CN104981467A - 制备l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮的方法 - Google Patents
制备l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮的方法 Download PDFInfo
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- CN104981467A CN104981467A CN201480005827.XA CN201480005827A CN104981467A CN 104981467 A CN104981467 A CN 104981467A CN 201480005827 A CN201480005827 A CN 201480005827A CN 104981467 A CN104981467 A CN 104981467A
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 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 3
- 150000001875 compounds Chemical class 0.000 claims description 80
- 239000002585 base Substances 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- -1 fluosulfonic acid ester Chemical class 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 239000003513 alkali 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 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 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 group 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003880 polar aprotic solvent Substances 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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical group CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-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-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-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
- 230000002140 halogenating effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012964 benzotriazole Substances 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- KCXYZMFPZHYUFO-UHFFFAOYSA-N n-methyl-n-phosphanylmethanamine Chemical compound CN(C)P KCXYZMFPZHYUFO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 150000003459 sulfonic acid esters Chemical class 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 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 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 239000003586 protic polar solvent Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 230000005907 cancer growth Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 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
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000000605 extraction Methods 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
- 238000001914 filtration Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000007821 HATU Substances 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 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
- FPSTYXLUOFPGNZ-UHFFFAOYSA-N n-chloro-n-fluoroaniline Chemical compound FN(Cl)C1=CC=CC=C1 FPSTYXLUOFPGNZ-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- BHXCPQHXDLLGAV-UHFFFAOYSA-N quinolin-6-yl acetate Chemical compound N1=CC=CC2=CC(OC(=O)C)=CC=C21 BHXCPQHXDLLGAV-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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)
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Abstract
本发明涉及在与常规方法相比更简单的过程中通过使4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-醇与N-酰基哌啶衍生物在惰性极性质子溶剂中在碱的存在下反应制备1-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-1-基)丙-2-烯-1-酮的新方法。
Description
发明领域
本发明涉及制备l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮——特异性药的游离碱形式(盐酸盐形式)——的新方法,其可以有选择地和有效地抑制由癌细胞的生长和酪氨酸激酶突变引起的抗药性。通过本发明的方法,目标化合物可以以与常规方法相比简单得多的过程制备。
发明背景
由下面式(IV)表示的盐酸l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮已知具有抗增殖活性,比如抗癌活性,并且其被认为是可以有选择地和有效地抑制由癌细胞生长和酪氨酸激酶突变引起的抗药性的重要药物。式(IV)的化合物的游离碱形式,即由下面式(I)表示的l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-1-基)丙-2-烯-l-酮,还称为CAS登记号1092364-38-9。
上面式(I)的化合物可以通过韩国专利号1013319中公开的方法制备,并且详细的反应过程在下面的反应方案1中描述。通过下面的反应方案1制备的式(I)的化合物可以与盐酸反应以得到其盐酸盐,即式(IV)的化合物:
反应方案1
其中R是卤素。
根据以上反应方案1中描述的制备方法,化合物10在高温比如210℃下与盐酸甲脒经历缩合反应以得到化合物9,然后使化合物9与L-蛋氨酸在有机酸比如甲磺酸中反应,由此化合物9的C-6位置处的甲基被去除以获得化合物8。
随后,化合物8在无水乙酸和碱比如吡啶中经历保护反应以产生化合物7,然后使化合物7与无机酸比如亚硫酰氯、磷酰氯等在催化量的N,N-二甲基甲酰胺存在下在回流条件下反应以获得盐酸盐形式的化合物6。
如此获得的化合物6通过在含有氨的醇溶液(例如,7N氨甲醇溶液)中搅拌经历脱保护反应以产生化合物5。化合物5与叔丁基4-羟基哌啶-1-碳酸盐化合物经历Mitsunobu反应以得到化合物4,然后使化合物4与苯胺在有机溶剂比如异丙醇或乙腈中经历取代反应以获得化合物3。化合物3与有机酸比如三氟乙酸或无机酸比如浓盐酸在有机溶剂比如二氯甲烷中经历反应,由此叔丁氧基羰基脱保护以获得化合物2。在上面的Mitsunobu反应中,可以使用偶氮二甲酸二异丙酯、偶氮二甲酸二乙酯或二叔丁基偶氮二羧酸酯和三苯基膦。
化合物1即本发明的式(I)的化合物通过使如此获得的化合物2与丙烯酰氯在水和有机溶剂比如四氢呋喃等的混合物中,或在二氯甲烷中在无机碱比如碳酸氢钠或有机碱比如吡啶或三乙胺存在下进行酰化反应而制备。可选地,化合物2通过使用偶联剂比如l-乙基-3-(3-二甲基氨基丙基)-碳二亚胺(EDC)或2-(lH-7-氮杂苯并三唑-l-基)-1,1,3,3-四甲基脲鎓六氟磷酸甲铵(HATU)与丙烯酸经历缩合反应。
然而,根据以上描述的方法,制备化合物9的步骤可能是有危险的,因为该步骤在高温无溶剂下进行,并且反应可能不均匀地进行。而且,过量的亚硫酰氯在制备化合物5的步骤中使用,使得后续步骤困难。因此,该方法不适合商业化。
制备化合物1的该方法的最显著的缺点是酰化(acrylization)反应的产率非常低,例如,13%,而且该反应伴随许多副反应,因此,其需要通过使用柱层析的纯化过程。而且,在化合物3通过Mitsunobu反应制备的情况下,可以形成许多副产物,这使得通过使用柱层析的纯化步骤成为必要,所述柱层析需要昂贵的硅胶和过量的流动相溶剂。因此,该方法对于商业化是不可行的。
因此,本发明人已经努力开发了以高纯度和高产率制备式(I)的化合物的新方法,其是经济的并且商业化也可行。
发明内容
因此,本发明的目的是提供制备l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-1-酮的新的和简单的方法。
根据本发明的一方面,提供了制备式(I)的化合物的方法,其包括使式(II)的化合物与式(III)的化合物在惰性极性质子溶剂中在碱的存在下反应的步骤:
其中X是甲苯磺酰氧基(OTs)、甲磺酰氧基(OMs)、三氟甲烷磺酸酯、氟磺酸酯或卤素;和Y是乙烯基或卤代乙基。
发明详述
根据本发明的方法,式(I)的化合物即l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮可以通过使式(II)的化合物即4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-醇与式(III)的化合物在惰性质子溶剂中在碱的存在下反应制备。该机制在下面的反应方案2中描述:
反应方案2
其中X和Y与上面限定的相同。
上面的反应中使用的惰性质子溶剂的具体实例包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷-2-酮、二甲基亚砜和其混合物。
上面的反应中使用的碱的具体实例为碱金属碳酸盐,比如,碳酸氢钠、碳酸钾、碳酸铯,和其混合物。优选地,基于1摩尔当量的式(II)的化合物,使用1到5摩尔当量的量的碱。
上述反应可以在60℃到100℃的温度下进行,优选地70℃到90℃,更优选地70℃到80℃。
用作本发明的原料的式(II)的化合物可以通过以下步骤制备(参见下面的反应方案3):
(i)使式(VII)的化合物与卤化剂在有机碱的存在下反应以产生式(VI)的化合物,然后使(VI)的化合物与式(VIII)的化合物反应以获得式(V)的化合物,即4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基乙酸酯;和
(ii)使式(V)的化合物与氨溶液在极性质子溶剂中反应。
反应方案3
上面的步骤(i)中使用的有机碱的具体例子包括二异丙胺、三乙胺、二异丙基乙基胺、二乙胺、吡啶、4-二甲基吡啶、吗啉和其混合物。卤化剂的具体实例包括亚硫酰氯、磷酰氯及其混合物。上述反应在50℃到150℃,优选地60℃到190℃,更优选地大约75℃下进行。在该步骤中,式(VI)的化合物以在有机溶剂中包含它的溶液的形式而不是分离形式制备。随后,使有机溶剂中包含的式(VI)的化合物与式(VIII)的化合物反应以获得式(V)的化合物,即4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基乙酸酯。
用作上述反应原料的式(VII)的化合物可以通过韩国专利号1013319中公开的方法制备。
在随后的步骤(ii)中,使前面步骤(i)中制备的式(V)的化合物与氨溶液或氨气在极性质子溶剂(比如,甲醇、乙醇、丙醇和其混合物)中在0℃到40℃,优选地10℃到30℃,更优选地大约25℃下反应以获得式(II)的4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-醇。
而且,用作本发明原料的式(III)的化合物可以通过使式(IX)的化合物或其盐与式(X)的化合物在碱或酰胺偶联剂的存在下反应制备(参见下面的反应方案4):
反应方案4
其中X和Y与上面限定的相同;并且Z是卤素或羟基。
上述反应可以在有机溶剂或有机溶剂和水的混合物中进行,所述有机溶剂比如四氢呋喃、乙酸乙酯、丙酮、1,4-二氧杂环己烷、乙腈、二氯甲烷、四氯化碳、氯仿、N,N-二甲基甲酰胺或二甲基亚砜。
碱的具体实例包括无机碱,比如碳酸钠、碳酸氢钠、碳酸钙、碳酸钾、氢氧化钠、氢氧化钾和碳酸铯;有机碱比如二异丙胺、三乙胺、二异丙基乙基胺和二乙胺、和其混合物。酰胺偶联剂的具体实例可包括1-乙基-3-(3-二甲基氨基丙基)碳二亚胺、羟基苯并三唑、六氟磷酸O-(7-氮杂苯并三唑-l-基)-N,N,N',N'-四甲基脲鎓、N,N'-二环己基碳二亚胺、1-羟基-7-氮杂苯并三唑、N-N'-二异丙基碳二亚胺、六氟磷酸(苯并三唑-1-基氧)三(二甲基氨基)鏻和其混合物。碱或酰胺偶联剂可以基于1摩尔当量的式(IX)化合物或其盐以3到5摩尔当量的量使用。
上述式(IX)的化合物的盐优选为盐酸盐(2HC1盐)或氢溴酸盐(2HBr盐)。上述反应可以在-30℃到30℃,优选地大约0℃至室温的温度下通过搅拌适合的时间期间进行。
根据本发明的方法,式(I)的目标化合物l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮可以以高纯度和高产率通过简单的方法进行制备。
而且,盐酸1-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-1–基)丙-2-烯-1-酮——其可以有选择地和有效地抑制由癌细胞的生长和酪氨酸激酶突变引起的抗药性——可以通过使式(I)的化合物与盐酸在有机溶剂(比如,甲醇、乙醇、丙醇、异丙醇、丁醇、乙酸乙酯、丙酮、四氢呋喃、乙腈、1,4-二氧杂环己烷和其混合物)中在0℃到60℃,优选地10℃到40℃,更优选地大约25℃下反应进行制备。
在下文中,通过下面的实施例更具体地描述了本发明,但是这些仅用于说明目的而提供,并且本发明不限于此。
制备实施例1:式(II)的化合物4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-醇的制备
步骤(i):式(V)的化合物4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑
啉-6-基乙酸酯的制备
将7-甲氧基-4-氧代-3,4-二氢喹唑啉-6-基乙酸酯(100g)加入到甲苯(850mL)和N,N-二异丙基乙基胺(82.5mL)中。将磷酰氯(100mL)在20分钟内在75℃下加入到其中,然后搅拌3小时。将甲苯(450mL)和3,4-二氯-氟苯胺(84.6g)加入到所得混合物中,然后搅拌2小时。反应完全之后,使所得混合物冷却至25℃,并将如此获得的固体在减压下过滤并用甲苯(400mL)洗涤。将异丙醇(1,000mL)加入到固体中,并使所得混合物搅拌2小时。将如此获得的固体过滤并用异丙醇(400mL)洗涤,然后在40℃下在烘箱中干燥以得到目标化合物(143g,产率:83%)。
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)。
步骤(ii):式(II)的化合物4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑
啉-6-醇的制备
将步骤(i)中制备的4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基乙酸酯(100g)与甲醇(1,000mL)混合。使混合物冷却至10到15℃,加入氨溶液(460g),并在25℃下搅拌3小时。将如此获得的固体过滤并用甲醇(200mL)和水(200mL)的混合溶剂洗涤。所得固体在40℃下在烘箱中干燥以获得目标化合物(74g,产率:83%)。
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)。
实施例1:式(I)的化合物l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-1-基)丙-2-烯-1-酮的制备
步骤(1-1):式(III)的化合物4-甲基苯磺酸l-丙烯酰基哌啶-4-基
酯的制备
将盐酸4-甲基苯磺酸哌啶-4-基酯(200g,685mmol)、四氢呋喃(THF,1.6L)和NaHCO3(172g,2047mmol)加入到水(2L)中,并使混合物冷却至0℃。将通过将丙烯酰氯(56mL,519mmol)加入到THF(0.4L)制备的溶液在30分钟内加入到其中,然后搅拌1小时。反应完全之后,将MeOH(0.4L)加入其中,用于淬灭。溶液用乙酸乙酯(2L)萃取,并用水(2L)洗涤。分离有机层,减压下蒸馏,并使如此获得的残留物从二氯甲烷-己烷重结晶以获得目标化合物(174g,产率:82%)。
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)。
步骤(1-2):式(I)化合物l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧
基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮的制备
使制备实施例1中制备的4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-醇(12g,34mmol)、步骤(1-1)中制备的4-甲基苯磺酸l-丙烯酰基哌啶-4-基酯(16g,51mmol)、K2CO3(9.4g,68mmol)和二甲基乙酰胺(DMAc,300mL)混合。将反应温度升至70℃,并使混合物搅拌24小时。反应完全之后,使混合物冷却至室温,用乙酸乙酯(300mL)萃取,然后用水(300mL)洗涤。分离有机层,并在减压下蒸馏。如此获得的固体通过加入乙酸乙酯固化,过滤并干燥以得到目标化合物(12.8g,产率:77%)。
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)。
实施例2:式(I)的化合物l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮的制备
步骤(2-1):式(III)的化合物4-甲基苯磺酸l-(3-氯丙酰基)哌啶-4-
基酯的制备
将盐酸4-甲基苯磺酸哌啶-4-基酯(20g,68mmol)和二氯甲烷(200mL)混合并使混合物冷却至0℃。将三乙胺(29mL,205mmol)和3-氯丙酰基氯(7.9mL,82mmol)加入其中,然后在室温下搅拌16小时。反应完全之后,反应混合物用乙酸乙酯(200mL)萃取,并用水(200mL)洗涤。分离有机层,在减压下蒸馏,并将如此获得的残留物纯化以得到目标化合物(18g,产率:76%)。
1H-NMR(300MHz,CDC13)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)。
步骤(2-2):式(I)的化合物l-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲
氧基喹唑啉-6-基氧)哌啶-l-基)丙-2-烯-l-酮的制备
除了上面步骤(2-1)中制备的4-甲基苯磺酸l-(3-氯丙酰基)哌啶-4-基酯(13g,35mmol)被用于代替步骤(1-1)中制备的4-甲基苯磺酸1-丙烯酰哌啶-4-基酯(16g,51mmol)之外,重复实施例1的步骤(1-2)的过程以得到目标化合物(7.4g,产率:58%)。
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 (13)
1.制备式(I)化合物的方法,其包括使式(II)的化合物与式(III)的化合物在惰性极性质子溶剂中在碱的存在下反应的步骤:
其中X是甲苯磺酰氧基(OTs)、甲磺酰氧基(OMs)、三氟甲烷磺酸酯、氟磺酸酯或卤素;和Y是乙烯基或卤代乙基。
2.权利要求1所述的方法,其中所述惰性极性质子溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷-2-酮、二甲基亚砜和其混合物。
3.权利要求1所述的方法,其中所述碱是碱金属碳酸盐,选自碳酸氢钠、碳酸钾、碳酸铯和其混合物。
4.权利要求1所述的方法,其中所述碱基于1摩尔当量的式(II)化合物以1到5摩尔当量的量使用。
5.权利要求1所述的方法,其中所述式(II)的化合物通过以下步骤制备:(i)使式(VII)的化合物与卤化剂在有机碱的存在下反应以产生式(VI)的化合物,然后使式(VI)的化合物与式(VIII)的化合物反应以获得式(V)的化合物;和(ii)使式(V)的化合物与氨溶液在极性质子溶剂中反应:
6.权利要求5所述的方法,其中所述有机碱选自二异丙胺、三乙胺、二异丙基乙基胺、二乙胺、吡啶、4-二甲基吡啶、吗啉和其混合物。
7.权利要求5所述的方法,其中所述卤化剂选自亚硫酰氯、磷酰氯和其混合物。
8.权利要求5所述的方法,其中所述极性质子溶剂选自甲醇、乙醇、丙醇和其混合物。
9.权利要求1所述的方法,其中所述式(III)的化合物通过使式(IX)的化合物或其盐与式(X)的化合物在碱或酰胺偶联剂的存在下反应制备:
其中X和Y与权利要求1中所限定的相同;和Z是卤素或羟基。
10.权利要求9所述的方法,其中式(IX)的化合物或其盐与式(X)的化合物之间的反应在有机溶剂或有机溶剂与水的混合物中进行;并且所述有机溶剂是四氢呋喃、乙酸乙酯、丙酮、1,4-二氧杂环己烷、乙腈、二氯甲烷、四氯化碳、氯仿、N,N-二甲基甲酰胺或二甲基亚砜。
11.权利要求9所述的方法,其中式(IX)的化合物或其盐与式(X)的化合物之间的反应中使用的碱选自碳酸钠、碳酸氢钠、碳酸钙、碳酸钾、氢氧化钠、氢氧化钾、碳酸铯、二异丙胺、三乙胺、二异丙基乙基胺、二乙胺和其混合物。
12.权利要求9所述的方法,其中所述酰胺偶联剂选自1-乙基-3-(3-二甲基氨基丙基)碳二亚胺、羟基苯并三唑、六氟磷酸O-(7-氮杂苯并三唑-l-基)-N,N,N',N'-四甲基脲鎓、N,N'-二环己基碳二亚胺、1-羟基-7-氮杂苯并三唑、N-N'-二异丙基碳二亚胺、六氟磷酸(苯并三唑-1-基氧)三(二甲基氨基)鏻和其混合物。
13.权利要求9所述的方法,其中式(IX)化合物的盐是盐酸盐或氢溴酸盐。
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KR10-2013-0009282 | 2013-01-28 | ||
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 |
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