了Tivozanib(Fotivda,盐酸替沃扎尼胶囊)的新药申请(NDA),用于治疗复发/难治性肾细胞癌(RCC)。基于TIVO-3第三阶段试验的数据,与索拉非尼(Nexavar)相比,Tivozanib(盐酸替沃扎尼胶囊)在高复发/难治性转移性肾细胞癌患者的无进展生存期(PFS)有显著改善,且总生存期(OS)相似。结果表明,OS(总生存期)的最终危险比(HR)为0.97。此外,对Tivozanib(盐酸替沃扎尼胶囊)和索拉非尼的中位随访时间分别为38个月和40个月,盐酸替沃扎尼胶囊的中位总生存期为16.4个月,索拉非尼的中位总生存期为19.2个月。
TIVO-3研究是一项对照、多中心、开放标签的III期临床试验,随机选取350名高度难治性转移性肾细胞癌患者,这些患者之前接受2种方案(包括VEGF-TKI治疗)均失败,以1:1的比例接受盐酸替沃扎尼胶囊或索拉非尼治疗(不允许双臂交叉治疗)。
部分缓解:Tivozanib组18%,索拉非尼组8%
客观缓解率:Tivozanib组34%,索拉非尼组24%
与索拉非尼相比,Tivozanib(盐酸替沃扎尼胶囊)的治疗普遍耐受性良好,安全性也较好。接受Tivozanib(盐酸替沃扎尼胶囊)治疗的84%(n=146)的患者和接受索拉非尼治疗的94%(n=160)的患者报告了治疗相关不良事件(TRAEs)。两组患者中,最常见的3级或4级不良事件是高血压。与接受Tivozanib(盐酸替沃扎尼胶囊)治疗相关的、最常见的不良事件为高血压(38%)、腹泻(33%)、疲劳(29%)和食欲下降(27%)。
由上可见,替沃扎尼是一款非常有效的治疗肾细胞癌的治疗药物。
专利EP1559715所述的合成替沃扎尼方法如下:
CN106967058中公开的合成替沃扎尼的方法,路线如下:
文献Heterocycles,2016,vol.92,#10,p.1882-1887中披露的方法路线如下:
比较以上三种方法可知,式Ⅰ化合物是合成替沃扎尼难以绕过的关键中间体,因而式Ⅰ化合物的制备方法,对于替沃扎尼的合成尤为重要。
WO2021/150792披露了如下路线:
由于原料中氨基是给电子基团,且氨基氢较为活泼,后续对接反应比较困难杂质较多,并且反应中需要用到叔丁醇钾等强碱,反应条件较为苛刻,不利于工业化生产。
为了解决现在制备方法存在的问题,急需一种新的制备方法来代替现有方法。
发明内容
本发明提供了一种原料易得,成本低廉,反应条件温和,产品易纯化,且收率高,适宜工业化大生产的制备式I化合物2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺的方法。
本发明第一方面,提供一种式Ⅰ化合物的制备方法,包括步骤:
s1)在惰性溶剂中,碱存在下,式Ⅲ化合物与式Ⅵ化合物发生反应,得到式Ⅱ化合物;所述反应的温度为40-80℃;
s2)在惰性溶剂中,催化剂存在下,式Ⅱ化合物与还原剂反应,得到式Ⅰ化合物。
在另一优选例中,步骤s1)中,所述碱为无机碱,且所述碱选自:氢氧化钠、氢氧化钾、钠氢、氨基钠、碳酸钾、碳酸钠,或其组合,优选地为氢氧化钠、氢氧化钾、碳酸钾、碳酸钠,或其组合。
在另一优选例中,步骤s1)中,惰性溶剂选自:N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、二甲亚砜、乙腈、四氢呋喃,或其组合。
在另一优选例中,步骤s1)中,所述式Ⅵ化合物与式Ⅲ化合物的摩尔比为1:0.8-2,较佳地,1:0.9-1.6,更佳地,1:1-1.5。
在另一优选例中,步骤s1)中,所述反应的温度为60-80℃,较佳地,50-70℃。
在另一优选例中,步骤s1)具有以下一个或多个特征:
所述反应的温度为40-80℃,较佳地,60-80℃,较佳地,50-70℃;
所述反应的时间为0.5-5h,较佳地,0.5-4h,更佳地,3-4h。
在另一优选例中,步骤s1)中,惰性溶剂为丙酮,碱为碳酸钾。
在另一优选例中,步骤s1)中,惰性溶剂为N,N-二甲基甲酰胺,碱为氢氧化钠。
在另一优选例中,步骤s2)中,还原剂为H2。
在另一优选例中,步骤s2)中,所述催化剂选自下组:钯碳、雷尼镍、二氧化铂,还原剂为H2。
在另一优选例中,步骤s2)中,还原剂为金属试剂,优选地为铁粉、锌粉、氯化亚锡。
在另一优选例中,步骤s2)中,催化试剂为酸性试剂,优选地为盐酸、醋酸、氯化铵水溶液。
在另一优选例中,步骤s2)中,所述酸性试剂和金属试剂的组合选自:盐酸和铁粉、盐酸和锌粉、醋酸和铁粉、氯化铵水溶液和铁粉、盐酸和氯化亚锡。
在另一优选例中,步骤s2)中,还原剂为H2,所述反应在高压釜中并带有一定压力下进行。
在另一优选例中,步骤s2)中,惰性溶剂选自:四氢呋喃、2-甲基四氢呋喃、乙醇、甲醇、异丙醇,或其组合。
在另一优选例中,步骤s2)中,惰性溶剂为四氢呋喃,催化剂为二氧化铂,还原剂为H2,所述反应在高压釜中并带有一定压力下进行。
在另一优选例中,步骤s2)中,惰性溶剂为四氢呋喃,催化剂为浓盐酸,还原剂为氯化亚锡。
在另一优选例中,步骤s2)具有以下一个或多个特征:
所述反应的温度为40-80℃,较佳地,60-80℃,较佳地,50-70℃,较佳地,45-55℃;
所述反应的时间为2-8h,较佳地,3-6h,更佳地,3-4h。
本发明第二方面,提供一种式Ⅱ化合物的制备方法,其中,所述方法包括步骤:
s1)在惰性溶剂中,碱存在下,式Ⅲ化合物与式Ⅵ化合物发生反应,得到式Ⅱ化合物。
本发明第三方面,提供一种式Ⅰ化合物的制备方法,其中,所述方法包括步骤:
s2)在惰性溶剂中,催化剂存在下,式Ⅱ化合物与还原剂反应,得到式Ⅰ化合物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
发明人经过广泛而深入的研究,通过大量筛选和测试,开发了一种利用式Ⅵ化合物4-氯-6,7-二甲氧基喹啉和式III化合物3-氯-4-硝基苯酚为原料,经过威廉姆森成醚反应得到式Ⅱ化合物2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-硝基苯,再经还原反应得到式Ⅰ化合物2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺的新方法。本发明的本发明提供了一种原料易得,成本低廉,反应条件温和,产品易纯化,且收率高,适宜工业化大生产。
术语
本发明中,“惰性溶剂”是指不与反应底物发生反应的试剂。
式I化合物的制备方法
本发明提供了式I化合物的制备方法,优选地,所述方法包括如下步骤
方法1
(ii)在第二溶剂中,在催化剂作用下,式Ⅱ化合物与氢气反应生成式Ⅰ化合物;
所述第二溶剂选自:四氢呋喃、2-甲基四氢呋喃、乙醇、甲醇、异丙醇,或其组合;
所述催化剂选自下组:钯碳、雷尼镍、二氧化铂;
所述催化剂催化下的氢化反应应当在高压釜中并带有一定压力下进行;
优选地,所使用的溶剂为四氢呋喃,二氧化铂作为催化剂。
方法2
(ii’)在第二溶剂中,使用金属试剂和酸性试剂的组合物,与式Ⅱ化合物反应生成式Ⅰ化合物;
所述第二溶剂同样选自四氢呋喃、2-甲基四氢呋喃、乙醇、甲醇、异丙醇,或其组合;
所述酸性试剂和金属试剂的组合可以为:盐酸和铁粉、盐酸和锌粉、醋酸和铁粉、氯化铵水溶液和铁粉、盐酸和氯化亚锡。
优选地,所述方法还包括步骤:
(i)在第一溶剂中,在强碱性试剂作用下,式Ⅲ化合物与式Ⅵ化合物发生威廉姆森成醚反应,得到式Ⅱ化合物;
其中所述强碱性试剂包括但不限于:氢氧化钠、氢氧化钾、钠氢、氨基钠、碳酸钾、碳酸钠,或其组合;
所述第一溶剂包括但不限于:N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、二甲亚砜、乙腈、四氢呋喃,或其组合;
所述式Ⅵ化合物与式Ⅲ化合物的摩尔比为1:0.8-2,较佳地,1:0.9-1.6,更佳地,1:1-1.5。
所述威廉姆森成醚反应具有以下一个或多个特征:
所述反应的温度为40-80℃,较佳地,60-80℃,较佳地,50-70℃;
所述反应的时间为0.5-5h,较佳地,0.5-4h,更佳地,3-4h;
优选地,使用丙酮作为反应溶剂,碳酸钾作为反应用碱性试剂。
优选地,采用N,N-二甲基甲酰胺作为反应溶剂,氢氧化钠作为反应用碱。
本发明的主要优点包括:
(1)本发明通过巧妙的设计更改了工艺中反应顺序,极大的提高了威廉姆森成醚的效率和收率。
(2)本发明尽可能的使用原有工艺中原料,减少了更换原料导致的工艺开发工作量。
(3)本发明步骤一由于对接的是硝基化合物,减少了反应位点,而且由于硝基的吸电子特性,提高了成醚成功率,进而提高了产物纯度。
(4)本发明成本低适宜工业化大生产。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
试剂
4-氯-6,7-二甲氧基喹啉可购自上海环孚实业有限公司
3-氯-4-硝基苯酚可购自上海毕得医药有限公司
实施例1 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-硝基苯(Ⅱ)的制备
向1L反应瓶加入19.0g(0.11mol)化合物Ⅲ和190mlN,N-二甲基甲酰胺,搅拌分批加入4.4g(0.11mol)氢氧化钠,控温0-10℃,加毕搅拌0.5小时,滴加入溶有22.3g(0.1mol)化合物Ⅵ的N,N-二甲基甲酰胺溶液100ml,升温到75-85℃,反应6小时。取样检测化合物Ⅵ消耗完毕降温至室温,浓缩所得反应液,浓缩近干,加入200ml乙酸乙酯和200ml水,搅拌分液,乙酸乙酯层水洗两次,每次100ml,乙酸乙酯层减压浓缩至干。所得残余物加入乙醇重结晶,得到黄色固体31.2g,摩尔收率90%。
MS(m/z):348(M+H)。
实施例2 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-硝基苯(Ⅱ)的制备
向500ml反应瓶加入19.0g(0.11mol)化合物Ⅲ和190ml丙酮,加入20.7g(0.11mol)碳酸钾,加入22.3g(0.1mol)化合物Ⅵ,升温到55℃,回流反应8小时。取样检测化合物Ⅵ消耗完毕降温至室温,过滤所得反应液,浓缩干。所得残余物加入乙醇重结晶,过滤,干燥得到黄色固体30.5g,摩尔收率88%。
MS(m/z):348(M+H)。
实施例3 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺(Ⅰ)的制备
向2L高压釜中加入34.7g(0.1mol)化合物Ⅱ2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-硝基苯和400ml四氢呋喃,搅拌加入0.45g(0.002mol)二氧化铂,氢气置换空气,加压至0.3MPa(3个大气压),升温到45-55℃,反应4小时,观察无明显吸气现象,取样检测,化合物Ⅱ消耗完毕。降温至室温,过滤所得反应液,母液浓缩干,加200ml水,搅拌过滤,再以200ml水洗一次,真空烘干,得到棕色固体31.4g,摩尔收率95%。
MS(m/z):331.12(M+H).1HNMR(400MHz,DMSO)δ:3.93(d,6H),5.42(s,2H),6.42(d,1H),6.91(d,1H),6.98-7.04(m,1H),7.20-7.21(m,1H),7.37(s,1H),7.48(s,1H),8.45(d,1H).
实施例4 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺(Ⅰ)的制备
向1L反应瓶中加34.7g(0.1mol)化合物Ⅱ2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-硝基苯和300ml乙醇,加入66.4g(0.35mol)氯化亚锡,搅拌升温至60℃,滴加67ml(0.8mol)浓盐酸,升到回流反应3小时,取样检测,化合物Ⅱ消耗完毕。降温,4N氢氧化钠溶液调节pH至9,过滤,所得反应液浓缩,水洗,真空烘干,得到褐色固体28.1g,摩尔收率85%。
MS(m/z):331.12(M+H).1HNMR(400MHz,DMSO)δ:3.93(d,6H),5.42(s,2H),6.42(d,1H),6.91(d,1H),6.98-7.04(m,1H),7.20-7.21(m,1H),7.37(s,1H),7.48(s,1H),8.45(d,1H).
对比例1 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺(Ⅰ)的制备
250ml反应瓶中加入4.5g(31.4mmol)4-氨基-3-氯苯酚,二甲亚砜50ml,搅拌加入1.26g钠氢(60%),控温10-25℃,搅拌0.5小时,加入5g(22.4mmol)化合物Ⅵ,搅拌升温至100℃,反应9小时,冷至15-20℃,将反应液倾入100ml冰水中,控温15-30℃,加入乙酸乙酯20ml,过滤所得混合物,固体再以10ml乙酸乙酯洗一次,真空烘干,得到5.18g化合物Ⅰ,摩尔收率70%。
对比例2 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺(Ⅰ)的制备
500ml反应瓶中加入22.4g(0.1mol)化合物Ⅵ,300mlN,N-二甲基甲酰胺,17.2g(0.12mol)4-氨基-3-氯苯酚,13.5g(0.12mol)叔丁醇钾,升温到120℃反应8小时,冷至室温,加500ml水,800ml*3二氯甲烷萃取,有机相用300ml*2水洗涤,再用盐水300ml洗涤。二氯甲烷干燥,柱层析纯化得到25.6g产物,收率77.6%。
对比例3 2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺(Ⅰ)的制备
向250ml反应瓶中加入4.74g(0.033mol)4-氨基-3-氯苯酚和70ml二甲亚砜,再加入2.64g(0.066mol)钠氢,搅拌15分钟,加入6.71g(0.03mol)式Ⅵ化合物,升温到160℃搅拌2小时,冷至室温,加入200ml水,600ml乙酸乙酯萃取。有机相以600ml*3盐水洗涤,有机相无水硫酸钠干燥,减压旋蒸,柱层析纯化,得到4.8g,收率48%。
综上,本发明原料易得,成本低廉,反应条件温和,产品易纯化,且收率高,是适宜工业化大生产的制备化合物2-氯-4-((6,7-二甲氧基喹啉-4-基)氧)-苯胺的方法。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式Ⅰ化合物的制备方法,其特征在于,包括步骤:
s1)在惰性溶剂中,碱存在下,式Ⅲ化合物与式Ⅵ化合物发生反应,得到式Ⅱ化合物;所述反应的温度为40-80℃;
s2)在惰性溶剂中,催化剂存在下,式Ⅱ化合物与还原剂反应,得到式Ⅰ化合物。
2.如权利要求1所述的方法,其特征在于,步骤s1)中,所述碱为无机碱,且所述碱选自:氢氧化钠、氢氧化钾、钠氢、氨基钠、碳酸钾、碳酸钠,或其组合,优选地为氢氧化钠、氢氧化钾、碳酸钾、碳酸钠,或其组合。
3.如权利要求1所述的方法,其特征在于,步骤s1)中,惰性溶剂选自:N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、二甲亚砜、乙腈、四氢呋喃,或其组合。
4.如权利要求1所述的方法,其特征在于,步骤s1)中,所述反应的温度为60-80℃,较佳地,50-70℃。
5.如权利要求1所述的方法,其特征在于,步骤s2)中,所述催化剂选自下组:钯碳、雷尼镍、二氧化铂,还原剂为H2。
6.如权利要求1所述的方法,其特征在于,步骤s2)中,还原剂为金属试剂,优选地为铁粉、锌粉、氯化亚锡。
7.如权利要求6所述的方法,其特征在于,步骤s2)中,催化试剂为酸性试剂,优选地为盐酸、醋酸、氯化铵水溶液。
8.如权利要求7所述的方法,其特征在于,步骤s2)中,所述酸性试剂和金属试剂的组合选自:盐酸和铁粉、盐酸和锌粉、醋酸和铁粉、氯化铵水溶液和铁粉、盐酸和氯化亚锡。
9.一种式Ⅱ化合物的制备方法,其特征在于,所述方法包括步骤:
s1)在惰性溶剂中,碱存在下,式Ⅲ化合物与式Ⅵ化合物发生反应,得到式Ⅱ化合物。
10.一种式Ⅰ化合物的制备方法,其特征在于,所述方法包括步骤:
s2)在惰性溶剂中,催化剂存在下,式Ⅱ化合物与还原剂反应,得到式Ⅰ化合物。
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