CN103570754B - 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 - Google Patents
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 Download PDFInfo
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- CN103570754B CN103570754B CN201210279813.XA CN201210279813A CN103570754B CN 103570754 B CN103570754 B CN 103570754B CN 201210279813 A CN201210279813 A CN 201210279813A CN 103570754 B CN103570754 B CN 103570754B
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- -1 amino 1H indazoles Chemical class 0.000 title claims abstract description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229910052731 fluorine Inorganic materials 0.000 title abstract description 6
- 239000011737 fluorine Substances 0.000 title abstract description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title abstract 2
- 235000013877 carbamide Nutrition 0.000 title abstract 2
- 150000003672 ureas Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- 229910000085 borane Inorganic materials 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 239000002585 base Substances 0.000 claims description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 229910052763 palladium Inorganic materials 0.000 claims description 15
- 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
- 239000003054 catalyst Substances 0.000 claims description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 14
- YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims description 10
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 10
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 8
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 235000011056 potassium acetate Nutrition 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 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 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HJIPMDRWTKBYCR-UHFFFAOYSA-N n-fluoro-3-methylaniline Chemical class CC1=CC=CC(NF)=C1 HJIPMDRWTKBYCR-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- BTQZKHUEUDPRST-UHFFFAOYSA-N 1-fluoro-3-methylbenzene Chemical class CC1=CC=CC(F)=C1 BTQZKHUEUDPRST-UHFFFAOYSA-N 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 82
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000004327 boric acid Substances 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 27
- 238000010792 warming Methods 0.000 description 22
- 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
- 238000001514 detection method Methods 0.000 description 19
- 150000002118 epoxides Chemical class 0.000 description 17
- 239000002994 raw material Substances 0.000 description 16
- 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 description 13
- 229910052796 boron Inorganic materials 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 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
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- SCWWDULYYDFWQV-UHFFFAOYSA-N (2-hydroxyphenoxy)boronic acid Chemical compound OB(O)OC1=CC=CC=C1O SCWWDULYYDFWQV-UHFFFAOYSA-N 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- GGBJHURWWWLEQH-UHFFFAOYSA-N butylcyclohexane Chemical compound CCCCC1CCCCC1 GGBJHURWWWLEQH-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 150000001924 cycloalkanes Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 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
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- 229910002666 PdCl2 Inorganic materials 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 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
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000005059 solid analysis Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- 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
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- XHDGJGJBAQDXON-UHFFFAOYSA-N 4,6,6-trimethylbicyclo[3.1.1]heptane-4,5-diol Chemical class C1C2(O)C(C)(C)C1CCC2(O)C XHDGJGJBAQDXON-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
- ZCZSIDMEHXZRLG-UHFFFAOYSA-N Heptyl acetate Chemical compound CCCCCCCOC(C)=O ZCZSIDMEHXZRLG-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
- NMARXKNYACRWOS-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.NC1=CC=C(C=C1)OB(O)O Chemical class OC(C)(C)C(C)(C)O.NC1=CC=C(C=C1)OB(O)O NMARXKNYACRWOS-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 150000001638 boron Chemical class 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 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
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000011630 iodine Substances 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 238000001556 precipitation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 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
- AVYGCQXNNJPXSS-UHFFFAOYSA-N 2,5-dichloroaniline Chemical class NC1=CC(Cl)=CC=C1Cl AVYGCQXNNJPXSS-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-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
- LJWAPDSCYTZUJU-UHFFFAOYSA-N 3-fluoro-4-methoxyaniline Chemical class COC1=CC=C(N)C=C1F LJWAPDSCYTZUJU-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
- HKVGLVBQYVEJRZ-UHFFFAOYSA-N CC=C.O=C=O Chemical compound CC=C.O=C=O HKVGLVBQYVEJRZ-UHFFFAOYSA-N 0.000 description 1
- NTTSSAONTDQRAV-UHFFFAOYSA-N CCC([O])=O Chemical compound CCC([O])=O NTTSSAONTDQRAV-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@](CIC)C(*C12)C(C(C)CCC3)[C@]3[C@]1C2(C)N Chemical compound C[C@](CIC)C(*C12)C(C(C)CCC3)[C@]3[C@]1C2(C)N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000008901 benefit 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- NEAXPWWDTURYGE-UHFFFAOYSA-N chlorobenzene ethyl acetate Chemical compound CCOC(C)=O.ClC1=CC=CC=C1 NEAXPWWDTURYGE-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000007796 conventional method Methods 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
- 229940079593 drug Drugs 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000012423 maintenance Methods 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
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical class COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- DJYLHNATHGUBMB-UHFFFAOYSA-N n-bromo-4-methylaniline Chemical class CC1=CC=C(NBr)C=C1 DJYLHNATHGUBMB-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 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
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical class CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
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- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- 239000001294 propane Substances 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
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux 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
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 238000012360 testing method Methods 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides 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.Specifically, the invention provides a kind of preparation method of Formulas I boric acid ester compound, including step：Formula III compound is reacted with formula IV compound reaction production V compounds, and Formula V compound with borane reagent, generates compound of formula I.This method has reaction convenient, and intermediate is easy to get, high income, and product purity is up to more than 98.5%, the features such as cost of material is low, is adapted to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of N- (4- (3- amino-1 h-indazoles -4-
Base) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea and its intermediate boric acid ester compound preparation method.
Background technology
Angiogenesis is the physiology course that capillary grows out from already present blood vessel network, can meet that tissue is given birth to
Into when nutrition supply, maintenance for tumour or growth are most important, and therefore, angiogenesis inhibitors are considered as that cancer is controlled
The effective means for the treatment of.The receptor tyrosine kinase (RTK) of blood vessel endothelium albumen plays an important roll in angiogenesis, can
As antineoplastic action target spot.
Abbott has developed a series of RTK inhibitor (WO2004113304A1), including indazole, benzoisoxazole and
Benzisothiazole kinase inhibitors, they can suppress all vascular endothelial growth factor receptors in nanomolar range specificity
(VEGFR) and platelet growth factor acceptor (PDGFR) family's EGFR-TK (TK) is active, wherein, N- (4- (3- amino-
1H- indazole -4- bases) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea is exactly most to have one of candidate compound of DEVELOPMENT PROSPECT.
N- (4- (3- amino-1 h-indazole -4- bases) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea (Linifanib, ABT-
869) structural formula is：
Preclinical study result shows that its antitumor activity is notable, and good pharmacokinetics is shown in different animals
Matter, the multinomial clinical test of this product is currently carried out, to evaluate it to Several Kinds of Malignancy, including kidney, liver cancer, Colon and rectum
The effect of cancer, breast cancer, non-small cell lung cancer and acute myeloid leukemia.
2009, Albert W.Kruger etc. were in document Org.Pro.Res.Dev.2009, disclosed in 13,1419-1425
Following synthetic route：
In the route, (one of compound i.e. of the invention to be synthesized --- the Formula IV chemical combination of midbody compound 4 is obtained
Thing) used in raw material 4- amino phenyl boric acid pinacols ester 2 and the fluoro- 5- methyl phenyl ester trivalent lattice of isocyanic acid 2- it is expensive and be not easy to obtain, it is former
Expect that cost is high, be not suitable for industrialized production.
In order to solve the problems, such as raw material 4- amino phenyl boric acid pinacol esters, bang dragon is waited《Chinese pharmaceutical chemistry magazine》,
22 (1), 26-28,2012.Following synthesis ABT-869 route is reported in document：
Above-mentioned route voluntarily synthesizes 4- amino phenyl boric acid pinacol esters, but to undergo the reaction of 5 steps, route length.Obtain centre
The yield of body 4 only has 38% or so, so being also not suitable for industrialized production.
In summary, there is an urgent need to efficient preparation N- (4- (the 3- ammonia of low, the suitable industrialized production of development cost for this area
Base -1H- indazole -4- bases) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea and similar compound technique.
The content of the invention
It is an object of the invention to provide a kind of novel preparation N- (4- (3- amino-1 h-indazole -4- bases) phenyl)-N ' -
The method of (the fluoro- 5- aminomethyl phenyls of 2-) urea (ABT-869) and its intermediate, the technique solve prior art because cost of material is held high
Expensive or route is long, yield low the problem of causing production cost high.
The first aspect of the present invention provides a kind of preparation method of compound of formula I, and this method comprises the following steps：
1) in the presence of a base, formula III compound is reacted with formula IV compound, forms Formula V compound；
2) in the presence of alkali and palladium catalyst, Formula V compound is reacted with borane reagent, forms compound of formula I；
It is above-mentioned it is various in,
R1 be on phenyl ring optional position one or more (such as 1,2,3,4 or 5) substituent, each R1 can it is identical or
It is different and independently selected from the following group：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；
R2 and R3 independently is hydroxyl or C1-6Alkoxy, C1-6Acyloxy, or R2 and R3 collectively form substitution or not taken
The C in generation1-8The epoxide of alkane two, C6-10Fragrant two epoxides, or C1-8The epoxide of cycloalkanes two；Wherein described substitution is that have one or more (such as
1-5 or 1-3) substituent that is selected from the group：C1-6Alkyl, halogen, phenyl, benzyl ,-CH2-、C1-6Alkoxy, C1-6Acyl group,
C1-6Acyloxy, C1-6Alkoxy carbonyl group；
R4 is selected from the group：H、F、Cl、Br、I.
In another preference, R2 and R3 independently are hydroxyl or C1-4Alkoxy.
In another preference, R1 be two be located at phenyl ring optional position identical or different substituents, the substitution
Base is selected from：F、Cl、Br、I、C1-6Alkyl；And/or
R2 and R3 collectively forms substituted or unsubstituted C2-8The epoxide of alkane two, wherein described substituted defined as described above；
And/or
R4 is Cl or Br.
In another preference, during as substituent, described phenyl includes substituted or unsubstituted phenyl, the benzyl
Including substituted or unsubstituted benzyl, and described substitution refers to and is selected from the group with one or more (such as 1-5 or 1-3)
Substituent：C1-6Alkyl, halogen, C1-6Alkoxy, OH, NH3。
In another preference, described compound of formula I is following structure：
In another preference, the alkali described in step 1) and step 2) is selected from organic base or inorganic base；
Preferably, described organic base is selected from the group：Triethylamine, diethylamine, diisopropylethylamine, pyridine or its combination；
More preferably, described alkali is triethylamine or diisopropylethylamine；
In another preference, described inorganic base is selected from sodium acetate, potassium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphorus
Acid dihydride potassium, dipotassium hydrogen phosphate, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, sodium hydroxide, potassium hydroxide or its group
Close.
In another preference, described alkaline reagent is selected from sodium acetate, potassium acetate, sodium acid carbonate, potassium carbonate, or its group
Close.
In another preference, the alkali of step 1) and step 2) is identical.
In another preference, the mol ratio of the dosage of alkali and formula III compound is 0.5~5 in step 1)：1, more preferably
For 2~3.5：1.
In another preference, the mol ratio of the compound of step 1) Chinese style IV and formula III compound is 0.2~1：1, preferably
0.8~1：1.
In another preference, reaction temperature is -20~100 DEG C in step 1), and more preferably, reaction temperature is -10~50
℃。
In another preference, the reaction time is 0.5~24 hour, more preferably 1~12 hour in step 1).
In another preference, the borane reagent described in step 2) is selected from the group：The boron of titanium dioxide two, tetramethoxy hypoboric acid
Ester, tetraethoxy diborate, four n-butoxy diborates, tetraisopropoxide diborate, four positive propoxy diborates,
It is duplex catechol borate, duplex pinacol borate, connection boric acid DOPCP, double [(-) pinane diol] two boron esters, double
(diisopropyl-L-TARTARIC ACID diethylester) diborate, the boron ester of double (1S, 2S, 3R, 5S) (+)-pinane diols two, duplex (2- first
Base -2,4-PD) borate, duplex (2,4- dimethyl -2,4-PD) borate, duplex (D- ethyl tartrates) boron
Acid esters or its combination.
In another preference, the borane reagent is selected from duplex catechol borate, duplex pinacol borate, duplex
(D- ethyl tartrates) borate；More preferably it is duplex pinacol borate.
In another preference, the dosage of the borane reagent is 0.8~5 with the mol ratio of the compound of formula V：1, preferably 1~
1.5：1.
In another preference, the dosage of the alkali described in step 2) is 0.5~5 with the mol ratio of the compound of formula V：1,
It is preferred that 2~3.5：1；And/or
Palladium catalyst described in step 2) 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 dosage of palladium catalyst described in step 2) is 0.01~0.2 with the mol ratio of the compound of formula V：1, be preferably
0.02~0.08:1.
In another preference, reaction temperature is 20~150 DEG C, preferably 60~100 DEG C in step 2).
In another preference, the reaction time is 0.5~24 hour, more preferably 1~12 hour in step 2).
In another preference, this method comprises the following steps：
I) in the presence of a base, the fluoro- 5- methyl phenyl esters of isocyanic acid 2- react with para-bromoaniline, form Formula VII compound；With
Ii) in atent solvent, in the presence of alkali and palladium catalyst, Formula VII compound is reacted with borane reagent, forms Formula IV
Compound：
In another preference, step i) reaction temperature is -10~50 DEG C.
In another preference, step ii) reaction temperature be 60~100 DEG C.
In another preference, the alkali in step i) is diisopropylethylamine.
In another preference, step ii) in, atent solvent be DMF (DMF), dimethyl sulfoxide (DMSO),
Or its combination.
In another preference, step ii) in VII compounds and the mol ratio of borane reagent, alkali, palladium catalyst be 1：0.8
~5：0.5~5：0.01~0.2；More preferably it is 1：1~1.5：2~3.5：0.02~0.08.
In another preference, methods described also includes passing through following steps formula III compounds：
1a) in atent solvent, in the presence of a base, Formula II compound is reacted with triphosgene, shape compound of Formula III：
It is above-mentioned it is various in, R1 is one or more substituents of the optional position on phenyl ring, and each R1 may be the same or different
And independently selected from the following group：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy.
In another preference, step 1a) in, described alkali is organic base (such as diisopropylethylamine).
In another preference, step 1a) in, described atent solvent is organic solvent, selected from esters solvent, halogenated hydrocarbons
Solvent, ether solvent, aromatic hydrocarbon solvent or its combination；More preferably, described organic solvent is ethyl acetate, dichloromethane, four
Hydrogen furans, or its combination.
The second aspect of the present invention, there is provided a kind of preparation method of formula A compounds, including step：
1) in the presence of a base, formula III compound is reacted with formula IV compound, forms Formula V compound；
2) in the presence of alkali and palladium catalyst, Formula V compound is reacted with borane reagent, forms compound of formula I；
It is above-mentioned it is various in,
R1 be on phenyl ring optional position one or more substituents, each R1 may be the same or different and independently selected from
The following group：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；
R2 and R3 independently is hydroxyl or C1-6Alkoxy, C1-6Acyloxy, or R2 and R3 collectively form substitution or not taken
The C in generation1-8The epoxide of alkane two, C6-10Fragrant two epoxides, or C1-8The epoxide of cycloalkanes two；Wherein described substitution is selected from one or more
The substituent of the following group：C1-6Alkyl, halogen, phenyl, benzyl ,-CH2-、C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alcoxyl
Carbonyl；
R4 is selected from the group：H, halogen;
3) compound of formula I and 3- amino -4- iodine indazole are reacted, form formula A compounds,
In formula, R isAnd X is that the one or more (such as 1,2,3,4 or 5) of optional position takes on phenyl ring
Dai Ji, each R1 may be the same or different and independently selected from the following groups：Halogen, C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy.
More preferably, X H, o-F, m-F, p-F, o-Me, m-Me, P-Me, m-Et, m-Cl, m-Br, m-CF3、m-OH、2-F-
5-Me、4-F-3-Me、3-F-Me、2-F-5-CF3、2-Cl-5-Cl、2-Me-4-Me、3-F-4-OMe、2-Br-4-Me、2-Me-
5-CF3。
In another preference, described compound of formula I is Formula IV compound, and formula A compounds are ABT-869.
In the third aspect of the present invention, there is provided a kind of N- (4- (3- amino-1 h-indazole -4- bases) phenyl)-N '-(2-
Fluoro- 5- aminomethyl phenyls) urea preparation method, including step：
Formula IV compound and 3- amino -4- iodine indazole are reacted, form N- (4- (3- amino-1 h-indazole -4- bases) benzene
Base)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea：
Methods described also includes：With the method formula VI compounds described in first aspect present invention.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical scheme.As space is limited, exist
This no longer tires out one by one states.
Embodiment
The present inventor by in-depth study extensively, develop first it is a kind of by following reaction, efficiently at low cost
The technique for preparing compound of formula I：
It can be used as the intermediate of chemical synthesis by compound of formula I made from the technique, for synthetic drug.It is representational
Medicine includes (but being not limited to)：Indazole, benzoisoxazole and benzisothiazole kinase disclosed in WO2004113304A1
Inhibitor.
, can be inexpensive, efficient by the Formula IV intermediate by taking Formula IV intermediate (a kind of preferable compound of formula I) as an example
Ground prepare compound ABT-869, thus it is especially suitable for industrialized production.Other Formulas I intermediates, pass through leaving group-B (R2)
(R3) similar reaction, the formula A compound similar with ABT-869 can be prepared.
Term
As used in the present invention, term " ABT-869 ", " compound ABT-869 " or " Linifanib " are used interchangeably, all
Referring to compound N-(4- (3- amino-1 h-indazole -4- bases) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea or its can pharmaceutically connect
The salt received.
As used herein, term " C1-6Alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, such as methyl, second
Base, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
Term " C1-6Alkoxy " refers to the straight or branched alkoxyl with 1-6 carbon atom, for example, methoxyl group, ethyoxyl,
Propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " C1-6Acyl group " refers to the acyl group with 1-6 carbon atom, such as formoxyl, acetyl group, propiono, isopropyl acyl
Base, bytyry, isobutyryl, secondary bytyry, tertiary bytyry or similar group.
Term " C1-6Acyloxy " refers to the acyloxy with 1-6 carbon atom, such as formyloxy, acetoxyl group, propionyl oxygen
Base, isopropenoxy, butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, tertiary butyryl acyloxy or similar group.
Term " C1-6Alkoxy carbonyl group " refers to the straight or branched alkoxy carbonyl group with 1-6 carbon atom, such as methoxycarbonyl group,
Carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl or similar
Group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.Term " halo " refers to by identical or different one or more above-mentioned
The group of halogen atom substitution, such as trifluoromethyl, pentafluoroethyl group or similar group.
Term " C1-8The epoxide of alkane two " refers to the epoxide of straight or branched alkane two with 1-8 carbon atom, such as-OC1-8Alkyl
O-、-OCH2CH2O-、-OCH2CH2CH2O-、-OCH2CH(CH3)CH2O-、-OCH2CH(CH3)CH(CH3)CH2O-、-OCH2C
(CH3)2CH2O- or similar groups.
Term " C1-8The epoxide of cycloalkanes two " refers to the epoxide of cycloalkanes two or the epoxide of bridged ring alkane two with 1-8 carbon atom, and such as 1,2-
Dioxy butylcyclohexane, 1,3- dioxies butylcyclohexane, the epoxide of (-) pinane two(1S,2S,3R,5S)
The epoxide of (+)-pinane twoOr similar group.
Term " phenyl " includes unsubstituted and substitution phenyl, wherein substitution refers to one or more hydrogen atom quilts on phenyl ring
It is substituted for halogen atom, C1-6Alkyl, C1-6Alkoxy or similar group.
Term " C6-10Fragrant two epoxides " refer to the epoxide of virtue two with 6-10 carbon atom, such as the epoxide benzene of 1,2- bis-, 1,2- bis-
Epoxide naphthalene or similar group.
Term " BTC " refers to triphosgene, molecular formula C3H6O3。
Term " esters solvent " refers to the based organic solvent with 2-20 (preferably 2-10) carbon atoms, such as acetic acid
Methyl esters, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, hexyl acetate, acetic acid
Heptyl ester, decyl acetate, ethylene acetate, or similar solvent.
Term " ether solvent " refers to the straight or branched alkoxyl with 2-20 (preferably 2-10) carbon atoms, such as
Ether, propyl ether, isopropyl ether, ethyl n-butyl ether, di-n-butyl ether, diamyl ether, tetrahydrofuran, oxirane, expoxy propane, 1,3-
Dioxolane or similar solvent.
Preparation method
Compound or compound ABT-869 can be made by following method shown in the logical formula (I) of the present invention.But it should manage
Solution, hereinafter given method actual conditions, such as the amount of reactant, solvent, alkali, compound used therefor, reaction temperature, reaction
Required time etc., it is exemplary not from the limited effect.The compounds of this invention will optionally can also describe in this manual
Or various synthetic methods known in the art combine and be easily made, such combination can be by art of the present invention
Technical staff readily carry out.
In the preparation process in accordance with the present invention, respectively react generally in atent solvent, reaction temperature is -20 DEG C to reflux temperature
Carried out under (preferably -10 DEG C to 100 DEG C).Reaction time is usually 0.1-24 hours, preferably 0.5-18 hours.
The preparation of compound of formula I
Compound of formula I can be prepared as follows:
In the presence of a base, formula III compound is reacted with formula IV compound, forms Formula V compound；
Then, in the presence of alkali and palladium catalyst, Formula V compound is reacted with borane reagent, forms compound of formula I.
Starting materials of formulae III compounds and formula IV compound can be prepared by a conventional method or be commercially available.
In the present invention, representational borane reagent includes (but being not limited to)：The boron of titanium dioxide two, tetramethoxy hypoboric acid
Ester, tetraethoxy diborate, four n-butoxy diborates, tetraisopropoxide diborate, four positive propoxy diborates,
It is duplex catechol borate, duplex pinacol borate, connection boric acid DOPCP, double [(-) pinane diol] two boron esters, double
(diisopropyl-L-TARTARIC ACID diethylester) diborate, the boron ester of double (1S, 2S, 3R, 5S) (+)-pinane diols two, duplex (2- first
Base -2,4-PD) borate, duplex (2,4- dimethyl -2,4-PD) borate, duplex (D- ethyl tartrates) boron
Acid esters or its combination.
Preferably, the borane reagent is selected from duplex catechol borate, duplex pinacol borate, duplex (D- winestones
Diethyl phthalate) borate；More preferably it is duplex pinacol borate.
Compound ABT-869 preparation
Compound ABT-869 can be following to prepare by intermediate Formula IV compound:
Formula IV compound and 3- amino -4- iodine indazole are reacted, form N- (4- (3- amino-1 h-indazole -4- bases) benzene
Base)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea：
Compared with prior art, the present invention has the advantage that：
1st, the inventive method can easily obtain N- (4- (3- amino-1 h-indazole -4- bases) phenyl)-N '-(2- is fluoro-
5- aminomethyl phenyls) urea key intermediate boric acid ester compound.
2nd, method high income of the invention.
3rd, the ABT-869 of high-purity can be easily made in the inventive method, and product purity is up to more than 98%.
4th, cost of material is low, is adapted to industrialized production.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
The compound 1-I of embodiment 1 preparation
Step A：
Triphosgene (8.9g, 30.0mmol) is dissolved in 100mL ethyl acetate, addition triethylamine (10.1g,
99.8mmol), -10~-5 DEG C are cooled under stirring, 2,5- dichloroanilines (8.1g, 50.0mmol) ethyl acetate is slowly added dropwise
(80mL) solution, about 0.5-1 hours are added dropwise.It is added dropwise, is warming up to 50 DEG C of stirring reaction 1-2 hours.TLC detection raw material reactions
Finish, be cooled to room temperature, reaction solution direct plunges into the next step.
Step B：
Previous step reaction solution is warming up to 25~30 DEG C, para-bromoaniline (6.9g, 40.1mmol), two are added dropwise into reaction solution
Ethyl acetate (50mL) solution of wopropyl ethyl amine (6.5g, 50.3mmol), about 0.5-1 hours are added dropwise.It is added dropwise, continues to control
25~30 DEG C of reaction 1-2 hours of temperature.Reaction solution is concentrated under reduced pressure half volume, 100mL water is added dropwise under stirring into system, has
White solid separates out, and filtering, filter cake is dried in vacuo to obtain 1-III compound 11.6g, yield 80.4%.MS(ESI)m/z：(M+H)
=361.0。
Step C：
The addition 1-III compounds (11.6g, 32.2mmol) into reaction bulb successively, the boron of titanium dioxide two (2.6g,
48.3mmol), sodium acid carbonate (6.7g, 79.8mmol) and water (100mL), stir, and add Pd (PPh3)4(1.1g,
1.0mmol).It is warming up to backflow, temperature control reaction 2-3 hours.TLC detection raw material reactions are finished, and reaction system is slowly cooled into 0
~5 DEG C, solid is separated out, continues insulated and stirred 0.5-1 hours.Filtering, filter cake recrystallized from acetonitrile, drying obtain 1-I compounds
8.7g, yield 83.1%, HPLC detection purity 98.7%.MS(ESI)m/z：(M+H)=326.0.
The compound 2-I of embodiment 2 preparation
Step A：
Triphosgene (14.8g, 100.0mmol) is dissolved in 100mL tetrahydrofurans, addition diisopropylethylamine (13.4g,
103.7mmol), -10~-5 DEG C are cooled under stirring, 1- amino -2,4- dimethyl benzene (12.1g, 100.0mmol) is slowly added dropwise
Tetrahydrofuran (120mL) solution, be added dropwise about 0.5-1 hours.It is added dropwise, is warming up to return stirring reaction 1-2 hours.TLC
Detection raw material reaction finishes, and is cooled to room temperature, reaction solution direct plunges into the next step.
Step B：
Previous step reaction solution is warming up to 25~30 DEG C, potassium carbonate (13.8g, 100.0mmol) is added, then to reaction solution
Middle tetrahydrofuran (50mL) solution that para-bromoaniline (17.2g, 100.0mmol) is added dropwise, is added dropwise about 0.5-1 hours.It is added dropwise,
Continue 25~30 DEG C of reaction 1-2 hours of temperature control.Reaction solution is concentrated under reduced pressure half volume, is added dropwise under stirring into system
100mL water, there is white solid precipitation.Filtering, filter cake are dried in vacuo to obtain 2-II I 25.6g, yield 80.2%.MS
(ESI)m/z：(M+H)=320.2, (M+Na)=342.2.
Step C：
The addition 2-III compounds (25.6g, 80.2mmol) into reaction bulb successively, the boron of tetramethoxy two (14.0g,
96.4mmol), potassium acetate (7.9g, 80.5mmol) and methanol (200mL), stir, and add PdCl2(dppf) (5.9g,
8.0mmol).It is warming up to backflow, temperature control reaction 2-3 hours.TLC detection raw material reactions are finished, and reaction system is cooled into room temperature,
500mL water is added, with 300ml points of 3 extractions of dichloromethane, 300mL saturated common salts water washing 1 time, anhydrous sodium sulfate drying.Filter
Liquid is concentrated under reduced pressure into dry that crude product 24.3g, recrystallized from acetonitrile, drying obtain 2-I compound 20.6g, yield 82.2%, HPLC inspections
Survey purity 99.1%.MS(ESI)m/z：(M+H)=313.1.
The compound 3-I of embodiment 3 preparation
Step A：
The fluoro- 5- methylanilines (5.0g, 39.9mmol) of 2- are dissolved in 150mL dichloromethane, add diisopropylethylamine
(6.2g, 48.0mmol).- 10~-5 DEG C are cooled under stirring, triphosgene (4.8g, 16.2mmol) dichloromethane is slowly added dropwise
(100mL) solution, about 0.5-1 hours are added dropwise.It is added dropwise, is warming up to and reaction 3-4 hours are stirred at room temperature, TLC detection raw materials is anti-
It should finish, reaction solution direct plunges into the next step.
Step B：
Previous step reaction solution is warming up to 25~30 DEG C, the dropwise addition para-bromoaniline (6.9g, 40.1mmol) into reaction solution, three
Dichloromethane (30mL) solution of ethamine (8.1g, 80.0mmol), about 0.5-1 hours are added dropwise.It is added dropwise, continuation temperature control 25~
30 DEG C of reaction 1-2 hours.Obtained reaction mixture is concentrated under reduced pressure half volume, 100mL is added dropwise under stirring into system
Water, there is white solid precipitation, filter, filter cake is dried in vacuo to obtain Formula VII compound 10.7g, yield 82.6%.MS(ESI)m/z：
(M+H)=324.1。
Step C：
The addition Formula VII compound (10.7g, 33.1mmol) into reaction bulb successively, duplex pinacol borate (9.2g,
36.3mmol), potassium acetate (9.7g, 98.8mmol) and DMF (100mL).Stir, add PdCl2(dppf) (1.2g,
1.7mmol), 80~85 DEG C are warming up to, temperature control reaction 2-3 hours.TLC detection raw material reactions are finished, and reaction system is cooled to
Room temperature, 200mL water is added, with 200ml points of 3 extractions of dichloromethane, 200mL saturated common salts water washing 1 time, anhydrous sodium sulfate is done
Dry, filtrate decompression is concentrated to dryness to obtain crude product 12.5g.Recrystallized from acetonitrile, dry and obtain Formula IV compound 10.6g, yield 86.5%,
HPLC detection purity is 99.2%.MS(ESI)m/z：(M+H)=371.2.
The compound 4-I of embodiment 4 preparation
Step A：
The bromo- 4- methylanilines (37.2g, 200.0mmol) of 2- are dissolved in 200mL toluene, addition pyridine (47.5g,
600.5mmol), -10~-5 DEG C are cooled under stirring, triphosgene (29.6g, 100.0mmol) toluene (150mL) is slowly added dropwise
Solution, about 0.5-1 hours are added dropwise.It is added dropwise, is warming up to return stirring reaction 1-2 hours.TLC detection raw material reactions finish,
Room temperature is cooled to, reaction solution direct plunges into the next step.
Step B：
Reaction solution adds potassium carbonate (41.4g, 300.0mmol) one step up, is warming up to 25~30 DEG C, and paraiodoaniline is added dropwise
Toluene (400mL) solution of (39.4g, 180.0mmol), about 1-2 hours are added dropwise.It is added dropwise, it is anti-continues 25~30 DEG C of temperature control
Answer 1-2 hours.Reaction solution is concentrated under reduced pressure half volume, 1000mL water is added dropwise under stirring into system, there is white solid analysis
Go out.Filtering, filter cake are dried in vacuo to obtain 4-III compound 63.2g, yield 81.4%.MS(ESI)m/z：(M+H)=432.1.
Step C：
4-III compounds (63.2g, 146.6mmol), duplex catechol borate are added into reaction bulb successively
(35.7g, 150.0mmol), potassium carbonate (27.6g, 200.0mmol), methanol (500mL) and water (500mL), stir, add
Enter Pd (PPh3)4(8.0g).60 DEG C are warming up to, temperature control reaction 2-3 hours.TLC detection raw material reactions finish, and reaction system is cold
But to 0-5 DEG C, solid is separated out, continues stirring 1 hour.Filtering, filter cake recrystallized from acetonitrile, drying obtain 4-I compounds
48.3g, yield 77.9%, HPLC detection purity is 98.5%.MS(ESI)m/z：(M+H)=424.1.
The compound 5-I of embodiment 5 preparation
Step A：
Triphosgene (5.9g, 20.0mmol) is dissolved in 100mL isopropyl acetates, addition diisopropylethylamine (6.5g,
50.3mmol), -10~-5 DEG C are cooled under stirring, the second of the fluoro- 4- aminoanisoles (7.1g, 50.0mmol) of 3- is slowly added dropwise
Isopropyl propionate (50mL) solution, about 0.5-1 hours are added dropwise.It is added dropwise, is warming up to and reaction 3-4 hours are stirred at room temperature.TLC is detected
Raw material reaction finishes, and reaction solution direct plunges into the next step.
Step B：
Reaction solution adds potassium carbonate (11.0g, 79.7mmol) one step up, is warming up to 25~30 DEG C, and para-bromoaniline is added dropwise
Isopropyl acetate (30mL) solution of (6.9g, 40.1mmol), about 0.5-1 hours are added dropwise.It is added dropwise, continues temperature control 45~50
DEG C reaction 1-2 hours.Reaction solution is concentrated under reduced pressure half volume, 100mL water is added dropwise under stirring into system, there is white solid
Separate out.Filtering, filter cake are dried in vacuo to obtain 5-II I 11.4g, yield 83.8%.MS(ESI)m/z：(M+H)=340.1.
Step C：
5-III compounds (11.4g, 33.6mmol), duplex (D- ethyl tartrates) boron are added into reaction bulb successively
Acid esters (15.1g, 35.0mmol), sodium acetate (8.2g, 100.0mmol) and isopropyl acetate (200mL), stir, and add
Pd(OAc)2(0.4g, 1.8mmol).90~100 DEG C are warming up to, temperature control reaction 2-3 hours.TLC detection raw material reactions finish, will
Reaction system is cooled to room temperature, adds 200mL water, with 200ml points of 3 extractions of dichloromethane, 200ml saturated common salts water washing 1
It is secondary, anhydrous sodium sulfate drying.Filtrate decompression is concentrated to dryness to obtain crude product 15.2g, recrystallized from acetonitrile, and drying obtains 5-I compounds
13.1g, yield 82.1%, HPLC detection purity is 98.8%.MS(ESI)m/z：(M+H)=475.2.
The compound 6-I of embodiment 6 preparation
Step A：
Triphosgene (5.9g, 20.0mmol) is dissolved in 100mL ethyl acetate, addition triethylamine (10.1g,
99.8mmol), -10~-5 DEG C are cooled under stirring, 2- methyl -5- 5-trifluoromethylanilines (8.8g, 50.0mmol) are slowly added dropwise
Ethyl acetate (80mL) solution, be added dropwise about 0.5-1 hours.It is added dropwise, is warming up to 60 DEG C of stirring reaction 1-2 hours.TLC is examined
Survey raw material reaction to finish, be cooled to room temperature, reaction solution direct plunges into the next step.
Step B：
Sodium hydroxide (2.0g, 50.0mmol) is added in reaction solution one step up, 25~30 DEG C is warming up to, is added dropwise to chlorobenzene
Ethyl acetate (50mL) solution of amine (5.7g, 45.0mmol), about 0.5-1h is added dropwise.It is added dropwise, continues 25~30 DEG C of temperature control
React 1-2 hours.Reaction solution is concentrated under reduced pressure half volume, 100mL water is added dropwise under stirring into system, there is white solid analysis
Go out.Filtering, filter cake are dried in vacuo to obtain 6-III compound 9.3g, yield 75.3%.MS(ESI)m/z：(M+H)=275.7.
Step C：
6-III compounds (9.3g, 33.9mmol), double (1S, 2S, 3R, 5S) (+)-pinanes are added into reaction bulb successively
The boron ester (12.2g, 34.0mmol) of glycol two, triethylamine (10.1g, 99.8mmol) and dioxane (100mL), stir,
Add Pd (PPh3)4(0.8g, 1.0mmol).It is warming up to backflow, temperature control reaction 2-3 hours.TLC detection raw material reactions finish, will
Reaction system is cooled to room temperature, adds 200mL water, with 200ml points of 3 extractions of dichloromethane, 200ml saturated common salts water washing 1
It is secondary, anhydrous sodium sulfate drying.Filtrate decompression is concentrated to dryness to obtain crude product 13.5g, recrystallized from acetonitrile, and drying obtains 6-I compounds
11.3g, yield 79.7%, HPLC detection purity is 98.6%.MS(ESI)m/z：(M+H)=419.3.
The compound 7-I of embodiment 7 preparation
Step A：
Triphosgene (8.9g, 30.0mmol) is dissolved in 100mL dichloromethane, addition diisopropylethylamine (12.9g,
99.8mmol), -10~-5 DEG C are cooled under stirring, 4- methylanilines (5.4g, 50.0mmol) dichloromethane is slowly added dropwise
(50mL) solution, about 0.5-1 hours are added dropwise.It is added dropwise, is warming up to and reaction 3-4 hours are stirred at room temperature.TLC detection raw material reactions
Finish, reaction solution direct plunges into the next step.
Step B：
Reaction solution adds potassium carbonate (11.0g, 80.0mmol) one step up, is warming up to 25~30 DEG C, and para-bromoaniline is added dropwise
Dichloromethane (30mL) solution of (6.9g, 40.0mmol), about 0.5-1 hours are added dropwise.It is added dropwise, continues 35~40 DEG C of temperature control
React 1-2 hours.Reaction solution is concentrated under reduced pressure half volume, 100mL water is added dropwise under stirring into system, there is white solid analysis
Go out.Filtering, filter cake are dried in vacuo to obtain 7-III compound 9.9g, yield 81.2%.MS(ESI)m/z：(M+H)=306.1.
Step C：
7-II Is (9.9g, 32.5mmol), duplex (2,4- dimethyl -2,4- penta are added into reaction bulb successively
Glycol) borate (11.3g, 40.0mmol), sodium acetate (4.1g, 50.0mmol) and tetrahydrofuran (200mL), stir,
Add Pd (OAc)2(0.4g, 1.6mmol).It is warming up to backflow temperature control reaction 2-3 hours.TLC detection raw material reactions finish, will be anti-
Answer system to be cooled to room temperature, add 200mL water, divided 3 times with dichloromethane 200ml and extracted, 200mL saturated common salts water washing 1 time,
Anhydrous sodium sulfate drying.Filtrate decompression is concentrated to dryness to obtain crude product 15.2g, recrystallized from acetonitrile, and drying obtains 7-I compound 9.6g,
Yield 80.7%, HPLC detection purity is 98.9%.MS(ESI)m/z：(M+H)=367.2.
The preparation of the N- of embodiment 8 (4- (3- amino-1 h-indazole -4- bases) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea
Formula IV compound (10.6g, 28.6mmol), the 3- amino -4- iodine that embodiment 3 obtains are added into reaction bulb successively
Indazole (8.1g, 31.3mmol), sodium carbonate (7.6g, 71.7mmol), ethanol 100mL, water 100mL.Lower addition is stirred at room temperature
PdCl2(dppf) (0.4g, 0.6mmol), it is warming up to backflow.After backflow 8 hours, decompression boils off ethanol.Second is added in residue
Acetoacetic ester 150mL, 20% aqueous ammonium chloride solution 50mL, stir 30 minutes.Organic layer is separated, is washed with water 3 times, anhydrous sodium sulfate
Dry.Organic layer evaporated under reduced pressure, obtained crude product dichloromethane-ethanol (10：1) recrystallize, obtain white solid 8.0g, receive
Rate 74.8%, HPLC detection purity is 99.0%.MS(ESI)m/z：(M+H)=376.4.
Similarly, by the reaction of leaving away of leaving group, the formula A compounds that X is 2-Cl-5-Cl are made with compound 1-I.
2-Me-4-Me formula A compounds are made with formula 2-I compounds.3-F-4-OMe formula A compounds are made with formula 5-I compounds.
After tested, these formulas A compounds have RTK inhibitory activity.
All it is incorporated as referring in this application in all documents that the present invention refers to, it is independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (14)
1. a kind of preparation method of Formula IV compound, it is characterised in that this method comprises the following steps：
I) in the presence of a base, the fluoro- 5- methyl phenyl esters of isocyanic acid 2- react with para-bromoaniline, form Formula VII compound；With
Ii) in atent solvent, in the presence of alkali and palladium catalyst, Formula VII compound is reacted with borane reagent, forms Formula IV chemical combination
Thing：
And step i) and step ii) described in alkali be organic base or inorganic base, wherein described organic base is selected from the group：Three second
Amine, diethylamine, diisopropylethylamine, pyridine, or its combination；Described inorganic base is selected from sodium acetate, potassium acetate, biphosphate
Sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, sodium hydroxide,
Potassium hydroxide or its combination；
Step ii) described in atent solvent for N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or its combination；
Step ii) described in borane reagent be selected from the group：Duplex pinacol borate；
Step ii) described in palladium catalyst be selected from 1,1 '-bis- (diphenylphosphine) ferrocene, four triphenyl phosphorus palladiums, palladium carbon, acetic acid
Palladium, or its combination.
2. the method as described in claim 1, it is characterised in that described alkali is triethylamine or diisopropylethylamine.
3. the method as described in claim 1, it is characterised in that described alkali is selected from sodium acetate, potassium acetate, sodium acid carbonate, carbon
Sour potassium, or its combination.
4. the method as described in claim 1, it is characterised in that para-bromoaniline and the fluoro- 5- methylbenzenes of isocyanic acid 2- in step i)
The mol ratio of ester is 0.2~1：1.
5. the method as described in claim 1, it is characterised in that para-bromoaniline and the fluoro- 5- methylbenzenes of isocyanic acid 2- in step i)
The mol ratio of ester is 0.8~1：1.
6. the method as described in claim 1, it is characterised in that the dosage of the borane reagent and the mol ratio of Formula VII compound
For 0.8~5：1.
7. the method as described in claim 1, it is characterised in that the dosage of the borane reagent and the mol ratio of Formula VII compound
For 1~1.5：1.
8. the method as described in claim 1, it is characterised in that step ii) described in alkali dosage and Formula VII compound
Mol ratio is 0.5~5：1.
9. the method as described in claim 1, it is characterised in that step ii) described in alkali dosage and Formula VII compound
Mol ratio is 2~3.5：1.
10. the method as described in claim 1, it is characterised in that step ii) described in palladium catalyst for 1,1 '-bis- (hexichol
Base phosphine) ferrocene, four triphenyl phosphorus palladiums.
11. the method as described in claim 1, it is characterised in that step ii) described in palladium catalyst dosage and Formula VII
The mol ratio of compound is 0.01~0.2：1.
12. the method as described in claim 1, it is characterised in that step ii) described in palladium catalyst dosage and Formula VII
The mol ratio of compound is 0.02~0.08:1.
13. the method as described in claim 1, it is characterised in that methods described also includes preparing isocyanic acid by following steps
The fluoro- 5- methyl phenyl esters of 2-：
1a) in atent solvent, in the presence of a base, the fluoro- 5- methylanilines of 2- react with triphosgene, form the fluoro- 5- of isocyanic acid 2-
Methyl phenyl ester：
Described alkali is selected from diisopropylethylamine；
Described atent solvent is selected from ethyl acetate, dichloromethane, tetrahydrofuran, or its combination.
14. a kind of preparation method of N- (4- (3- amino-1 h-indazole -4- bases) phenyl)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea,
It is characterised in that it includes step：
I) in the presence of a base, the fluoro- 5- methyl phenyl esters of isocyanic acid 2- react with para-bromoaniline, form Formula VII compound；With
Ii) in atent solvent, in the presence of alkali and palladium catalyst, Formula VII compound is reacted with borane reagent, forms Formula IV chemical combination
Thing：
Iii) Formula IV compound and 3- amino -4- iodine indazole are reacted, form N- (4- (3- amino-1 h-indazole -4- bases) benzene
Base)-N '-(the fluoro- 5- aminomethyl phenyls of 2-) urea：
And step i) and step ii) described in alkali be organic base or inorganic base, wherein described organic base is selected from the group：Three second
Amine, diethylamine, diisopropylethylamine, pyridine, or its combination；Described inorganic base is selected from sodium acetate, potassium acetate, biphosphate
Sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, sodium hydroxide,
Potassium hydroxide or its combination.
Step ii) described in atent solvent for N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or its combination.
Step ii) described in borane reagent be selected from the group：Duplex pinacol borate；
Step ii) described in palladium catalyst be selected from 1,1 '-bis- (diphenylphosphine) ferrocene, four triphenyl phosphorus palladiums, palladium carbon, acetic acid
Palladium, or its combination.
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| N-（4-氯-3-三氟甲基苯基）-N"-(4-溴苯基)脲的合成;闫凤美等;《中国医药工业杂志》;20091231;第40卷(第9期);656-657 * |
| The Discovery and Development of a Safe, Practical Synthesis of ABT-869;Albert W. Kruger et al.;《Organic Process Research & Development》;20091028;第13卷(第6期);1419-1425 * |
| 抗肿瘤药物linifanib的合成;刘海龙等;《中国药物化学杂志》;20120229;第22卷(第1期);26-28,32 * |
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