DK2948441T3 - Fremgangsmåde til fremstilling af 1-(4-(4-(3,4-dichlor-2-fluorphenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-on - Google Patents
Fremgangsmåde til fremstilling af 1-(4-(4-(3,4-dichlor-2-fluorphenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-on Download PDFInfo
- Publication number
- DK2948441T3 DK2948441T3 DK14743689.3T DK14743689T DK2948441T3 DK 2948441 T3 DK2948441 T3 DK 2948441T3 DK 14743689 T DK14743689 T DK 14743689T DK 2948441 T3 DK2948441 T3 DK 2948441T3
- Authority
- DK
- Denmark
- Prior art keywords
- compound
- formula
- mixture
- reaction
- base
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- LPFWVDIFUFFKJU-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one Chemical compound C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F LPFWVDIFUFFKJU-UHFFFAOYSA-N 0.000 title abstract description 11
- 239000003586 protic polar solvent Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 74
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- -1 4-dimethylpyridine Chemical compound 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000007822 coupling agent Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- UQSQSQZYBQSBJZ-UHFFFAOYSA-M fluorosulfonate Chemical compound [O-]S(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-M 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 125000004969 haloethyl group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- CPTQHBBUSNGMOV-UHFFFAOYSA-N 4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-ol Chemical compound C=12C=C(O)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F CPTQHBBUSNGMOV-UHFFFAOYSA-N 0.000 abstract description 5
- 238000007796 conventional method Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- XKAOGJXMKDSICG-UHFFFAOYSA-N (1-prop-2-enoylpiperidin-4-yl) 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1CCN(C(=O)C=C)CC1 XKAOGJXMKDSICG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- 206010071990 Tyrosine kinase mutation Diseases 0.000 description 3
- UCTDOFAZOPZERI-UHFFFAOYSA-N [4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] acetate Chemical compound C=12C=C(OC(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F UCTDOFAZOPZERI-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- OMYSOLOMWJFVNK-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one;hydrochloride Chemical compound Cl.C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F OMYSOLOMWJFVNK-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- QZTMSQQRHNPHSJ-UHFFFAOYSA-N piperidin-4-yl 4-methylbenzenesulfonate;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1S(=O)(=O)OC1CCNCC1 QZTMSQQRHNPHSJ-UHFFFAOYSA-N 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- SOLQIFINSOHAQD-UHFFFAOYSA-N (7-methoxy-4-oxo-1h-quinazolin-6-yl) acetate Chemical compound N1C=NC(=O)C2=C1C=C(OC)C(OC(C)=O)=C2 SOLQIFINSOHAQD-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- ZPTBUEKFZSYXBD-UHFFFAOYSA-N 3,4-dichloro-2-fluoroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1F ZPTBUEKFZSYXBD-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- OZNRLHIQDJLXAN-UHFFFAOYSA-N [1-(3-chloropropanoyl)piperidin-4-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1CCN(C(=O)CCCl)CC1 OZNRLHIQDJLXAN-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Claims (13)
1. Fremgangsmåde til fremstilling af en forbindelse med formlen (I), hvilken fremgangsmåde omfatter et trin, der går ud på at lade forbindelsen med formlen (II) reagere med forbindelsen med formlen (III) i et inert, polært, aprotisk opløsningsmiddel i nærvær af en base:
hvor X er tosyloxy (OTs), mesyloxy (OMs), trifluormethansulfonat, fluorsulfonat eller halogen; og Y er ethenyl eller halogenethyl.
2. Fremgangsmåde ifølge krav 1, hvor det inerte, polære, aprotiske opløsningsmiddel er valgt fra gruppen bestående af A, A-dimeth ylform am id, Α,Α-dimethylacetamid, A-methylpyrrolidin- 2-on, dimethylsulfoxid og en blanding deraf.
3. Fremgangsmåde ifølge krav 1, hvor basen er et alkalimetalcarbonat valgt fra gruppen bestående af natriumhydrogencarbonat, kaliumcarbonat, cæsiumcarbonat og en blanding deraf.
4. Fremgangsmåde ifølge krav 1, hvor basen anvendes i en mængde på 1 til 5 molækvivalenter baseret på 1 molækvivalent af forbindelsen med formlen (II).
5. Fremgangsmåde ifølge krav 1, hvor forbindelsen med formlen (II) fremstilles ved (i) at underkaste en forbindelse med formlen (VII) en reaktion med et halo generingsmiddel i nærvær af en organisk base for at frembringe forbindelsen med formlen (VI), som dernæst underkastes en reaktion med en forbindelse med formlen (VIII) for at opnå forbindelsen med formlen (V); og (ii) at underkaste forbindelsen med formlen (V) en reaktion med en opløsning af ammoniak i et polært, protisk opløsningsmiddel:
6. Fremgangsmåde ifølge krav 5, hvor den organiske base er valgt fra gruppen bestående af diisopropylamin, triethylamin, diisopropylethylamin, diethylamin, pyridin, 4-dimethylpyridin, morpholin og en blanding deraf.
7. Fremgangsmåde ifølge krav 5, hvor halogeneringsmidlet er valgt fra gruppen bestående af thionylchlorid, phosphorylchlorid og en blanding deraf.
8. Fremgangsmåde ifølge krav 5, hvor det polære, protiske opløsningsmiddel er valgt fra gruppen bestående af methanol, ethanol, propanol og en blanding deraf.
9. Fremgangsmåde ifølge krav 1, hvor forbindelsen med formlen (III) fremstilles ved at lade forbindelsen med formlen (IX) eller saltet deraf reagere med forbindelsen med formlen (X) i nærvær af en base eller et amidkoblingsmiddel:
hvor X og Y er de samme som defineret i krav 1; og Z er halogen eller hydroxyl.
10. Fremgangsmåde ifølge krav 9, hvor reaktionen mellem forbindelsen med formlen (IX) eller saltet deraf og forbindelsen med formlen (X) udføres i et organisk opløsningsmiddel eller en blanding af et organisk opløsningsmiddel og vand; og det organiske opløsningsmiddel er tetrahydrofuran, ethylacetat, acetone, 1,4-dioxan, acetonitril, dichlormethan, carbontetrachlorid, chloroform, /V,/V-dimcthylformamid eller dimethylsulfoxid.
11. Fremgangsmåde ifølge krav 9, hvor basen, der anvendes i reaktionen mellem forbindelsen med formlen (IX) eller saltet deraf og forbindelsen med formlen (X), er valgt fra gruppen bestående af natriumcarbonat, natriumhydrogencarbonat, calciumcarbonat, kaliumcarbonat, natriumhydroxid, kaliumhydroxid, cæsiumcarbonat, diisopropylamin, triethylamin, diisopropylethylamin, diethylamin og en blanding deraf.
12. Fremgangsmåde ifølge krav 9, hvor amidkoblingsmidlet er valgt fra gruppen af l-ethyl-3-(3-dimethylaminopropyl)carbodiimid, hydroxybenzotriazol, 0-(7-azabenzotriazol- 1-yl)-A^A^A^jV’-tetramethyluroniumhexafluorphosphat, /V,/V’-dicycl()hexylcarboimid, l-hydroxy-7-azabenzotriazol, /V-'V’-diisopropylcarboimid, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium-hexafluorphosphat og en blanding deraf.
13. Fremgangsmåde ifølge krav 9, hvor saltet af forbindelsen med formlen (IX) er et hydrochlorid- eller hydrobromidsalt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020130009282A KR20140096571A (ko) | 2013-01-28 | 2013-01-28 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법 |
| PCT/KR2014/000752 WO2014116070A1 (en) | 2013-01-28 | 2014-01-27 | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2948441T3 true DK2948441T3 (da) | 2018-03-26 |
Family
ID=51227806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK14743689.3T DK2948441T3 (da) | 2013-01-28 | 2014-01-27 | Fremgangsmåde til fremstilling af 1-(4-(4-(3,4-dichlor-2-fluorphenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-on |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US9518043B2 (da) |
| EP (1) | EP2948441B1 (da) |
| JP (4) | JP6461011B2 (da) |
| KR (1) | KR20140096571A (da) |
| CN (1) | CN104981467B (da) |
| AU (1) | AU2014210494B2 (da) |
| BR (1) | BR112015017597B1 (da) |
| CA (2) | CA2898433C (da) |
| DK (1) | DK2948441T3 (da) |
| ES (1) | ES2662863T3 (da) |
| IL (2) | IL240197B (da) |
| MX (2) | MX362763B (da) |
| NO (1) | NO2948441T3 (da) |
| PH (2) | PH12015501636A1 (da) |
| RU (2) | RU2018137882A (da) |
| WO (1) | WO2014116070A1 (da) |
| ZA (1) | ZA201506241B (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20140096571A (ko) * | 2013-01-28 | 2014-08-06 | 한미약품 주식회사 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법 |
| AU2016304852B2 (en) * | 2015-08-11 | 2020-12-10 | Principia Biopharma, Inc. | Processes for preparing an FGFR inhibitor |
| US20220040324A1 (en) | 2018-12-21 | 2022-02-10 | Daiichi Sankyo Company, Limited | Combination of antibody-drug conjugate and kinase inhibitor |
| US20210221792A1 (en) * | 2020-01-16 | 2021-07-22 | Hanmi Pharm Co., Ltd. | Convergent synthesis of poziotinib derivative |
| US20220064145A1 (en) * | 2020-08-28 | 2022-03-03 | Hanmi Science Co., Ltd. | Synthesis of poziotinib derivative |
| CN117567466B (zh) * | 2024-01-16 | 2024-04-16 | 成都金瑞基业生物科技有限公司 | 一种喹唑啉衍生物的制备方法 |
Family Cites Families (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02275891A (ja) | 1988-12-29 | 1990-11-09 | Tsumura & Co | 新規な複核白金錯体および該錯体を有効成分とする抗腫瘍剤 |
| HU227759B1 (en) | 1994-08-23 | 2012-02-28 | Smithkline Beecham Plc | Improved pharmaceutical formulations containing ibuprofen and codeine |
| KR980008219A (ko) | 1996-07-16 | 1998-04-30 | 김상응 | 안정화된 주사제용 약제학적 조성물 |
| GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| JP3687025B2 (ja) | 1998-06-04 | 2005-08-24 | 東和薬品株式会社 | 安定なマレイン酸エナラプリル錠剤 |
| CA2384291A1 (en) | 1999-09-21 | 2001-03-29 | Astrazeneca Ab | Quinazoline derivatives and their use as pharmaceuticals |
| DE10042058A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| DE10042061A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| TWI324597B (en) * | 2002-03-28 | 2010-05-11 | Astrazeneca Ab | Quinazoline derivatives |
| JP4776882B2 (ja) | 2002-03-30 | 2011-09-21 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びそれらの調製方法 |
| ES2279441T3 (es) * | 2003-09-19 | 2007-08-16 | Astrazeneca Ab | Derivados de quinazolina. |
| CN1882570B (zh) * | 2003-09-19 | 2010-12-08 | 阿斯利康(瑞典)有限公司 | 喹唑啉衍生物 |
| WO2005030757A1 (en) | 2003-09-25 | 2005-04-07 | Astrazeneca Ab | Quinazoline derivatives |
| GB0322409D0 (en) * | 2003-09-25 | 2003-10-29 | Astrazeneca Ab | Quinazoline derivatives |
| DE10345875A1 (de) * | 2003-09-30 | 2005-04-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Vewendung und Verfahren zu ihrer Herstellung |
| US7687502B2 (en) | 2004-03-23 | 2010-03-30 | Banyu Pharmaceutical Co., Ltd. | Substituted quinazoline or pyridopyrimidine derivative |
| KR20050104152A (ko) | 2004-04-28 | 2005-11-02 | 최승호 | 경구용 약물의 흡수를 증진하는 약제학적 조성물 |
| KR20070107151A (ko) * | 2005-02-26 | 2007-11-06 | 아스트라제네카 아베 | 티로신 키나제 억제제로서의 퀴나졸린 유도체 |
| CA2619037A1 (en) | 2005-08-22 | 2007-03-01 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles medicaments comprising said compounds use and method for production thereof |
| JP2009518450A (ja) | 2005-12-12 | 2009-05-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 二環式複素環化合物、その化合物を含む薬剤、その使用及び製造方法 |
| DK1847258T4 (da) | 2006-04-13 | 2013-04-15 | Acino Pharma Ag | Partialglycerider som smøremiddel til farmaceutiske sammensætninger indeholdende thieno[3,2-c]pyridin-derivater |
| WO2007118854A1 (en) * | 2006-04-13 | 2007-10-25 | Euro-Celtique S.A. | Benzenesulfonamide compounds and the use thereof |
| AU2008212999A1 (en) * | 2007-02-06 | 2008-08-14 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof |
| TWI377944B (en) | 2007-06-05 | 2012-12-01 | Hanmi Holdings Co Ltd | Novel amide derivative for inhibiting the growth of cancer cells |
| MX2009013499A (es) | 2007-06-22 | 2010-01-18 | Bristol Myers Squibb Co | Composiciones comprimidas que contienen atazanavir. |
| JP2012509321A (ja) * | 2008-11-21 | 2012-04-19 | ミレニアム ファーマシューティカルズ， インコーポレイテッド | 癌および他の疾患または障害の処置のための、４−［６−メトキシ−７−（３−ピペリジン−１−イル−プロポキシ）キナゾリン−４−イル］ピペラジン−１−カルボン酸（４−イソプロポキシフェニル）−アミドの乳酸塩およびその薬学的組成物 |
| MY144136A (en) | 2009-04-20 | 2011-08-10 | Univ Sains Malaysia | Throttle and brake lock |
| BR112012017084A2 (pt) | 2010-01-12 | 2016-04-12 | Nestec Sa | métodos para previsão de resposta de câncer de mama triplo-negativo à terapia |
| KR101217526B1 (ko) * | 2010-06-11 | 2013-01-02 | 한미사이언스 주식회사 | 아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 조성물 |
| KR101317809B1 (ko) * | 2011-06-07 | 2013-10-16 | 한미약품 주식회사 | 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물 |
| KR101272613B1 (ko) * | 2011-10-05 | 2013-06-10 | 한미사이언스 주식회사 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온 염산염의 제조 방법 및 이에 사용되는 중간체 |
| KR20140096571A (ko) * | 2013-01-28 | 2014-08-06 | 한미약품 주식회사 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법 |
-
2013
- 2013-01-28 KR KR1020130009282A patent/KR20140096571A/ko not_active Withdrawn
-
2014
- 2014-01-27 AU AU2014210494A patent/AU2014210494B2/en active Active
- 2014-01-27 RU RU2018137882A patent/RU2018137882A/ru unknown
- 2014-01-27 MX MX2015009232A patent/MX362763B/es active IP Right Grant
- 2014-01-27 ES ES14743689.3T patent/ES2662863T3/es active Active
- 2014-01-27 JP JP2015555109A patent/JP6461011B2/ja active Active
- 2014-01-27 CN CN201480005827.XA patent/CN104981467B/zh active Active
- 2014-01-27 RU RU2015129994A patent/RU2671843C2/ru active
- 2014-01-27 BR BR112015017597-0A patent/BR112015017597B1/pt not_active IP Right Cessation
- 2014-01-27 US US14/763,295 patent/US9518043B2/en active Active
- 2014-01-27 MX MX2019000647A patent/MX388687B/es unknown
- 2014-01-27 DK DK14743689.3T patent/DK2948441T3/da active
- 2014-01-27 CA CA2898433A patent/CA2898433C/en active Active
- 2014-01-27 EP EP14743689.3A patent/EP2948441B1/en active Active
- 2014-01-27 NO NO14743689A patent/NO2948441T3/no unknown
- 2014-01-27 WO PCT/KR2014/000752 patent/WO2014116070A1/en not_active Ceased
- 2014-01-27 CA CA3129936A patent/CA3129936A1/en not_active Abandoned
-
2015
- 2015-07-23 PH PH12015501636A patent/PH12015501636A1/en unknown
- 2015-07-28 IL IL240197A patent/IL240197B/en active IP Right Grant
- 2015-08-26 ZA ZA2015/06241A patent/ZA201506241B/en unknown
-
2018
- 2018-12-25 JP JP2018241276A patent/JP6784743B2/ja active Active
-
2019
- 2019-06-12 IL IL267303A patent/IL267303B/en active IP Right Grant
- 2019-07-22 PH PH12019501676A patent/PH12019501676A1/en unknown
-
2020
- 2020-04-06 JP JP2020068550A patent/JP7051929B2/ja active Active
-
2022
- 2022-03-30 JP JP2022056875A patent/JP7377307B2/ja active Active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7377307B2 (ja) | １－（４－（４－（３，４－ジクロロ－２－フルオロフェニルアミノ）－７－メトキシキナゾリン－６－イルオキシ）ピペリジン－１－イル）プロパ－２－エン－１－オンの製造方法 | |
| DK2558448T3 (da) | Fremgangsmåde til fremstilling af 4-{4-[({[4-chlor-3-(trifluormethyl)-phenyl]amino}carbonyl)amino]-3-fluorphenoxy}-n-methylpyridin-2-carboxamid, dets salte og monohydrat | |
| CA2850055E (en) | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein | |
| KR101950942B1 (ko) | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법 | |
| HK40010388A (en) | Preparation method for hydrochloride compound | |
| HK1196132A (en) | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein | |
| HK1196132B (zh) | 用於制备1-(4-(4-(3，4-二氯-2-氟苯氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-丙-2-烯-1-酮盐酸盐的方法及其中使用的中间产物 | |
| HK1205105A1 (zh) | 制备化合物的方法及其合成中间体 |