CN103570754A - Preparation method of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N'-(2-fluoro-5-methylphenyl) urea and intermediate thereof - Google Patents
Preparation method of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N'-(2-fluoro-5-methylphenyl) urea and intermediate thereof Download PDFInfo
- Publication number
- CN103570754A CN103570754A CN201210279813.XA CN201210279813A CN103570754A CN 103570754 A CN103570754 A CN 103570754A CN 201210279813 A CN201210279813 A CN 201210279813A CN 103570754 A CN103570754 A CN 103570754A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- phenyl
- acid ester
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- -1 borate ester compound Chemical class 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 229910052796 boron Inorganic materials 0.000 claims abstract description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 33
- 239000003513 alkali Substances 0.000 claims description 32
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 25
- 241000790917 Dioxys <bee> Species 0.000 claims description 23
- 239000004327 boric acid Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910000085 borane Inorganic materials 0.000 claims description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 14
- 239000004202 carbamide Substances 0.000 claims description 14
- 229910052763 palladium Inorganic materials 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- WGLLSSPDPJPLOR-UHFFFAOYSA-N tetramethylethylene Natural products CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 claims description 8
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 150000001638 boron Chemical class 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 229960004249 sodium acetate Drugs 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 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 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000004408 titanium dioxide Substances 0.000 claims description 4
- 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 description 4
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 62
- 239000002994 raw material Substances 0.000 abstract description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000010792 warming Methods 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MMSPHSKLNXQAOH-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.B(O)(O)O.NC1=CC=CC=C1 Chemical compound OC(C)(C)C(C)(C)O.B(O)(O)O.NC1=CC=CC=C1 MMSPHSKLNXQAOH-UHFFFAOYSA-N 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- NUPSHWCALHZGOV-UHFFFAOYSA-N Decyl acetate Chemical compound CCCCCCCCCCOC(C)=O NUPSHWCALHZGOV-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- AOGQPLXWSUTHQB-UHFFFAOYSA-N hexyl acetate Chemical compound CCCCCCOC(C)=O AOGQPLXWSUTHQB-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 229950002216 linifanib Drugs 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical compound CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 description 1
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 description 1
- JTXMVXSTHSMVQF-UHFFFAOYSA-N 2-acetyloxyethyl acetate Chemical compound CC(=O)OCCOC(C)=O JTXMVXSTHSMVQF-UHFFFAOYSA-N 0.000 description 1
- BLNVISNJTIRAHF-UHFFFAOYSA-N 4-chlorobenzamide Chemical compound NC(=O)C1=CC=C(Cl)C=C1 BLNVISNJTIRAHF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- ZCZSIDMEHXZRLG-UHFFFAOYSA-N acetic acid heptyl ester Natural products CCCCCCCOC(C)=O ZCZSIDMEHXZRLG-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- JPXGPRBLTIYFQG-UHFFFAOYSA-N heptan-4-yl acetate Chemical compound CCCC(CCC)OC(C)=O JPXGPRBLTIYFQG-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
Abstract
The invention provides a preparation method of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N'-(2-fluoro-5-methylphenyl) urea and an intermediate thereof. Specifically, the invention provides a preparation method of a borate ester compound as shown in a formula I, and the preparation method comprises the following steps: enabling a compound as shown in a formula III to react with a compound as shown in a formula IV to generate a compound as shown in a formula V, and enabling the compound as shown in the formula V to react with a boron reagent to generate the compound as shown in the formula I. The method has the characteristics of convenience in reaction, easiness in obtainment of the intermediate, high yield, high product purity of above 98.5%, low cost of raw materials and the like, and is suitable for industrial application.
Description
Technical field
The invention belongs to the synthetic field of medicine, particularly, the present invention relates to the preparation method of a kind of N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea and intermediate boric acid ester compound thereof.
Background technology
Vasculogenesis is the physiological process that capillary vessel grows out from already present blood vessel network, nutrition supply in the time of can meeting tissue generation, for the maintaining or grow most importantly of tumour, therefore, angiogenesis inhibitor is considered to the effective means of cancer therapy.The receptor tyrosine kinase of blood vessel endothelium albumen (RTK) has vital role in angiogenesis, can be used as antitumour drug action target spot.
Abbott has developed a series of RTK inhibitor (WO2004113304A1), comprise indazole, benzoisoxazole and benzisothiazole kinase inhibitors, they can suppress all vascular endothelial growth factor receptors (VEGFR) and PDGF acceptor (PDGFR) family's Tyrosylprotein kinase (TK) activity in the horizontal specificity of nmole, wherein, N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea is exactly to have one of candidate compound of DEVELOPMENT PROSPECT most.
N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea (Linifanib, ABT-869) structural formula is:
Preclinical study result shows, its anti-tumor activity is remarkable, in different animals, all show good pharmacokinetics character, carrying out at present the multinomial clinical trial of this product, to evaluate it to Several Kinds of Malignancy, comprise the curative effect of kidney, liver cancer, colorectal cancer, mammary cancer, nonsmall-cell lung cancer and acute myeloid leukemia.
2009, Albert W.Kruger etc., at document Org.Pro.Res.Dev.2009, disclosed following synthetic route in 13,1419-1425:
In this route, obtain midbody compound 4 (be the present invention will be synthetic one of compound---formula VI compound) raw material 4-amino-benzene boric acid pinacol ester 2 used and the fluoro-5-methyl of isocyanic acid 2-phenyl ester 3 expensive and be not easy to obtain, raw materials cost is high, is not suitable for suitability for industrialized production.
In order to solve the problem of raw material 4-amino-benzene boric acid pinacol ester, bang dragon is waited the pharmaceutical chemistry magazine > > in < < China, 22 (1), 26-28,2012.In document, reported the route of following synthetic ABT-869:
Above-mentioned route is synthetic 4-amino-benzene boric acid pinacol ester voluntarily, but will experience 5 step reactions, and route is long.The yield that obtains intermediate 4 only has 38% left and right, so be not suitable for equally suitability for industrialized production.
In sum, efficient preparation N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of the 2-) urea of low in the urgent need to cost of development, the applicable suitability for industrialized production in this area and the technique of similar compound.
Summary of the invention
Object of the present invention is just to provide a kind of method of preparing N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea (ABT-869) and intermediate thereof of novelty, and this technique has solved prior art because of expensive raw material price or route is long, yield is low causes the problem that production cost is high.
A first aspect of the present invention provides a kind of preparation method of formula I compound, and the method comprises the following steps:
1) under alkali exists, formula III compound reacts with formula IV compound, forms formula V compound;
2) under the existence of alkali and palladium catalyst, formula V compound reacts with borane reagent, forms formula I compound;
Above-mentioned various in,
R1 is one or more (as 1,2,3, the 4 or 5) substituting group that is positioned at optional position on phenyl ring, and each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group;
R2 and R3 are hydroxyl or C independently
1-6alkoxyl group, C
1-6acyloxy, or R2 and R3 jointly form and replace or unsubstituted C
1-8alkane dioxy base, C
6-10virtue dioxy base, or C
1-8cycloalkanes dioxy base; Wherein said replacement is to have one or more (as 1-5 or 1-3) to be selected from the substituting group of lower group: C
1-6alkyl, halogen, phenyl, benzyl ,-CH
2-, C
1-6alkoxyl group, C
1-6acyl group, C
1-6acyloxy, C
1-6carbalkoxy;
R4 is selected from lower group: H, F, Cl, Br, I.
In another preference, R2 and R3 are hydroxyl or C independently
1-4alkoxyl group.
In another preference, R1 is two identical or different substituting groups that are positioned at phenyl ring optional position, and described substituting group is selected from: F, Cl, Br, I, C
1-6alkyl; And/or
R2 and R3 form replacement or unsubstituted C jointly
2-8alkane dioxy base, the definition of wherein said replacement is as previously mentioned; And/or
R4 is Cl or Br.
In another preference, during as substituting group, described phenyl comprises and replacing or unsubstituted phenyl, and described benzyl comprises and replacing or unsubstituted benzyl, and described replacement refers to have one or more (as 1-5 or 1-3) and is selected from the substituting group of lower group: C
1-6alkyl, halogen, C
1-6alkoxyl group, OH, NH
3.
In another preference, described formula I compound is following structure:
In another preference, step 1) and step 2) described in alkali be selected from organic bases or mineral alkali;
Preferably, described organic bases is selected from lower group: triethylamine, diethylamine, diisopropylethylamine, pyridine or its combination; More preferably, described alkali is triethylamine or diisopropylethylamine;
In another preference, described mineral alkali is selected from sodium-acetate, Potassium ethanoate, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium primary phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide or its combination.
In another preference, described alkaline reagents is selected from sodium-acetate, Potassium ethanoate, sodium bicarbonate, salt of wormwood, or its combination.
In another preference, step 1) and step 2) alkali be identical.
In another preference, step 1) in, the consumption of alkali and the mol ratio of formula III compound are 0.5～5:1, are more preferably 2～3.5:1.
In another preference, step 1) mol ratio of Chinese style IV compound and formula III compound is 0.2～1:1, preferably 0.8～1:1.
In another preference, step 1) in, temperature of reaction is-20～100 ℃, and more preferably, temperature of reaction is-10～50 ℃.
In another preference, step 1) in, the reaction times is 0.5～24 hour, more preferably 1～12 hour.
In another preference, step 2) borane reagent described in is selected from lower group: titanium dioxide two boron, tetramethoxy hypoboric acid ester, tetraethoxy hypoboric acid ester, four n-butoxy hypoboric acid esters, tetraisopropoxide hypoboric acid ester, four positive propoxy hypoboric acid esters, duplex pyrocatechol boric acid ester, duplex tetramethyl ethylene ketone boric acid ester, connection boric acid DOPCP, two [(-) pinine glycol] two boron esters, two (di-isopropyl-L-TARTARIC ACID diethyl ester) hypoboric acid ester, two (1S, 2S, 3R, 5S) (+)-pinine glycol two boron esters, duplex (2-methyl-2, 4-pentanediol) boric acid ester, duplex (2, 4-dimethyl-2, 4-pentanediol) boric acid ester, duplex (D-diethyl tartrate) boric acid ester, or its combination.
In another preference, described borane reagent is selected from duplex pyrocatechol boric acid ester, duplex tetramethyl ethylene ketone boric acid ester, duplex (D-diethyl tartrate) boric acid ester; It is more preferably duplex tetramethyl ethylene ketone boric acid ester.
In another preference, the mol ratio of the consumption of described borane reagent and formula V compound is 0.8～5:1, preferably 1～1.5:1.
In another preference, step 2) consumption of alkali and the mol ratio of formula V compound described in are 0.5～5:1, preferably 2～3.5:1; And/or
Step 2) palladium catalyst described in is selected from 1,1 '-bis-(diphenylphosphine) ferrocene, four triphenyl phosphorus palladiums, palladium carbon, palladium, or its combination, preferably 1,1 '-bis-(diphenylphosphine) ferrocene, four triphenyl phosphorus palladiums; And/or
The mol ratio of the consumption of the palladium catalyst step 2) and formula V compound is 0.01～0.2:1, is preferably 0.02～0.08:1.
In another preference, step 2) in, temperature of reaction is 20～150 ℃, preferably 60～100 ℃.
In another preference, step 2) in, the reaction times is 0.5～24 hour, more preferably 1～12 hour.
In another preference, the method comprises the steps:
I) under alkali exists, the fluoro-5-methyl of isocyanic acid 2-phenyl ester reacts with para-bromoaniline, forms formula VII compound; With
Ii), in inert solvent, under alkali and palladium catalyst existence, formula VII compound reacts with borane reagent, forms formula VI compound:
In another preference, step I) temperature of reaction is-10～50 ℃.
In another preference, step I i) temperature of reaction is 60～100 ℃.
In another preference, step I) alkali in is diisopropylethylamine.
In another preference, step I i) in, inert solvent is DMF (DMF), dimethyl sulfoxide (DMSO) or its combination.
In another preference, step I i) in, the mol ratio of VII compound and borane reagent, alkali, palladium catalyst is 1:0.8～5:0.5～5:0.01～0.2; It is more preferably 1:1～1.5:2～3.5:0.02～0.08.
In another preference, described method also comprises by following steps prepares formula III compound:
1a) in inert solvent, under alkali exists, formula II compound reacts with triphosgene, forms formula III compound:
Above-mentioned various in, R1 is the one or more substituting groups that are positioned at optional position on phenyl ring, each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group.
In another preference, step 1a) in, described alkali is organic bases (as diisopropylethylamine etc.).
In another preference, step 1a) in, described inert solvent is organic solvent, is selected from esters solvent, halogenated hydrocarbon solvent, ether solvent, aromatic hydrocarbon solvent or its combination; More preferably, described organic solvent is ethyl acetate, methylene dichloride, tetrahydrofuran (THF), or its combination.
A second aspect of the present invention, provides a kind of preparation method of formula A compound, comprises step:
1) under alkali exists, formula III compound reacts with formula IV compound, forms formula V compound;
2) under the existence of alkali and palladium catalyst, formula V compound reacts with borane reagent, forms formula I compound;
Above-mentioned various in,
R1 is the one or more substituting groups that are positioned at optional position on phenyl ring, and each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group;
R2 and R3 are hydroxyl or C independently
1-6alkoxyl group, C
1-6acyloxy, or R2 and R3 jointly form and replace or unsubstituted C
1-8alkane dioxy base, C
6-10virtue dioxy base, or C
1-8cycloalkanes dioxy base; Wherein said replacement is to have one or more substituting groups that are selected from lower group: C
1-6alkyl, halogen, phenyl, benzyl ,-CH
2-, C
1-6alkoxyl group, C
1-6acyl group, C
1-6acyloxy, C
1-6carbalkoxy;
R4 is selected from lower group: H, halogen;
3) formula I compound is reacted with 3-amino-4-iodine indazole, forms formula A compound,
In formula, R is
and X is one or more (as 1,2,3, the 4 or 5) substituting group that is positioned at optional position on phenyl ring, each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group.
More preferably, X is H, o-F, m-F, p-F, o-Me, m-Me, P-Me, m-Et, m-Cl, m-Br, m-CF
3, m-OH, 2-F-5-Me, 4-F-3-Me, 3-F-Me, 2-F-5-CF
3, 2-Cl-5-Cl, 2-Me-4-Me, 3-F-4-OMe, 2-Br-4-Me, 2-Me-5-CF
3.
In another preference, described formula I compound is formula VI compound, and formula A compound is ABT-869.
In a third aspect of the present invention, a kind of N-(4-(3-amino-1 h-indazole-4-yl) phenyl) preparation method of-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea is provided, comprise step:
Formula VI compound is reacted with 3-amino-4-iodine indazole, forms N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea:
Described method also comprises: with the method preparation formula VI compound described in first aspect present invention.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, at this, tire out and state no longer one by one.
Embodiment
The inventor is through extensive and deep research, developed first a kind of by following reaction, efficiently, the technique of preparation I compound at low cost:
The formula I compound making by this technique can be used as the intermediate of chemosynthesis, for the synthesis of medicine.Representational medicine comprises (but being not limited to): disclosed indazole, benzoisoxazole and benzisothiazole kinase inhibitors in WO2004113304A1.
The formula VI intermediate (a kind of preferred formula I compound) of take is example, by this formula VI intermediate, can prepare low-cost, efficiently compd A BT-869, thereby is applicable to very much suitability for industrialized production.Other formulas I intermediate, by leavings group-B (R2) similar reaction (R3), can prepare the similar formula A compound with ABT-869.
Term
As used in the present invention, term " ABT-869 ", " compd A BT-869 " or " Linifanib " are used interchangeably, and all refer to compound N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea or its pharmacy acceptable salt.
As used herein, term " C
1-6alkyl " refer to have the straight or branched alkyl of 1-6 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or similar group.
Term " C
1-6alkoxyl group " refer to have the straight or branched alkoxyl group of 1-6 carbon atom, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy or similar group.
Term " C
1-6acyl group " refer to have the acyl group of 1-6 carbon atom, for example formyl radical, ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, secondary butyryl radicals, tertiary butyryl radicals or similar group.
Term " C
1-6acyloxy " refer to have the acyloxy of 1-6 carbon atom, for example methanoyl, acetoxyl group, propionyloxy, isopropyl acyloxy, butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, tertiary butyryl acyloxy or similar group.
Term " C
1-6carbalkoxy " refer to have the straight or branched carbalkoxy of 1-6 carbon atom, for example methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, isopropyl oxygen carbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl or similar group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.Term " halo " refers to the group being replaced by identical or different one or more above-mentioned halogen atom, for example trifluoromethyl, pentafluoroethyl group or similar group.
Term " C
1-8alkane dioxy base " refer to have the straight or branched alkane dioxy base of 1-8 carbon atom, as-OC
1-8alkyl O-,-OCH
2cH
2o-,-OCH
2cH
2cH
2o-,-OCH
2cH (CH
3) CH
2o-,-OCH
2cH (CH
3) CH (CH
3) CH
2o-,-OCH
2c (CH
3)
2cH
2o-or similar group.
Term " C
1-8cycloalkanes dioxy base " refer to have cycloalkanes dioxy base or the bridged ring alkane dioxy base of 1-8 carbon atom, as 1,2-dioxy basic ring hexane, 1,3-dioxy basic ring hexane, (-) pinane dioxy base
(1S, 2S, 3R, 5S) (+)-pinane dioxy base
or similar group.
Term " phenyl " comprises phenyl unsubstituted and that replace, wherein replaces and refers to that on phenyl ring, one or more hydrogen atoms are replaced by halogen atom, C
1-6alkyl, C
1-6alkoxyl group or similar group.
Term " C
6-10virtue dioxy base " refer to have the fragrant dioxy base of 6-10 carbon atom, as 1,2-dioxy base benzene, 1,2-dioxy base naphthalene or similar group.
Term " BTC " refers to triphosgene, and molecular formula is C
3h
6o
3.
Term " esters solvent " refers to have the ester class organic solvent of 2-20 individual (preferably 2-10) carbon atom, for example methyl acetate, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, isobutyl acetate, pentyl acetate, hexyl acetate, heptyl acetate, decyl acetate, glycol diacetate, or similar solvent.
Term " ether solvent " refers to have the straight or branched alkoxyl group of 2-20 individual (preferably 2-10) carbon atom, for example ether, propyl ether, isopropyl ether, ethyl n-butyl ether, di-n-butyl ether, diamyl ether, tetrahydrofuran (THF), oxyethane, propylene oxide, 1,3-dioxolane or similar solvent.
Preparation method
Shown in general formula of the present invention (I), compound or compd A BT-869 can make by following method.Yet should be understood that hereinafter given method actual conditions, such as the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc., is exemplary not from the limited effect.The compounds of this invention can also be optionally by describe in this manual or various synthetic method known in the art combine and make easily, such combination can be easy to carry out by those skilled in the art in the invention.
In preparation method of the present invention, each reaction is conventionally in inert solvent, and temperature of reaction is carried out to reflux temperature (preferably-10 ℃ to 100 ℃) for-20 ℃.Reaction times is generally 0.1-24 hour, is preferably 0.5-18 hour.
The preparation of formula I compound
Formula I compound can be prepared as follows:
Under alkali exists, formula III compound reacts with formula IV compound, forms formula V compound;
Then, under the existence of alkali and palladium catalyst, formula V compound reacts with borane reagent, forms formula I compound.
Raw material formula III compound and formula IV compound can be prepared maybe and can be bought and obtain by ordinary method.
In the present invention, representational borane reagent comprises (but being not limited to): titanium dioxide two boron, tetramethoxy hypoboric acid ester, tetraethoxy hypoboric acid ester, four n-butoxy hypoboric acid esters, tetraisopropoxide hypoboric acid ester, four positive propoxy hypoboric acid esters, duplex pyrocatechol boric acid ester, duplex tetramethyl ethylene ketone boric acid ester, connection boric acid DOPCP, two [(-) pinine glycol] two boron esters, two (di-isopropyl-L-TARTARIC ACID diethyl ester) hypoboric acid ester, two (1S, 2S, 3R, 5S) (+)-pinine glycol two boron esters, duplex (2-methyl-2, 4-pentanediol) boric acid ester, duplex (2, 4-dimethyl-2, 4-pentanediol) boric acid ester, duplex (D-diethyl tartrate) boric acid ester, or its combination.
Preferably, described borane reagent is selected from duplex pyrocatechol boric acid ester, duplex tetramethyl ethylene ketone boric acid ester, duplex (D-diethyl tartrate) boric acid ester; It is more preferably duplex tetramethyl ethylene ketone boric acid ester.
The preparation of compd A BT-869
Compd A BT-869 can pass through intermediate formula VI compound, is prepared as follows:
Formula VI compound is reacted with 3-amino-4-iodine indazole, forms N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea:
Compared with prior art, the present invention has following advantage:
1, the inventive method can obtain N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea key intermediate boric acid ester compound easily.
2, method yield of the present invention is high.
3, the inventive method can make highly purified ABT-869 easily, and product purity can reach more than 98%.
4, raw materials cost is low, is applicable to suitability for industrialized production.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
The preparation of embodiment 1 compound 1-I
Steps A:
By triphosgene (8.9g, 30.0mmol) be dissolved in 100mL ethyl acetate, add triethylamine (10.1g, 99.8mmol), stir borehole cooling to-10～-5 ℃, slowly drip 2,5-dichlorphenamide bulk powder (8.1g, ethyl acetate 50.0mmol) (80mL) solution, drips about 0.5-1 hour.Dropwise, be warming up to 50 ℃ of stirring reaction 1-2 hour.It is complete that TLC detects raw material reaction, is cooled to room temperature, and reaction solution directly drops into the next step.
Step B:
Previous step reaction solution is warming up to 25～30 ℃, and ethyl acetate (50mL) solution to dripping para-bromoaniline (6.9g, 40.1mmol), diisopropylethylamine (6.5g, 50.3mmol) in reaction solution, drips about 0.5-1 hour.Dropwise, continue 25～30 ℃ of reaction 1-2 hour of temperature control.Reaction solution concentrating under reduced pressure is fallen to half volume, under stirring, in system, drip 100mL water, adularescent solid is separated out, and filters, and filter cake vacuum-drying obtains 1-III compound 11.6g, yield 80.4%.MS(ESI)m/z：(M+H)=361.0。
Step C:
In reaction flask, add 1-III compound (11.6g, 32.2mmol) successively, titanium dioxide two boron (2.6g, 48.3mmol), sodium bicarbonate (6.7g, 79.8mmol) and water (100mL), stir, and adds Pd (PPh
3)
4(1.1g, 1.0mmol).Be warming up to backflow, temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is slowly cooled to 0～5 ℃, separates out solid, continues insulated and stirred 0.5-1 hour.Filter, filter cake acetonitrile recrystallization, dries and obtains 1-I compound 8.7g, yield 83.1%, and HPLC detects purity 98.7%.MS(ESI)m/z：(M+H)=326.0。
The preparation of embodiment 2 compound 2-I
Steps A:
By triphosgene (14.8g, 100.0mmol) be dissolved in 100mL tetrahydrofuran (THF), add diisopropylethylamine (13.4g, 103.7mmol), stir borehole cooling to-10～-5 ℃, slowly drip 1-amino-2,4-dimethyl benzene (12.1g, tetrahydrofuran (THF) 100.0mmol) (120mL) solution, drips about 0.5-1 hour.Dropwise, be warming up to return stirring reaction 1-2 hour.It is complete that TLC detects raw material reaction, is cooled to room temperature, and reaction solution directly drops into the next step.
Step B:
Previous step reaction solution is warming up to 25～30 ℃, adds salt of wormwood (13.8g, 100.0mmol), then, to tetrahydrofuran (THF) (50mL) solution that drips para-bromoaniline (17.2g, 100.0mmol) in reaction solution, drip about 0.5-1 hour.Dropwise, continue 25～30 ℃ of reaction 1-2 hour of temperature control.Reaction solution concentrating under reduced pressure is fallen to half volume, under stirring, in system, drip 100mL water, adularescent solid is separated out.Filter, filter cake vacuum-drying obtains 2-II I compound 25.6g, yield 80.2%.MS(ESI)m/z：(M+H)=320.2，(M+Na)=342.2。
Step C:
In reaction flask, add 2-III compound (25.6g, 80.2mmol) successively, tetramethoxy two boron (14.0g, 96.4mmol), Potassium ethanoate (7.9g, 80.5mmol) and methyl alcohol (200mL), stir, and adds PdCl
2(dppf) (5.9g, 8.0mmol).Be warming up to backflow, temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is cooled to room temperature, adds 500mL water, with methylene dichloride 300ml, divides 3 extractions, 300mL saturated common salt water washing 1 time, anhydrous sodium sulfate drying.Filtrate decompression is concentrated into dry crude product 24.3g, and acetonitrile recrystallization is dried and obtained 2-I compound 20.6g, yield 82.2%, and HPLC detects purity 99.1%.MS(ESI)m/z：(M+H)=313.1。
The preparation of embodiment 3 compound 3-I
Steps A:
The fluoro-5-monomethylaniline of 2-(5.0g, 39.9mmol) is dissolved in 150mL methylene dichloride, adds diisopropylethylamine (6.2g, 48.0mmol).Stir borehole cooling to-10～-5 ℃, slowly drip methylene dichloride (100mL) solution of triphosgene (4.8g, 16.2mmol), drip about 0.5-1 hour.Dropwise, be warming up to stirring at room reaction 3-4 hour, it is complete that TLC detects raw material reaction, and reaction solution directly drops into the next step.
Step B:
Previous step reaction solution is warming up to 25～30 ℃, in reaction solution, drips para-bromoaniline (6.9g, 40.1mmol), the methylene dichloride of triethylamine (8.1g, 80.0mmol) (30mL) solution, drips about 0.5-1 hour.Dropwise, continue 25～30 ℃ of reaction 1-2 hour of temperature control.The reaction mixture concentrating under reduced pressure obtaining is fallen to half volume, under stirring, in system, drip 100mL water, adularescent solid is separated out, and filters, and filter cake vacuum-drying obtains formula VII compound 10.7g, yield 82.6%.MS(ESI)m/z：(M+H)=324.1。
Step C:
In reaction flask, add formula VII compound (10.7g, 33.1mmol) successively, duplex tetramethyl ethylene ketone boric acid ester (9.2g, 36.3mmol), Potassium ethanoate (9.7g, 98.8mmol) and DMF (100mL).Stir, add PdCl
2(dppf) (1.2g, 1.7mmol), is warming up to 80～85 ℃, temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is cooled to room temperature, adds 200mL water, with methylene dichloride 200ml, divides 3 extractions, 200mL saturated common salt water washing 1 time, and anhydrous sodium sulfate drying, filtrate decompression is concentrated into dry crude product 12.5g.Acetonitrile recrystallization, dries and obtains formula VI compound 10.6g, yield 86.5%, and it is 99.2% that HPLC detects purity.MS(ESI)m/z：(M+H)=371.2。
The preparation of embodiment 4 compound 4-I
Steps A:
By the bromo-4-monomethylaniline of 2-(37.2g, 200.0mmol) be dissolved in 200mL toluene, add pyridine (47.5g, 600.5mmol), stir borehole cooling to-10～-5 ℃, slowly drip toluene (150mL) solution of triphosgene (29.6g, 100.0mmol), drip about 0.5-1 hour.Dropwise, be warming up to return stirring reaction 1-2 hour.It is complete that TLC detects raw material reaction, is cooled to room temperature, and reaction solution directly drops into the next step.
Step B:
Upwards single step reaction liquid adds salt of wormwood (41.4g, 300.0mmol), is warming up to 25～30 ℃, drips toluene (400mL) solution of paraiodoaniline (39.4g, 180.0mmol), drips about 1-2 hour.Dropwise, continue 25～30 ℃ of reaction 1-2 hour of temperature control.Reaction solution concentrating under reduced pressure is fallen to half volume, under stirring, in system, drip 1000mL water, adularescent solid is separated out.Filter, filter cake vacuum-drying obtains 4-III compound 63.2g, yield 81.4%.MS(ESI)m/z：(M+H)=432.1。
Step C:
In reaction flask, add 4-III compound (63.2g, 146.6mmol) successively, duplex pyrocatechol boric acid ester (35.7g, 150.0mmol), salt of wormwood (27.6g, 200.0mmol), methyl alcohol (500mL) and water (500mL), stir, and adds Pd (PPh
3)
4(8.0g).Be warming up to 60 ℃, temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is cooled to 0-5 ℃, separates out solid, continues to stir 1 hour.Filter, filter cake acetonitrile recrystallization, dries and obtains 4-I compound 48.3g, yield 77.9%, and it is 98.5% that HPLC detects purity.MS(ESI)m/z：(M+H)=424.1。
The preparation of embodiment 5 compound 5-I
Steps A:
By triphosgene (5.9g, 20.0mmol) be dissolved in 100mL isopropyl acetate, add diisopropylethylamine (6.5g, 50.3mmol), stir borehole cooling to-10～-5 ℃, slowly drip isopropyl acetate (50mL) solution of the fluoro-4-anisidine of 3-(7.1g, 50.0mmol), drip about 0.5-1 hour.Dropwise, be warming up to stirring at room reaction 3-4 hour.It is complete that TLC detects raw material reaction, and reaction solution directly drops into the next step.
Step B:
Upwards single step reaction liquid adds salt of wormwood (11.0g, 79.7mmol), is warming up to 25～30 ℃, drips isopropyl acetate (30mL) solution of para-bromoaniline (6.9g, 40.1mmol), drips about 0.5-1 hour.Dropwise, continue 45～50 ℃ of reaction 1-2 hour of temperature control.Reaction solution concentrating under reduced pressure is fallen to half volume, under stirring, in system, drip 100mL water, adularescent solid is separated out.Filter, filter cake vacuum-drying obtains 5-II I compound 11.4g, yield 83.8%.MS(ESI)m/z：(M+H)=340.1。
Step C:
In reaction flask, add 5-III compound (11.4g successively, 33.6mmol), duplex (D-diethyl tartrate) boric acid ester (15.1g, 35.0mmol), sodium-acetate (8.2g, 100.0mmol) and isopropyl acetate (200mL), stir, add Pd (OAc)
2(0.4g, 1.8mmol).Be warming up to 90～100 ℃, temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is cooled to room temperature, adds 200mL water, with methylene dichloride 200ml, divides 3 extractions, 200ml saturated common salt water washing 1 time, anhydrous sodium sulfate drying.Filtrate decompression is concentrated into dry crude product 15.2g, and acetonitrile recrystallization is dried and obtained 5-I compound 13.1g, yield 82.1%, and it is 98.8% that HPLC detects purity.MS(ESI)m/z：(M+H)=475.2。
The preparation of embodiment 6 compound 6-I
Steps A:
By triphosgene (5.9g, 20.0mmol) be dissolved in 100mL ethyl acetate, add triethylamine (10.1g, 99.8mmol), stir borehole cooling to-10～-5 ℃, slowly drip ethyl acetate (80mL) solution of 2-methyl-5-5-trifluoromethylaniline (8.8g, 50.0mmol), drip about 0.5-1 hour.Dropwise, be warming up to 60 ℃ of stirring reaction 1-2 hour.It is complete that TLC detects raw material reaction, is cooled to room temperature, and reaction solution directly drops into the next step.
Step B:
Upwards in single step reaction liquid, add sodium hydroxide (2.0g, 50.0mmol), be warming up to 25～30 ℃, drip ethyl acetate (50mL) solution of p-Chlorobenzoic acid amide (5.7g, 45.0mmol), drip about 0.5-1h.Dropwise, continue 25～30 ℃ of reaction 1-2 hour of temperature control.Reaction solution concentrating under reduced pressure is fallen to half volume, under stirring, in system, drip 100mL water, adularescent solid is separated out.Filter, filter cake vacuum-drying obtains 6-III compound 9.3g, yield 75.3%.MS(ESI)m/z：(M+H)=275.7。
Step C:
In reaction flask, add 6-III compound (9.3g successively, 33.9mmol), two (1S, 2S, 3R, 5S) (+)-pinine glycol two boron ester (12.2g, 34.0mmol), triethylamine (10.1g, 99.8mmol) and dioxane (100mL), stir, add Pd (PPh
3)
4(0.8g, 1.0mmol).Be warming up to backflow, temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is cooled to room temperature, adds 200mL water, with methylene dichloride 200ml, divides 3 extractions, 200ml saturated common salt water washing 1 time, anhydrous sodium sulfate drying.Filtrate decompression is concentrated into dry crude product 13.5g, and acetonitrile recrystallization is dried and obtained 6-I compound 11.3g, yield 79.7%, and it is 98.6% that HPLC detects purity.MS(ESI)m/z：(M+H)=419.3。
The preparation of embodiment 7 compound 7-I
Steps A:
By triphosgene (8.9g, 30.0mmol) be dissolved in 100mL methylene dichloride, add diisopropylethylamine (12.9g, 99.8mmol), stir borehole cooling to-10～-5 ℃, slowly drip methylene dichloride (50mL) solution of 4-monomethylaniline (5.4g, 50.0mmol), drip about 0.5-1 hour.Dropwise, be warming up to stirring at room reaction 3-4 hour.It is complete that TLC detects raw material reaction, and reaction solution directly drops into the next step.
Step B:
Upwards single step reaction liquid adds salt of wormwood (11.0g, 80.0mmol), is warming up to 25～30 ℃, drips methylene dichloride (30mL) solution of para-bromoaniline (6.9g, 40.0mmol), drips about 0.5-1 hour.Dropwise, continue 35～40 ℃ of reaction 1-2 hour of temperature control.Reaction solution concentrating under reduced pressure is fallen to half volume, under stirring, in system, drip 100mL water, adularescent solid is separated out.Filter, filter cake vacuum-drying obtains 7-III compound 9.9g, yield 81.2%.MS(ESI)m/z：(M+H)=306.1。
Step C:
In reaction flask, add 7-II I compound (9.9g successively, 32.5mmol), duplex (2,4-dimethyl-2,4-pentanediol) boric acid ester (11.3g, 40.0mmol), sodium-acetate (4.1g, 50.0mmol) and tetrahydrofuran (THF) (200mL), stir, add Pd (OAc)
2(0.4g, 1.6mmol).Be warming up to backflow temperature control reaction 2-3 hour.It is complete that TLC detects raw material reaction, and reaction system is cooled to room temperature, adds 200mL water, with methylene dichloride 200ml, divides 3 extractions, 200mL saturated common salt water washing 1 time, anhydrous sodium sulfate drying.Filtrate decompression is concentrated into dry crude product 15.2g, and acetonitrile recrystallization is dried and obtained 7-I compound 9.6g, yield 80.7%, and it is 98.9% that HPLC detects purity.MS(ESI)m/z：(M+H)=367.2。
The preparation of embodiment 8 N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea
Successively to the formula VI compound (10.6g, 28.6mmol), 3-amino-4-iodine indazole (8.1g, 31.3mmol), sodium carbonate (7.6g, 71.7mmol), ethanol 100mL, the water 100mL that add embodiment 3 to obtain in reaction flask.Under stirring at room, add PdCl
2(dppf) (0.4g, 0.6mmol), is warming up to backflow.Reflux after 8 hours, pressure reducing and steaming ethanol.In residue, add ethyl acetate 150mL, 20% aqueous ammonium chloride solution 50mL, stir 30 minutes.Separate organic layer, wash anhydrous sodium sulfate drying with water 3 times.Organic layer evaporated under reduced pressure, dichloromethane-ethanol for crude product (10:1) recrystallization obtaining, obtains white solid 8.0g, yield 74.8%, it is 99.0% that HPLC detects purity.MS(ESI)m/z：(M+H)=376.4。
Similarly, by the reaction of leaving away of leavings group, with compound 1-I, make the formula A compound that X is 2-Cl-5-Cl.With formula 2-I compound, make the formula A compound of 2-Me-4-Me.With formula 5-I compound, make the formula A compound of 3-F-4-OMe.After tested, it is active that these formulas A compound has RTK inhibition.
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document, are quoted as a reference separately.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (12)
1. a preparation method for formula I compound, is characterized in that, the method comprises the following steps:
1) under alkali exists, formula III compound reacts with formula IV compound, forms formula V compound;
2) under the existence of alkali and palladium catalyst, formula V compound reacts with borane reagent, forms formula I compound;
Above-mentioned various in,
R1 is the one or more substituting groups that are positioned at optional position on phenyl ring, and each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group;
R2 and R3 are hydroxyl or C independently
1-6alkoxyl group, C
1-6acyloxy, or R2 and R3 jointly form and replace or unsubstituted C
1-8alkane dioxy base, C
6-10virtue dioxy base, or C
1-8cycloalkanes dioxy base; Wherein said replacement is to have one or more substituting groups that are selected from lower group: C
1-6alkyl, halogen, phenyl, benzyl ,-CH
2-, C
1-6alkoxyl group, C
1-6acyl group, C
1-6acyloxy, C
1-6carbalkoxy;
R4 is selected from lower group: H, halogen.
2. the method for claim 1, is characterized in that, R1 is two identical or different substituting groups that are positioned at phenyl ring optional position, and described substituting group is selected from: halogen, C
1-6alkyl; And/or
R2 and R3 form replacement or unsubstituted C jointly
2-8alkane dioxy base, the definition of wherein said replacement is as claimed in claim 1; And/or
R4 is Cl or Br.
3. method as claimed in claim 2, is characterized in that, described formula I compound is following structure:
4. the method for claim 1, is characterized in that step 1) and step 2) described in alkali be selected from organic bases or mineral alkali;
Preferably, described organic bases is selected from lower group: triethylamine, diethylamine, diisopropylethylamine, pyridine or its combination; More preferably, described alkali is triethylamine or diisopropylethylamine;
In another preference, described mineral alkali is selected from sodium-acetate, Potassium ethanoate, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, potassium primary phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide or its combination.
5. the method for claim 1, is characterized in that step 1) mol ratio of Chinese style IV compound and formula III compound is 0.2～1:1, preferably 0.8～1:1.
6. the method for claim 1, it is characterized in that, step 2) borane reagent described in is selected from lower group: titanium dioxide two boron, tetramethoxy hypoboric acid ester, tetraethoxy hypoboric acid ester, four n-butoxy hypoboric acid esters, tetraisopropoxide hypoboric acid ester, four positive propoxy hypoboric acid esters, duplex pyrocatechol boric acid ester, duplex tetramethyl ethylene ketone boric acid ester, connection boric acid DOPCP, two [(-) pinine glycol] two boron esters, two (di-isopropyl-L-TARTARIC ACID diethyl ester) hypoboric acid ester, two (1S, 2S, 3R, 5S) (+)-pinine glycol two boron esters, duplex (2-methyl-2, 4-pentanediol) boric acid ester, duplex (2, 4-dimethyl-2, 4-pentanediol) boric acid ester, duplex (D-diethyl tartrate) boric acid ester, or its combination.
7. the method for claim 1, is characterized in that, the mol ratio of the consumption of described borane reagent and formula V compound is 0.8～5:1, preferably 1～1.5:1.
8. the method for claim 1, is characterized in that step 2) described in the consumption of alkali and the mol ratio of formula V compound be 0.5～5:1, preferably 2～3.5:1; And/or
Step 2) palladium catalyst described in is selected from 1,1 '-bis-(diphenylphosphine) ferrocene, four triphenyl phosphorus palladiums, palladium carbon, palladium, or its combination, preferably 1,1 '-bis-(diphenylphosphine) ferrocene, four triphenyl phosphorus palladiums; And/or
The mol ratio of the consumption of the palladium catalyst step 2) and formula V compound is 0.01～0.2:1, is preferably 0.02～0.08:1.
9. as the method as described in arbitrary in claim 1-8, it is characterized in that, the method comprises the steps:
I) under alkali exists, the fluoro-5-methyl of isocyanic acid 2-phenyl ester reacts with para-bromoaniline, forms formula VII compound; With
Ii), in inert solvent, under alkali and palladium catalyst existence, formula VII compound reacts with borane reagent, forms formula VI compound:
10. the method for claim 1, is characterized in that, described method also comprises by following steps prepares formula III compound:
1a) in inert solvent, under alkali exists, formula II compound reacts with triphosgene, forms formula III compound:
Above-mentioned various in, R1 is the one or more substituting groups that are positioned at optional position on phenyl ring, each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group.
The preparation method of 11. 1 kinds of formula A compounds, comprises step:
1) under alkali exists, formula III compound reacts with formula IV compound, forms formula V compound;
2) under the existence of alkali and palladium catalyst, formula V compound reacts with borane reagent, forms formula I compound;
Above-mentioned various in,
R1 is the one or more substituting groups that are positioned at optional position on phenyl ring, and each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group;
R2 and R3 are hydroxyl or C independently
1-6alkoxyl group, C
1-6acyloxy, or R2 and R3 jointly form and replace or unsubstituted C
1-8alkane dioxy base, C
6-10virtue dioxy base, or C
1-8cycloalkanes dioxy base; Wherein said replacement is to have one or more substituting groups that are selected from lower group: C
1-6alkyl, halogen, phenyl, benzyl ,-CH
2-, C
1-6alkoxyl group, C
1-6acyl group, C
1-6acyloxy, C
1-6carbalkoxy;
R4 is selected from lower group: H, halogen;
3) formula I compound is reacted with 3-amino-4-iodine indazole, forms formula A compound,
In formula, R is
and X is the one or more substituting groups that are positioned at optional position on phenyl ring, each R1 can be identical or different and independently selected from lower group: halogen, C
1-6alkyl, C
1-6haloalkyl or C
1-6alkoxyl group.
The preparation method of 12. 1 kinds of N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea, is characterized in that, comprises step:
Formula VI compound is reacted with 3-amino-4-iodine indazole, forms N-(4-(3-amino-1 h-indazole-4-yl) phenyl)-N '-(the fluoro-5-aminomethyl phenyl of 2-) urea:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210279813.XA CN103570754B (en) | 2012-08-07 | 2012-08-07 | The preparation method of N (4 (base of 3 amino 1H indazoles 4) phenyl) N ' (aminomethyl phenyl of 2 fluorine 5) ureas and its intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210279813.XA CN103570754B (en) | 2012-08-07 | 2012-08-07 | The preparation method of N (4 (base of 3 amino 1H indazoles 4) phenyl) N ' (aminomethyl phenyl of 2 fluorine 5) ureas and its intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103570754A true CN103570754A (en) | 2014-02-12 |
| CN103570754B CN103570754B (en) | 2018-01-26 |
Family
ID=50043530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210279813.XA Active CN103570754B (en) | 2012-08-07 | 2012-08-07 | The preparation method of N (4 (base of 3 amino 1H indazoles 4) phenyl) N ' (aminomethyl phenyl of 2 fluorine 5) ureas and its intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103570754B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326985A (en) * | 2014-09-24 | 2015-02-04 | 安润医药科技（苏州）有限公司 | Preparation method of linifanib |
| CN114105946A (en) * | 2020-08-26 | 2022-03-01 | 浙江苏泊尔制药有限公司 | Tedizolid phosphate intermediate and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2879601B1 (en) * | 2004-12-22 | 2007-01-19 | Galderma Res & Dev | NOVEL COMPOUNDS DERIVED FROM PHENYL-BORONIC ACID AND PROCESS FOR PREPARING THE SAME |
| CN102219733A (en) * | 2010-04-14 | 2011-10-19 | 上海医药工业研究院 | Method for preparing sorafenib |
-
2012
- 2012-08-07 CN CN201210279813.XA patent/CN103570754B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326985A (en) * | 2014-09-24 | 2015-02-04 | 安润医药科技（苏州）有限公司 | Preparation method of linifanib |
| CN114105946A (en) * | 2020-08-26 | 2022-03-01 | 浙江苏泊尔制药有限公司 | Tedizolid phosphate intermediate and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103570754B (en) | 2018-01-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102267985B (en) | The preparation method of vilazodone or its hydrochloride | |
| CN101628912B (en) | Anti-tumor compound containing triazole heterocyclic structure and application thereof | |
| PL217629B1 (en) | Pyrazole derivatives and pharmaceutical compositions containing them and their application for HIV treatment | |
| CN102584795A (en) | Preparing method of crizotinib | |
| AU2018449575B2 (en) | Catalyst system and method for preparing azoxystrobin or intermediates thereof by using catalyst system | |
| ES2411713T3 (en) | Asymmetric hydrogenation of 1,1,1-trifluoroacetone | |
| CN101044119B (en) | Process for the preparation of pyrazoles | |
| CN103570754A (en) | Preparation method of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N'-(2-fluoro-5-methylphenyl) urea and intermediate thereof | |
| CN103896940B (en) | A kind of synthetic method of Eliquis | |
| WO2016041505A1 (en) | Tedizolid phosphate, intermediate and preparation method thereof | |
| EP2958893B1 (en) | Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide | |
| CN111072605B (en) | Preparation method of fluoroalkyl-substituted benzofuran derivative or indole derivative | |
| CN109824579B (en) | Preparation method of (S) -phenyl (pyridine-2-yl) methanol derivative | |
| CN103554064B (en) | The preparation method of 3-hydroxyl oxygen heterocycle butane | |
| WO2014022975A1 (en) | N-(4-(3-amino-1h-indazol-4-yl)phenyl)-n'-(2-fluoro-5-methylphenyl)carbamide and preparation method for intermediate thereof | |
| CN109810066A (en) | A kind of synthetic method of the ambroxol hydrochloride in relation to substance | |
| CN104829470B (en) | One is combined into the midbody compound of Ivabradine and its application | |
| CN104672180B (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| JP2017508790A (en) | Intermediate compound for producing rosuvastatin calcium and method for producing rosuvastatin calcium using the same | |
| CN111410604B (en) | Asymmetric hydrogenation of olefinic acid compounds | |
| EP2627627B1 (en) | Process for the synthesis of chiral propargylic alcohols | |
| CN104086342B (en) | A kind of synthetic method of medicine intermediate aryl substituted carbinol compound | |
| CN101503358A (en) | Method for preparing chiral alpha-hydroxy-beta-dicarbonyl compound with lappaconitine as catalyst | |
| CN104650143B (en) | The method for preparing fosaprepitant dimeglumine intermediate | |
| CN115919817B (en) | Gem diselenide compound and its synthesis method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180928 Address after: 024000 84 East Street, Hongshan District, Chifeng, the Inner Mongolia Autonomous Region Patentee after: CHIFENG PHARMACEUTICAL Co.,Ltd. Address before: 201203 room 687-21, 2 building, No. 351, Guo Shou Jing Road, Zhangjiang hi tech park, Pudong New Area, Shanghai. Patentee before: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of N - (4 - (3-amino-1h-indazole-4-yl) phenyl) - n u2032 - (2-fluoro-5-methylphenyl) urea and its intermediates Effective date of registration: 20200322 Granted publication date: 20180126 Pledgee: Agricultural Bank of China Limited Chifeng Baima sub branch Pledgor: CHIFENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2020150000008 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210222 Granted publication date: 20180126 Pledgee: Agricultural Bank of China Limited Chifeng Baima sub branch Pledgor: CHIFENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2020150000008 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of N - (4 - (3-amino-1h-indazol-4-yl) phenyl) - n - (2-fluoro-5-methylphenyl) urea and its intermediates Effective date of registration: 20210223 Granted publication date: 20180126 Pledgee: Agricultural Bank of China Limited Chifeng Baima sub branch Pledgor: CHIFENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2021150000018 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Granted publication date: 20180126 Pledgee: Agricultural Bank of China Limited Chifeng Baima sub branch Pledgor: CHIFENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2021150000018 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Method for preparing N - (4- (3-amino-1H-indole-4-yl) phenyl) - N '- (2-fluoro-5-methylphenyl) urea and its intermediates Granted publication date: 20180126 Pledgee: Agricultural Bank of China Limited Chifeng Baima sub branch Pledgor: CHIFENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2024150000003 |