JP7377307B2 - 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 - Google Patents
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 Download PDFInfo
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- JP7377307B2 JP7377307B2 JP2022056875A JP2022056875A JP7377307B2 JP 7377307 B2 JP7377307 B2 JP 7377307B2 JP 2022056875 A JP2022056875 A JP 2022056875A JP 2022056875 A JP2022056875 A JP 2022056875A JP 7377307 B2 JP7377307 B2 JP 7377307B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 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 description 6
- 150000001875 compounds Chemical class 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- -1 trifluoromethanesulfonic acid ester Chemical class 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 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 4
- 239000007822 coupling agent Substances 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 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 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 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
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- ARKJKNYQCXJVIR-UHFFFAOYSA-N CC(C=C1)=CC(C2CCNCC2)=C1S(O)(=O)=O Chemical compound CC(C=C1)=CC(C2CCNCC2)=C1S(O)(=O)=O ARKJKNYQCXJVIR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000009702 cancer cell proliferation Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 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
- RESPXSHDJQUNTN-UHFFFAOYSA-N 1-piperidin-1-ylprop-2-en-1-one Chemical compound C=CC(=O)N1CCCCC1 RESPXSHDJQUNTN-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
- DOHPCRULOPVJFL-UHFFFAOYSA-N 2-tert-butyl-4-hydroxypiperidine-1-carboxylic acid Chemical compound CC(C)(C)C1CC(O)CCN1C(O)=O DOHPCRULOPVJFL-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-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
- 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 1
- 239000007821 HATU Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 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
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010071990 Tyrosine kinase mutation Diseases 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-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
- 229910021529 ammonia Inorganic materials 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
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000004440 column chromatography Methods 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
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 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
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 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
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- General Health & Medical Sciences (AREA)
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- 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)
Description
(i)有機塩基の存在下、式(VII)の化合物をハロゲン化剤との反応に供し、式(VI)の化合物を得る。その後、式(VI)の化合物を、式(VIII)の化合物との反応に供し、式(V)の化合物すなわち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-イル酢酸塩を得る;および
(ii)式(V)の化合物を、プロトン性極性溶媒中で、アンモニア溶液との反応に供する。
1H-NMR(DMSO-d6、300MHz、ppm)δ8.92(s、1H)、8.76(s、1H)、7.69-7.57(m、3H)、4.01(s、3H)、2.38(s、3H)。
1H-NMR(DMSO-d6、300MHz、ppm)δ9.57(br、2H)、8.35(s、1H)、7.68(s、1H)、7.61-7.52(m、2H)、7.21(s、1H)、3.97(s、3H)。
1H-NMR(300MHz、DMSO-d6)δ7.82(d、2H)、7.48(d、2H)、6.80-6.71(m、1H)、6.10-6.03(m、1H)、5.67-5.62(m、1H)、4.76-4.71(m、1H)、3.70-3.68(m、2H)、3.43-3.31(m、2H)、2.42(s、3H)1.73(m、2H)、1.52(m、2H)。
1H-NMR(300MHz、DMSO-d6)δ9.65(bs、1H)、8.40(s、1H)、7.88(s、1H)、7.64-7.56(m、2H)、7.24(s、1H)、6.89-6.80(m、1H)、6.15-6.08(m、1H)、5.70-5.66(m、1H)、4.78(m、1H)、3.94(s、3H)、3.87(m、2H)、3.48(m、2H)、2.03(m、2H)、1.70(m、1H)。
1H-NMR(300MHz、CDCl3)δ7.80(d、2H)、4.76-4.72(m、1H)、3.80(t、2H)、3.64-3.57(m、3H)、3.40(m、1H)、2.77(t、2H)、2.46(s、3H)、1.85-1.70(m、4H)。
1H-NMR(300MHz、DMSO-d6)δ9.65(bs、1H)、8.40(s、1H)、7.88(s、1H)、7.64-7.56(m、2H)、7.24(s、1H)、6.89-6.80(m、1H)、6.15-6.08(m、1H)、5.70-5.66(m、1H)、4.78(m、1H)、3.94(s、3H)、3.87(m、2H)、3.48(m、2H)、2.03(m、2H)、1.70(m、1H)。
Claims (9)
- 式(I)の化合物の塩酸塩製造方法であって、(a)塩基の存在下、不活性の非プロトン性極性溶媒中で、式(II)の化合物を式(III)の化合物と反応させ、前記式(I)の化合物を得ること:
(b)有機溶媒中、式(I)の化合物を塩酸と反応させること、
を含む、方法。 - 前記有機溶媒が、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、酢酸エチル、アセトン、テトラヒドロフラン、アセトニトリル、1,4-ジオキサンおよびこれらの混合物からなる群から選択される、請求項1の方法。
- 前記式(I)の化合物と前記塩酸との反応が、0℃~60℃の温度で行われる、請求項1の方法。
- 前記式(I)の化合物と前記塩酸との反応が、25℃の温度で行われる、請求項1の方法。
- 前記式(III)におけるYがエテニル基である、請求項1の方法。
- 前記式(III)におけるYがハロゲノエチル基である、請求項1の方法。
- 前記式(III)におけるXがトシルオキシ基(OTs)である、請求項1の方法。
- 前記不活性の非プロトン性極性溶媒が、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリジン-2-オン、ジメチルスルホキシドおよびこれらの混合物からなる群から選択される、請求項1の方法。
- 前記塩基が、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウムおよびこれらの混合物からなる群から選択されるアルカリ金属炭酸塩である、請求項1の方法。
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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 |
JP2020068550A JP7051929B2 (ja) | 2013-01-28 | 2020-04-06 | 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 |
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JP2018241276A Active JP6784743B2 (ja) | 2013-01-28 | 2018-12-25 | 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 |
JP2020068550A Active JP7051929B2 (ja) | 2013-01-28 | 2020-04-06 | 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 |
JP2022056875A Active JP7377307B2 (ja) | 2013-01-28 | 2022-03-30 | 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 |
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JP2018241276A Active JP6784743B2 (ja) | 2013-01-28 | 2018-12-25 | 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 |
JP2020068550A Active JP7051929B2 (ja) | 2013-01-28 | 2020-04-06 | 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 |
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US (1) | US9518043B2 (ja) |
EP (1) | EP2948441B1 (ja) |
JP (4) | JP6461011B2 (ja) |
KR (1) | KR20140096571A (ja) |
CN (1) | CN104981467B (ja) |
AU (1) | AU2014210494B2 (ja) |
BR (1) | BR112015017597B1 (ja) |
CA (2) | CA2898433C (ja) |
DK (1) | DK2948441T3 (ja) |
ES (1) | ES2662863T3 (ja) |
IL (2) | IL240197B (ja) |
MX (1) | MX362763B (ja) |
NO (1) | NO2948441T3 (ja) |
PH (2) | PH12015501636B1 (ja) |
RU (2) | RU2671843C2 (ja) |
WO (1) | WO2014116070A1 (ja) |
ZA (1) | ZA201506241B (ja) |
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EP3334735A1 (en) * | 2015-08-11 | 2018-06-20 | Principia Biopharma Inc. | Processes for preparing an fgfr inhibitor |
CN113195000A (zh) | 2018-12-21 | 2021-07-30 | 第一三共株式会社 | 抗体-药物缀合物和激酶抑制剂的组合 |
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 |
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