JP4842816B2 - Cf3−置換ピリミジンの選択的合成 - Google Patents
Cf3−置換ピリミジンの選択的合成 Download PDFInfo
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- JP4842816B2 JP4842816B2 JP2006525198A JP2006525198A JP4842816B2 JP 4842816 B2 JP4842816 B2 JP 4842816B2 JP 2006525198 A JP2006525198 A JP 2006525198A JP 2006525198 A JP2006525198 A JP 2006525198A JP 4842816 B2 JP4842816 B2 JP 4842816B2
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- JP
- Japan
- Prior art keywords
- group
- amine
- lewis acid
- aromatic
- mhz
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 150000003230 pyrimidines Chemical class 0.000 title description 8
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 150000001412 amines Chemical class 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 34
- -1 perfluoroalkyl sulfonate Chemical compound 0.000 claims description 28
- 239000002841 Lewis acid Substances 0.000 claims description 26
- 150000007517 lewis acids Chemical class 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 150000004982 aromatic amines Chemical class 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 11
- 150000004820 halides Chemical class 0.000 claims description 10
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 230000000269 nucleophilic effect Effects 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- 230000014759 maintenance of location Effects 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- ARMJRBKSXKGWSD-UHFFFAOYSA-N 4-chloro-n-(4-methylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=CC(C)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 ARMJRBKSXKGWSD-UHFFFAOYSA-N 0.000 description 7
- 239000012038 nucleophile Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- OZWOVYUILXZEPP-UHFFFAOYSA-N 2-chloro-n-(4-methylphenyl)-5-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(C)=CC=C1NC1=NC(Cl)=NC=C1C(F)(F)F OZWOVYUILXZEPP-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- DBGFGNCFYUNXLD-UHFFFAOYSA-N 4-chloropyrimidin-2-amine Chemical compound NC1=NC=CC(Cl)=N1 DBGFGNCFYUNXLD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- LPBDZVNGCNTELM-UHFFFAOYSA-N 2-chloropyrimidin-4-amine Chemical compound NC1=CC=NC(Cl)=N1 LPBDZVNGCNTELM-UHFFFAOYSA-N 0.000 description 2
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 2
- UWPIJBRPRPTDTI-UHFFFAOYSA-N 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine Chemical class NC1=NC=C(C(F)(F)F)C(Cl)=N1 UWPIJBRPRPTDTI-UHFFFAOYSA-N 0.000 description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229910052718 tin Inorganic materials 0.000 description 2
- 239000011135 tin Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YCWDFBMSOFDYJZ-UHFFFAOYSA-N 1-n-[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]-4-n,4-n-dimethylbenzene-1,4-diamine Chemical compound C1=CC(N(C)C)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 YCWDFBMSOFDYJZ-UHFFFAOYSA-N 0.000 description 1
- DQXNTSXKIUZJJS-UHFFFAOYSA-N 2,4-dichloro-5-methylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1Cl DQXNTSXKIUZJJS-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- KQJVDEBWHJRJBT-UHFFFAOYSA-N 3,4-dihydro-1h-1,8-naphthyridin-2-one Chemical compound C1=CN=C2NC(=O)CCC2=C1 KQJVDEBWHJRJBT-UHFFFAOYSA-N 0.000 description 1
- VXFMNHKLXSDLKL-UHFFFAOYSA-N 3,4-dihydro-2h-pyrano[2,3-b]pyridine Chemical compound C1=CC=C2CCCOC2=N1 VXFMNHKLXSDLKL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WJXISSUHFHNULL-UHFFFAOYSA-N 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 WJXISSUHFHNULL-UHFFFAOYSA-N 0.000 description 1
- ZOXGRMKKPZGUFQ-UHFFFAOYSA-N 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 ZOXGRMKKPZGUFQ-UHFFFAOYSA-N 0.000 description 1
- HUWAGARMESVAMM-UHFFFAOYSA-N 4-chloro-2-piperidin-1-yl-5-(trifluoromethyl)pyrimidine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1N1CCCCC1 HUWAGARMESVAMM-UHFFFAOYSA-N 0.000 description 1
- PMRAHSMOEVKPKR-UHFFFAOYSA-N 4-chloro-5-methyl-2-piperidin-1-ylpyrimidine Chemical compound N1=C(Cl)C(C)=CN=C1N1CCCCC1 PMRAHSMOEVKPKR-UHFFFAOYSA-N 0.000 description 1
- KBAHWKSEADHPSV-UHFFFAOYSA-N 4-chloro-n-(2-methoxyphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound COC1=CC=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 KBAHWKSEADHPSV-UHFFFAOYSA-N 0.000 description 1
- NCJNZTIOVATIRN-UHFFFAOYSA-N 4-chloro-n-(2-methylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound CC1=CC=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 NCJNZTIOVATIRN-UHFFFAOYSA-N 0.000 description 1
- UMXQDYUFBZTTIE-UHFFFAOYSA-N 4-chloro-n-(3,4-dichlorophenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NC1=CC=C(Cl)C(Cl)=C1 UMXQDYUFBZTTIE-UHFFFAOYSA-N 0.000 description 1
- DKVUTKNLQRBUKJ-UHFFFAOYSA-N 4-chloro-n-(3-chlorophenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NC1=CC=CC(Cl)=C1 DKVUTKNLQRBUKJ-UHFFFAOYSA-N 0.000 description 1
- AXBJSICLLSHPPE-UHFFFAOYSA-N 4-chloro-n-(4-chlorophenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NC1=CC=C(Cl)C=C1 AXBJSICLLSHPPE-UHFFFAOYSA-N 0.000 description 1
- LVVPPOIKTHGTEX-UHFFFAOYSA-N 4-chloro-n-(4-methoxyphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=CC(OC)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 LVVPPOIKTHGTEX-UHFFFAOYSA-N 0.000 description 1
- LREBAJBACVYPKK-UHFFFAOYSA-N 4-chloro-n-(4-methylsulfonylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 LREBAJBACVYPKK-UHFFFAOYSA-N 0.000 description 1
- XHHWDWKYOZEPTJ-UHFFFAOYSA-N 4-chloro-n-(4-nitrophenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=CC([N+](=O)[O-])=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 XHHWDWKYOZEPTJ-UHFFFAOYSA-N 0.000 description 1
- AXNROEFFPMULEP-UHFFFAOYSA-N 4-chloro-n-(cyclohexylmethyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NCC1CCCCC1 AXNROEFFPMULEP-UHFFFAOYSA-N 0.000 description 1
- RXLUXCFXLDCISZ-UHFFFAOYSA-N 4-chloro-n-[(4-methylphenyl)methyl]-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=CC(C)=CC=C1CNC1=NC=C(C(F)(F)F)C(Cl)=N1 RXLUXCFXLDCISZ-UHFFFAOYSA-N 0.000 description 1
- JODQKUQHKQJEQW-UHFFFAOYSA-N 4-chloro-n-[3-(1,3-oxazol-5-yl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NC1=CC=CC(C=2OC=NC=2)=C1 JODQKUQHKQJEQW-UHFFFAOYSA-N 0.000 description 1
- FBYNXPUIAGSSRB-UHFFFAOYSA-N 4-chloro-n-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NC1CCCCC1 FBYNXPUIAGSSRB-UHFFFAOYSA-N 0.000 description 1
- GTBJWXNDQRNLLG-UHFFFAOYSA-N 4-chloro-n-methyl-n-(4-methylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound N=1C=C(C(F)(F)F)C(Cl)=NC=1N(C)C1=CC=C(C)C=C1 GTBJWXNDQRNLLG-UHFFFAOYSA-N 0.000 description 1
- LMNPKIOZMGYQIU-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical compound FC(F)(F)C1=CNC(=O)NC1=O LMNPKIOZMGYQIU-UHFFFAOYSA-N 0.000 description 1
- LHTJEBJSHUCUDT-UHFFFAOYSA-N 5-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1,3-dihydroindol-2-one Chemical compound N1=C(Cl)C(C(F)(F)F)=CN=C1NC1=CC=C(NC(=O)C2)C2=C1 LHTJEBJSHUCUDT-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- BZORFPDSXLZWJF-UHFFFAOYSA-N N,N-dimethyl-1,4-phenylenediamine Chemical compound CN(C)C1=CC=C(N)C=C1 BZORFPDSXLZWJF-UHFFFAOYSA-N 0.000 description 1
- 229920001774 Perfluoroether Chemical group 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005422 alkyl sulfonamido group Chemical group 0.000 description 1
- 125000005227 alkyl sulfonate group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002081 enamines Chemical group 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Description
X2は、ハライド、アリールスルホネート、アルキルスルホネート、ペルアルキルスルホネート、アリールスルフィネート又はアルキルスルフィネートの様な脱離基であり;そして、
R3及びR4は、水素、芳香族基及び脂肪族基から成るグループから独立に選択される置換基であり、又は、それらが共同して成る−NR3R4は、4から11員環の芳香族又は脂肪族環を形成することができる;
を製造する方法であって、式10の化合物:
2,4−ジクロロ−5−トリフルオロメチルピリミジンの製造:
5−トリフルオロメチルウラシル(250g、1.39mol)及びオキシ塩化リン(655mL、6.94mol、5当量)を、オーバーヘッド撹拌機、還流凝縮器、滴下漏斗及び内部熱伝対を備えた3Lの四つ口フラスコに注入した。内容物を窒素雰囲気下に保持し、濃リン酸(85wt%、9.5mL、0.1当量)をスラリーに一度に加えた結果、温和な発熱が見られた。次いで、ジイソプロピルエチルアミン(245mL、1.39mol、1当量)を、添加後の内部の反応温度が85から90℃に達するように、15分間かけて滴下した。アミン添加が終わるまでには、反応混合物は均一な薄橙色の溶液を呈した。加熱を開始し、橙色の溶液を100℃で20時間保持した。その時点で、反応混合物のHPLC分析は、出発物質が消費されていることを示唆した。外部加熱を止め、フラスコの内容物を40℃に冷却し、次いで、3NのHCl(5L,10当量)とジエチルエーテル(2L)の冷却した混合液に、滴下しながら加えた。その間、クエンチ・ポットの温度を10℃と15℃の間に保持した。層が分離し、水層をエーテル(1L)で1度抽出した。有機層を併せて、洗浄液が中性になるまで水で洗浄し(1.5L洗浄液×5)、MgSO4で乾燥し、濃縮して薄黄色−橙色の油状物質(288g、収率95%)を得た。HPLCによる純度は96%であった。この物質を蒸留により更に精製できる(沸点109℃/79mmHg)。
非選択的アミン付加の一般的手順:
方法A:(2−クロロ−5−トリフルオロメチル−ピリミジン−4−イル)−p−トリル−アミン(9)及び(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−p−トリル−アミン(8)の混合物
DCE/t−ブタノール(20mL)中5−トリフルオロメチル−2,4−ジクロロピリミジン(500mg、2.3mmol)の溶液へ、4−メチルアニリン(247mg、1当量)を加え、次いで、トリエチルアミン(1.1当量)を滴下して加えた。終夜撹拌した後、反応液を濃縮し、酢酸エチルで回収し、NaHCO3飽和水溶液で洗浄し、Na2SO4で乾燥し、溶媒を除去した。分析用HPLCにより、粗反応混合物には、化合物8:化合物9=1.4:1の混合物が含まれていることが分かった。得られた異性体の混合物は、Shimadzu分取用HPLC装置で、標準勾配溶媒条件(Waters XTerra分取MS、C18カラム、5m、50×50mm;40〜90%ACN/H2O中0.1%NH4OH含有溶液、75mL/分、15分勾配溶出)を用いて分離し、(2−クロロ−5−トリフルオロメチル−ピリミジン−4−イル)−p−トリル−アミン(9)(122mg):1HNMR(CDCl3,400MHz)δ:2.35(s,3H),6.99(br s,1H),7.19(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),8.38(s,1H);13CNMR(CDCl3,100MHz)δ:163.9,157.6,156.0(q,J=5Hz),136.1,133.7,130.0,123.8(q,J=270Hz),122.8,106.6(q,J=32Hz),21.2;HPLC保持時間:7.236分;LRMS(M+):288.1,290.1;及び(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−p−トリル−アミン(8)(205mg):1HNMR(CDCl3,400MHz)δ:2.33(s,3H)7.17(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),7.46(br s,1H),8.52(s,1H);13CNMR(CDCl3,100MHz)δ:160.9,157.6(br),134.9,134.8,129.9,122.8(q,J=269Hz),121.1,113.7(q,J=34Hz),21.1;HPLC保持時間:8.137分;LRMS(M+):288.1,290.1を得た。単結晶X線分析により、2つの異性体の構造を確認した。
方法B:(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−p−トリル−アミン(8)
DCE/t−BuOH(1:1、80mL)中5−トリフルオロメチル−2,4−ジクロロピリミジン(2g、9.2mmol)の溶液に、0℃で塩化亜鉛(1Mエーテル溶液、11mL、1.2当量)を加えた。1時間後、4−メチルアニリン(988mg、1当量)を加え、続いてDCE/t−BuOH(10mL)中トリエチルアミン(1.03g、1.1当量)の溶液を滴下して加えた。1.5時間攪拌後、反応溶液を濃縮した。分析用HPLCにより、粗反応混合物は、5%未満の異性体9を含むことが分かった。所望の生成物8は、白色固体(2.25g;85%)として得た後、メタノールから結晶化した。HPLC保持時間:8.169分;LRMS(M+):288.2,290.1。
5−(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イルアミノ)−1,3−ジヒドロ−インドール−2−オン:1HNMR(DMSO−d6,400MHz)δ:3.29(s,2H),6.76(d,J=7.9Hz,2H),7.39(d,J=8.3Hz),7.51(br s,1H),8.71(s,1H),10.33(s,1H),10.49(s,1H);13CNMR(DMSO−d6,100MHz)δ:177.0,161.3,158.7(br),140.7,132.8,126.9,123.7(q,J=268Hz),121.0,118.7,111.2,(q,J=32Hz),109.6,36.7;HPLC保持時間:5.759分;LRMS(M+)329.1,331,1。
(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−(4−ニトロ−フェニル)−アミン:1HNMR(CDCl3,400MHz)δ:7.80(br s,1H),7.82(d,J=24Hz,2H),8.26(d,J=23Hz,2H),8.67(s,1H);13CNMR(DMSO−d6,100MHz)δ:160.7,158.9(q,4.5Hz),158.6,145.7,142.7,125.6,123.3(q,J=269Hz),120.0,113.8(q,J=34Hz);HPLC保持時間:7.720分;LRMS(M+)318.3,320.3。
(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−o−トリル−アミン:1HNMR(CDCl3,400MHz)δ:2.30(s,3H),7.15(m,2H),7.26(m,3H),7.35(d,J=7.5Hz,1H),8.51(s,1H);13CNMR(CDCl3,100MHz)δ:161.5,159.7,157.8(q,J=4.5Hz),135.4,131.1,127.0,126.3,124.0,122.8(q,J=270Hz),113.8(q,J=34Hz),18.3;HPLC保持時間:7.663分;LRMS(M+)288.1,290.1。
(4−クロロ−フェニル)−(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−アミン:1HNMR(CDCl3,400MHz)δ:7.33(d,J=9.1Hz,2H),7.42(s,1H),7.53(d,J=8.7Hz,2H),8.56(s,1H);13CNMR(CDCl3,100MHz)δ:160.5,159.7,157.6(q,J=5Hz),136.2,129.8,129.4,122.7(q,J=270Hz),118.6,114.4(q,J=34Hz);HPLC保持時間:8.316分;LRMS(M+)308.1,310.0。
(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−(3−オキサゾール−5−イル−フェニル)−アミン:1HNMR(DMSO−d6,400MHz)δ:7.44(m,2H),7.63(s,1H),7.65(m,1H),8.07(s,1H),8.44(s,1H),8.82(s,1H),10.78(s,1H);13CNMR(DMSO−d6,100MHz)δ:161.2,158.9(br),158.4,152.6,151.0,139.8,130.2,128.5,123.6(q,J=269Hz),122.9,121.2,120.1,116.4,112.3(q,J=34Hz);HPLC保持時間:7.374分;LRMS(M+)341.2,343.1。
(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−(4−メタンスルホニル−フェニル)−アミン:1HNMR(DMSO−d6,400MHz)δ:3.15(s,3H),7.87(d,J=8.7Hz,2H),7.93(d,J=8.7Hz,2H),8.89(s,1H),11.10(s,1H):13CNMR(DMSO−d6,100MHz)δ:60.9,158.9(br),158.5,143.9,135.3,128.8,123.4(q,J=269Hz),120.4,113.3(q,J=34Hz),44.5;HPLC保持時間:6.542分;LRMS(M+)352.1,354.1。
アミン求核剤が、ルイス酸に対する多座配位子として作用することが可能な脂肪族又は芳香族アミンである場合、反応を選択的に進めるためには、他の同等のルイス酸が必要である。
DCE/t−BuOH(1:1、20mL)中5−トリフルオロメチル−2,4−ジクロロピリミジン(500mg、2.3mmol)の溶液へ、塩化亜鉛(1Mエーテル溶液、5.1mL、2.2当量)を0℃で加えた。1時間後、N,N−ジメチル−1,4−フェニレンジアミン(313mg、1当量)を加え、次いで、DCE/t−BuOH(5mL)中トリエチルアミン(279mg、1.1当量)の溶液を滴下して加えた。24時間攪拌後、反応溶液を濃縮した。生成物を薄緑色固体(531mg、73%)として得た後、25%H2O/メタノール溶液から結晶化した。1HNMR(DMSO−d6,400MHz)δ:2.83(s,6H),6.69(m,2H),7.39(m,2H),8.65(s,1H),10.32(s,1H);13CNMR(CDCl3,100MHz)δ:161.3,158.8(br),158.5(br),148.3,128.2,123.8(q,J=268Hz),123.0,113.1,110.8(br),41.0;HPLC保持時間:7.901分;LRMS(M+)317.3,319.3。
(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−(2−メトキシ−フェニル)−アミン:1HNMR(CDCl3,400MHz)δ:3.90(s,3H),6.91(d,J=8.1Hz,1H),7.01(m,1H),7.07(m,1H),8.09(s,1H),8.38(d,J=7.9Hz,1H),8.57(s,1H);13CNMR(CDCl3,100MHz)δ:160.4,159.3,157.5(q,J=4.5Hz),148.6,127.4,124.1,122.9(q,J=269Hz),121.1,119.8,113.7(q,J=34Hz),110.4,56.0;HPLC保持時間:8.151分;LRMS(M+)304.2,306.2。
(4−クロロ−5−トリフルオロメチル−ピリミジン−2−イル)−シクロヘキシル−アミン:1HNMR(DMSO−d6,400MHz)δ:1.10(m,1H),1.23(m,4H),1.55(m,1H),1.65(m,2H),1.81(m,2H),3.69(m,2H),8.47(m,1H),8.55(2br s,1H);HPLC保持時間:8.548分;LRMS(M+)280.1,282.1。
4−クロロ−2−ピペリジン−1−イル−5−トリフルオロメチル−ピリミジン:1HNMR(CDCl3−d6,400MHz)δ:1.60(m,4H),1.68(m,2H),3.82(m,4H),8.36(s,1H);13CNMR(DMSO−d6,100MHz)δ:161.5,159.1,157.2(q,J=4.5Hz),123.4(q,J=268Hz),109.8(q,J=34Hz),45.4,25.9,24.7;HPLC保持時間:8.915分;LRMS(M+)266.1,268.2。
Claims (9)
- 式11:
R3及びR4は、水素、芳香族基及び脂肪族基から成るグループから独立に選択される置換基であり、又は、それらが共同して成る−NR3R4は、4から11員環の芳香族又は脂肪族環を形成することができる)
の化合物を製造する方法であって、式10:
の化合物を、ルイス酸、ここでルイス酸はZnイオンの塩である、及び非求核性塩基の存在下で、式3のアミン(HNR3R4)と反応させて、式11の化合物を形成することを含む方法。 - X1及びX2が、同一又は異なり、そして互いに独立にハライドである、請求項1に記載の方法。
- X1及びX2がクロリドである、請求項2に記載の方法。
- アミンHNR3R4が芳香族アミンであり、そしてピリミジン10の量に対して、0.25から10当量のルイス酸が使用される、請求項1に記載の方法。
- アミンHNR3R4が芳香族アミンであり、そしてピリミジン10の量に対して、0.
5から3当量のルイス酸が使用される、請求項1に記載の方法。 - ルイス酸がZnCl2である、請求項4に記載の方法。
- アミンHNR3R4がルイス酸に対して多座配位子として作用することができる脂肪族アミン又は芳香族アミンであり、そしてピリミジン10の量に対して、0.5から10当量のルイス酸が使用される、請求項1に記載の方法。
- アミンHNR3R4が、ルイス酸に対して多座配位子として作用することができる脂肪族アミン又は芳香族アミンであり、そしてピリミジン10の量に対して、1から4当量のルイス酸が使用される、請求項1に記載の方法。
- ルイス酸がZnCl2である、請求項7に記載の方法。
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Publication number | Priority date | Publication date | Assignee | Title |
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MXPA06002608A (es) * | 2002-12-20 | 2007-01-23 | Pfizer Prod Inc | Derivados de pirimidina para el tratamiento del crecimiento celular anormal. |
US20060205945A1 (en) * | 2004-05-14 | 2006-09-14 | Pfizer Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
JP4778717B2 (ja) * | 2005-03-25 | 2011-09-21 | 富士フイルム株式会社 | 複素環式化合物の製造方法 |
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AP2009005010A0 (en) | 2007-04-18 | 2009-10-31 | Pfizer Prod Inc | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
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UY31714A (es) * | 2008-03-20 | 2009-11-10 | Boehringer Ingelheim Int | Preparación selectiva de pirimidinas sustituidas |
JP2011515372A (ja) * | 2008-03-20 | 2011-05-19 | 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 | 置換ピリミジン類の位置選択的製造法 |
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TW201100441A (en) | 2009-06-01 | 2011-01-01 | Osi Pharm Inc | Amino pyrimidine anticancer compounds |
JP5539518B2 (ja) * | 2009-08-14 | 2014-07-02 | 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 | 2−アミノ−5−トリフルオロメチルピリミジン誘導体の位置選択的調製 |
US8933227B2 (en) * | 2009-08-14 | 2015-01-13 | Boehringer Ingelheim International Gmbh | Selective synthesis of functionalized pyrimidines |
EP2646448B1 (en) | 2010-11-29 | 2017-08-30 | OSI Pharmaceuticals, LLC | Macrocyclic kinase inhibitors |
US8546443B2 (en) | 2010-12-21 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Benzylic oxindole pyrimidines |
US20130324532A1 (en) | 2011-02-17 | 2013-12-05 | Cancer Therapeutics Crc Pty Limited | Fak inhibitors |
US9174946B2 (en) | 2011-02-17 | 2015-11-03 | Cancer Therapeutics Crc Pty Ltd | Selective FAK inhibitors |
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GB2538476B (en) * | 2014-05-08 | 2019-03-20 | Tosoh F Tech Inc | 5-(Trifluoromethyl)pyrimidine derivatives and method for producing same |
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JP6391988B2 (ja) * | 2014-05-21 | 2018-09-19 | 東ソー・ファインケム株式会社 | 5−(トリフルオロメチル)ピリミジン誘導体の製造方法及び新規5−(トリフルオロメチル)ピリミジン誘導体 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
WO2003032997A1 (de) * | 2001-10-17 | 2003-04-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pyrimidinderivate, arzneimittel enthaltend diese verbindungen, deren verwendung und verfahren zu ihrer herstellung |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
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