CN103288755B - Midbody 4-chlorine-6-amino-7-hydroxy-quinazoline for synthesizing nilotinib type antineoplastic drug and preparation method for midbody 4-chlorine-6-amino-7-hydroxy-quinazoline - Google Patents
Midbody 4-chlorine-6-amino-7-hydroxy-quinazoline for synthesizing nilotinib type antineoplastic drug and preparation method for midbody 4-chlorine-6-amino-7-hydroxy-quinazoline Download PDFInfo
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- CN103288755B CN103288755B CN201310181198.3A CN201310181198A CN103288755B CN 103288755 B CN103288755 B CN 103288755B CN 201310181198 A CN201310181198 A CN 201310181198A CN 103288755 B CN103288755 B CN 103288755B
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- hydroxyquinazoline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 title abstract 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 title abstract 2
- 229960001346 nilotinib Drugs 0.000 title abstract 2
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000010719 annulation reaction Methods 0.000 claims abstract description 6
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 12
- -1 alkyl chloroformate Chemical compound 0.000 claims description 10
- IZVRAXUGTRXXMC-UHFFFAOYSA-N C(C)(=O)NC1=CC=CC(=C1[As](O)(O)=O)O Chemical compound C(C)(=O)NC1=CC=CC(=C1[As](O)(O)=O)O IZVRAXUGTRXXMC-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- BYGOPQKDHGXNCD-UHFFFAOYSA-N tripotassium;iron(3+);hexacyanide Chemical compound [K+].[K+].[K+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] BYGOPQKDHGXNCD-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims 5
- 238000007171 acid catalysis Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000006396 nitration reaction Methods 0.000 abstract description 4
- UGTVVIHMAMPKJT-UHFFFAOYSA-N (2-acetamidophenyl) acetate Chemical compound CC(=O)NC1=CC=CC=C1OC(C)=O UGTVVIHMAMPKJT-UHFFFAOYSA-N 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 13
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- 239000005785 Fluquinconazole Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000000118 anti-neoplastic effect Effects 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000005461 Canertinib Substances 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229960001413 acetanilide Drugs 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 229950002826 canertinib Drugs 0.000 description 2
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 2
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 2
- 229950002205 dacomitinib Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- SZWLHIDOTWYYJU-UHFFFAOYSA-N 6-amino-4-chloroquinazolin-7-ol Chemical compound ClC1=NC=NC2=CC(=C(C=C12)N)O SZWLHIDOTWYYJU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FRJZRJQWLFVEDT-UHFFFAOYSA-K O.[Cl-].[Cl-].[Cl-].[Fe+3].NN Chemical compound O.[Cl-].[Cl-].[Cl-].[Fe+3].NN FRJZRJQWLFVEDT-UHFFFAOYSA-K 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical group NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- KVSLPQXJQYNHIK-UHFFFAOYSA-N c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O Chemical compound c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O KVSLPQXJQYNHIK-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a midbody 4-chlorine-6-amino-7-hydroxy-quinazoline for synthesizing a nilotinib type antineoplastic drug and a preparation method for the midbody 4-chlorine-6-amino-7-hydroxy-quinazoline. The preparation method comprises the following steps of performing nitration reaction, reduction reaction, annulation reaction, oxidization reaction, chlorination reaction and hydrolysis reaction on o-acetoxyl acetanilide serving as a raw material to prepare the 4-chlorine-6-amino-7-hydroxy-quinazoline (I). The preparation method is simple, quick, low in cost and suitable for industrialization.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly one is for the required chloro-6-amino of intermediate 4--7-hydroxyquinazoline of Buddhist nun's class antitumour drug synthesis and preparation method thereof.
Background technology
Protein tyrosine kinase (PTK) is modal growth factor receptors, by blocking the tumoricidal signal transmission of Tyrosylprotein kinase, thus reaches antineoplastic object.Receptor tyrosine kinase inhibitors comprises single target spot tyrosine kinase inhibitor and multiple receptor tyrosine kinases inhibitor.What current research was relatively more active just belongs to multiple receptor tyrosine kinases inhibitor for Buddhist nun's series antineoplastic medicament, has the effects such as anti-prostate cancer, lung cancer, cancer of the stomach, leukemia, mammary cancer, intestinal cancer, carcinoma of the pancreas and courage cancer.
Analyze for the molecular structure of Buddhist nun's class medicine, having is take quinazoline as the micromolecular compound of core greatly, as Gefitinib, Tarceva, Conmana and ZD6474 etc. show good biological activity clinically.Especially, how the Ah method of fresh market replaces Buddhist nun (Dacomitinib) then all to have the quinazoline structure of 6-position hydroxyl and 7-bit amino for Buddhist nun (Canertinib), Da Ke meter for Buddhist nun (Afatinib) and the card just among clinical study.
No. WO0250043A1st, world patent and No. WO03094921A2 report the preparation method of Ah method for Buddhist nun: with parent nucleus 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-nitro-7-fluquinconazole quinoline (VI) for raw material, successively through the conversion reaction of the functional groups such as replacement, reduction, amidation and amination, the Ah method that obtains is for Buddhist nun.
" Chinese Journal of Pharmaceuticals " the 41st volume the 6th phase in 2010 the 404th page and " Shandong medicine thing " 30 volumes the 10th phase in 2011 the 559th page report card respectively how for the synthetic method of Buddhist nun, 7-fluquinconazole quinoline-4-ketone (VII) is utilized to be raw material, respectively through different order nitrated, reduction and chlorination, prepare 4-chloro-6-nitro-7-fluquinconazole quinoline (VII) or the chloro-6-amino of 4--7-fluquinconazole quinoline (VIII), again through the modification of side chain, how prepare card for Buddhist nun.
This shows, the quinazoline derivant that 7-fluorine replaces is the important intermediate preparing such medicine at present.No. CN102311438th, Chinese patent reports and is reacted into ring with adjacent amino parafluorobenzoic acid and FORMAMIDINE ACETATE and obtains 7-fluquinconazole quinoline-4-ketone (VI), the same with above-mentioned document, this intermediate (VI) can prepare 4-chloro-6-nitro-7-fluquinconazole quinoline (VII) or the chloro-6-amino of 4--7-fluquinconazole quinoline (VIII) through nitrated, chloro and reduction.Meanwhile, this patent also mentions the method being prepared methoxy derivatives (IX) by fluorine-containing derivant (VIII).
Visible, the 7-position of disclosed intermediate is halogen, more for fluorine replaces.Due to fluorochemicals raw material not easily obtain, high expensive, and there is the reaction conditions that alkoxyl group substitution reaction needs high temperature reflux etc. violent.So, be necessary to develop a kind of newly for for the medicine intermediate of Buddhist nun's series antineoplastic medicament and simple and fast thereof, with low cost and applicable industrialized preparation method.Like this, how the production and preparation of Buddhist nun (Dacomitinib) etc. is replaced to have very important realistic meaning for Buddhist nun (Canertinib) and Da Ke meter for antitumor drug such as the Ah method based on quinazoline structure for Buddhist nun (Afatinib), card.
Summary of the invention
The object of the present invention is to provide a kind of chloro-6-amino of medicine intermediate 4--7-hydroxyquinazoline and preparation method thereof for Buddhist nun's series antineoplastic medicament newly, and this preparation method's simple and fast, with low cost and applicable industrialization.
To achieve these goals, main technical schemes provided by the present invention is as follows: a kind of for required chloro-6-amino of intermediate 4--7-hydroxyquinazoline (I) of Buddhist nun's class antitumour drug synthesis and preparation method thereof,
It is characterized in that described preparation method comprises the steps: with adjacent acetoxyl group Acetanilide as raw material, through nitration reaction, reduction reaction, annulation, oxidizing reaction, chlorination reaction and hydrolysis reaction, preparation 4-chloro-6-amino-7-hydroxyquinazoline (I).
In addition, the present invention also provides following attached technical scheme:
The nitrating agent of described nitration reaction is nitrosonitric acid, and the molar ratio of described adjacent acetoxyl group Acetanilide and described nitrosonitric acid is 1:1-2, preferred 1:2.
The reductive agent of described reduction reaction can be the hydrogenation under V-Brite B, hydrazine hydrate, iron powder, zinc powder or the catalysis of palladium charcoal, the hydrogenation under preferred V-Brite B or the catalysis of palladium charcoal.
Described annulation comprises step: first use alkyl chloroformate as protecting group, the amino of 2-acetoxyl group-4-amino acetanilide (III) to be formed to the transition state of N-protected; this transition state becomes ring with vulkacit H (HMTA) under trifluoracetic acid (TFA) catalysis; deprotection base under the effect of the Tripotassium iron hexacyanide and alkali, obtains 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline (IV) subsequently.
Alkyl R in described protecting group alkyl chloroformate is methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl, preferred ethyl.
The solvent of described annulation is toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, methylene dichloride, 1,2-ethylene dichloride or tetrahydrofuran (THF), preferred alcohol or methyl alcohol.
The oxygenant of described oxidizing reaction is ceric ammonium nitrate, sodium wolframate, chromium trioxide, persulfuric acid silver, peroxide alcohol, peroxy acid, oxygen or hydrogen peroxide, preferred ceric ammonium nitrate.
The solvent of described oxidizing reaction is acetic acid, acetonitrile, cyanophenyl or dioxane, preferred acetic acid.
Compared to prior art, the chloro-6-amino of medicine intermediate 4--7-hydroxyquinazoline for Buddhist nun's series antineoplastic medicament involved in the present invention and preparation method thereof, the features such as this operational path has process stabilizing, raw material is easy to get, with low cost, its Core Superiority is merged classics reaction and novel modern synthetic technology.This preparation method is applicable to industrialization and amplifies requirement, and the preparation for quinazoline ditosylate salt antitumour drug provides another important and new intermediate of practicality.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described.
Wherein, nitrated, reduction, chlorination and hydrolysis are known classics reaction.Particularly, nitration reaction can see " chemistry world " 25 volumes the 4th phase in 2003 the 237th page or " Tetrahedron Letters " 53 volumes the 40th phase in 2012 the 5393rd page.Reduction reaction can adopt palladium hydrogenated carbon system, iron powder acetate system, hydrazine hydrate iron trichloride system or V-Brite B (vat powder) system.Chlorination reaction can adopt phosphorus oxychloride or thionyl chloride to be chlorizating agent, hydrolysis reaction can adopt the alkaline hydrolysises such as sodium hydroxide, salt of wormwood or ammoniacal liquor, and concrete steps can see West China Journal of Pharmaceutical Sciences 27 volumes the 4th phase in 2012 the 362nd page, " Chinese Journal of Pharmaceuticals " 39 volumes the 6th phase in 2008 the 401st page or " China Medicine University's journal " 36 volumes the 1st phase in 2005 the 92nd page.
Embodiment one:
Under room temperature, 2-acetoxyl group-4-amino acetanilide (III) (4.16g is added in 100mL there-necked flask, 20mmol) with methylene dichloride 50mL, Vinyl chloroformate (2.4g is dripped at 10 DEG C, 22mmol) with triethylamine 1mL, stirring at room temperature 1 hour, washing, anhydrous sodium sulfate drying, is concentrated into dry.Vulkacit H (HMTA) (2.0g, 14.3mmol) and trifluoracetic acid (TFA) 20mL is added in residue.Reaction system is placed in microwave reactor, keeps 110 DEG C, microwave preheating 1 minute, react 10 minutes.Cooling, adds 20% potassium hydroxide 50mL and ethanol 50mL, adds the Tripotassium iron hexacyanide (6.6g often criticizes 2.2g, 20mmol) in three batches, carry out microwave reaction in triplicate.Reaction conditions is maintenance 110 DEG C, microwave preheating 1 minute, reacts 10 minutes.After cooling, add 50mL water, and be extracted with ethyl acetate 4 times (100mLx4), merge organic phase, concentrating under reduced pressure recycling design, residue ethyl alcohol recrystallization, obtain light yellow solid 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline (IV) 4.1g, yield is 83.7%.
Embodiment two:
In 100mL there-necked flask, add 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline (IV) (2.5g, 10mmol) and acetic acid 5mL, under room temperature, drip the 50mL aqueous solution of ceric ammonium nitrate (16.4g, 30mmol).Stirring reaction 2 hours, TLC detection reaction terminates.Filter, filter cake acetic acid washs, and obtains white solid 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline-4-one (V) 2.5g, yield 95.8%.
Embodiment three:
In 250mL there-necked flask, add 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline-4-one (V) (5.2g, 20mmol), phosphorus oxychloride (14mL, 80mmol) and methylene dichloride 100mL, reflux 4 hours.After cooling, use water, 5% sodium hydrogen carbonate solution and water washing successively, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure recycling design.Resistates recrystallisation from isopropanol, obtains white chloride solids.This solid is put in 10% potassium hydroxide solution 30mL, add methyl alcohol 100mL, keep 50-60 DEG C to react 6 hours.Cooling, with 1M salt acid for adjusting pH to 5-6, has solid to produce, and filter, wash with a small amount of cold methanol, vacuum-drying, obtain the chloro-6-amino of light yellow solid 4--7-hydroxyquinazoline (I) 2.8g, two step total recoverys are 71.8%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (5)
1., for a preparation method for the required chloro-6-amino of intermediate 4--7-hydroxyquinazoline (I) of Buddhist nun's class antitumour drug synthesis, its chemical formula is such as formula (I):
It is characterized in that described preparation method comprises the steps: to be formed the amino of 2-acetoxyl group-4-amino acetanilide (III) as protecting group with alkyl chloroformate the transition state of N-protected; this transition state and vulkacit H carry out annulation under trifluoracetic acid catalysis; again by the effect deprotection base of the Tripotassium iron hexacyanide and alkali; obtain 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline (IV)
Compound 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline (IV) obtains 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline-4-one (V) through the effect of oxygenant; Compound 6-acetylaminohydroxyphenylarsonic acid 7-acetoxyl group quinazoline-4-one (V), through chlorination and hydrolysis reaction, obtains the chloro-6-amino of described 4--7-hydroxyquinazoline (I),
2., as claimed in claim 1 for the preparation method of the required chloro-6-amino of intermediate 4--7-hydroxyquinazoline (I) of Buddhist nun's class antitumour drug synthesis, it is characterized in that: the alkyl R in described alkyl chloroformate is methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl or benzyl.
3. as claimed in claim 1 for the preparation method of the required chloro-6-amino of intermediate 4--7-hydroxyquinazoline (I) of Buddhist nun's class antitumour drug synthesis, it is characterized in that: the solvent of described annulation is toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, methylene dichloride, 1,2-ethylene dichloride or tetrahydrofuran (THF).
4., as claimed in claim 1 for the preparation method of the required chloro-6-amino of intermediate 4--7-hydroxyquinazoline (I) of Buddhist nun's class antitumour drug synthesis, it is characterized in that: the oxygenant of described oxidizing reaction is ceric ammonium nitrate, sodium wolframate, chromium trioxide, persulfuric acid silver, peroxide alcohol, peroxy acid, oxygen or hydrogen peroxide.
5., as claimed in claim 1 for the preparation method of the required chloro-6-amino of intermediate 4--7-hydroxyquinazoline (I) of Buddhist nun's class antitumour drug synthesis, it is characterized in that: the solvent of described oxidizing reaction is acetic acid, acetonitrile, cyanophenyl or dioxane.
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Denomination of invention: Intermediate 4-chloro-6-amino-7-hydroxyquinazoline required for the synthesis of tinib antitumor drugs and its preparation method Effective date of registration: 20220222 Granted publication date: 20150218 Pledgee: Laishang Bank Co.,Ltd. Heze juancheng sub branch Pledgor: JUANCHENG PEOPLE'S Hospital Registration number: Y2022980001744 |