JP7384963B2 - 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 - Google Patents
3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 Download PDFInfo
- Publication number
- JP7384963B2 JP7384963B2 JP2022086917A JP2022086917A JP7384963B2 JP 7384963 B2 JP7384963 B2 JP 7384963B2 JP 2022086917 A JP2022086917 A JP 2022086917A JP 2022086917 A JP2022086917 A JP 2022086917A JP 7384963 B2 JP7384963 B2 JP 7384963B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- salt
- added
- compound represented
- equiv
- 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.)
- Active
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 31
- -1 3,6-disubstituted imidazo[1,2-b]pyridazine Chemical class 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 25
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000001361 adipic acid Substances 0.000 claims description 5
- 235000011037 adipic acid Nutrition 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 229910052763 palladium Inorganic materials 0.000 description 19
- 239000003054 catalyst Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- 239000013078 crystal Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical group COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 6
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- MPZDNIJHHXRTIQ-UHFFFAOYSA-N 6-chloroimidazo[1,2-b]pyridazine Chemical compound N1=C(Cl)C=CC2=NC=CN21 MPZDNIJHHXRTIQ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000010499 C–H functionalization reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 238000007080 aromatic substitution reaction Methods 0.000 description 4
- 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 4
- URQYCXJSMFGDRO-UHFFFAOYSA-N 6-fluoroimidazo[1,2-b]pyridazine Chemical compound N1=C(F)C=CC2=NC=CN21 URQYCXJSMFGDRO-UHFFFAOYSA-N 0.000 description 3
- UXRCVYPXTYUNMN-UHFFFAOYSA-N 6-fluoroimidazo[1,2-b]pyridazine methanesulfonic acid Chemical compound CS(=O)(=O)O.FC=1C=CC=2N(N=1)C=CN=2 UXRCVYPXTYUNMN-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- SJHOPMGZPCUOJY-CYBMUJFWSA-N tert-butyl N-[(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl]carbamate Chemical compound FC=1C=CC=2N(N=1)C(=CN=2)C1=CC=C(OC[C@@H](C)NC(OC(C)(C)C)=O)C=C1 SJHOPMGZPCUOJY-CYBMUJFWSA-N 0.000 description 3
- WIHQWGAILKFWDB-SNVBAGLBSA-N tert-butyl n-[(2r)-1-(4-bromophenoxy)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C)COC1=CC=C(Br)C=C1 WIHQWGAILKFWDB-SNVBAGLBSA-N 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 150000004892 pyridazines Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FKGBPJQFQONHGQ-CYBMUJFWSA-N tert-butyl N-[(2R)-1-[4-(6-chloroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl]carbamate Chemical compound ClC=1C=CC=2N(N=1)C(=CN=2)C1=CC=C(OC[C@@H](C)NC(OC(C)(C)C)=O)C=C1 FKGBPJQFQONHGQ-CYBMUJFWSA-N 0.000 description 2
- ASNVMKIDRJZXQZ-ZCFIWIBFSA-N (1r)-1-(3-fluorophenyl)ethanamine Chemical compound C[C@@H](N)C1=CC=CC(F)=C1 ASNVMKIDRJZXQZ-ZCFIWIBFSA-N 0.000 description 1
- BKMMTJMQCTUHRP-GSVOUGTGSA-N (2r)-2-aminopropan-1-ol Chemical compound C[C@@H](N)CO BKMMTJMQCTUHRP-GSVOUGTGSA-N 0.000 description 1
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- PFHPKMPWBFJZEY-UHFFFAOYSA-N 3-bromo-6-chloroimidazo[1,2-b]pyridazine Chemical compound N1=C(Cl)C=CC2=NC=C(Br)N21 PFHPKMPWBFJZEY-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- DCLWNTIANRACSB-UHFFFAOYSA-N imidazo[1,2-b]pyridazin-6-amine Chemical compound N1=C(N)C=CC2=NC=CN21 DCLWNTIANRACSB-UHFFFAOYSA-N 0.000 description 1
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical group N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/14—Adipic acid
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
(1)式(I):
式(II):
式(III):
(2)上記式(II)及び(III)において、PGがtert-ブトキシカルボニル基である、(1)に記載の製造方法。
(3)パラジウム触媒が、酢酸パラジウム及びトリス(2-メチルフェニル)ホスフィンからなる触媒である、(1)または(2)のいずれかに記載の製造方法。
(4)塩基が、炭酸カリウムである、(1)乃至(3)のいずれか1に記載の製造方法。
(5)溶媒がジエチレングリコールジメチルエーテルである、(1)乃至(4)のいずれか1に記載の製造方法。
(6)(1)乃至(5)のいずれか1に記載の製造方法を用いて式(III)で表される化合物またはその塩を製造し、
式(IV):
窒素原子上のPGを脱保護する工程を包含することを特徴とする、式(V):
(7)(6)に記載の製造方法を用いて式(V)で表される化合物を製造し、次いで、アジピン酸を用いて塩化する工程を包含することを特徴とする、式(V)で表される化合物のアジピン酸塩の製造方法。
本発明の「パラジウム触媒」には、例えば、塩化パラジウム、酢酸パラジウム等のパラジウム化合物に、例えば、トリフェニルホスフィン、トリt-ブチルホスフィン、トリス(2-メチルフェニル)ホスフィン等の単座配位型ホスフィン配位子、或いは1,1-ビス(ジフェニルホスフィノ)メタン、1,2-ビス(ジフェニルホスフィノ)エタン等の二座配位型ホスフィン配位子等を作用させて反応系内で調製された触媒も含む。
チルエーテル、1,4-ジオキサン、ジエチレングリコールジメチルエーテル等があげられる。水と混和する溶媒が好ましく、例えば、ジエチレングリコールジメチルエーテル等があげられる。
項1
式(V):
で表される化合物またはその塩の製造方法であって、式(III):
で表される化合物またはその塩を、式(IV):
で表される化合物またはその塩と反応させる工程:及び
窒素原子上のPGを脱保護する工程を含み、
式中、PGは、窒素原子の保護基を示す、製造方法。
項2
アジピン酸を用いて、式(V)で表される化合物の塩を形成する工程をさらに含む、項1に記載の製造方法。
項3
PGがtert-ブトキシカルボニル基である、項1または2に記載の製造方法。
項4
PGがベンジルオキシカルボニル基である、項1または2に記載の製造方法。
項5
図1に実質的に示されるX線回折(XRD)パターンを有する、3-{4-[(2R)-2-アミノプロポキシ]フェニル}-N-[(1R)-1-(3-フルオロフェニル)エチル]イミダゾ[1,2-b]ピリダジン-6-アミン アジピン酸塩の結晶。
g : グラム,mL: ミリリットル,L:リットル,MHz : メガヘルツ。
装置:Bruker Axs株式会社 D8 Discover with GADDS CST
X線源:CuKα λ=1.54オングストローム
方法:反射法
管電圧:40 kV
管電流:40 mA
走査範囲:2~42°
走査速度:10°/min
tert-ブチル[(2R)-1-(4-ブロモフェノキシ)プロパン-2-イル]カルバメート(1)
6-フルオロイミダゾ[1,2-b]ピリダジン メタンスルホン酸塩(2)
tert-ブチル{(2R)-1-[4-(6-フルオロイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ]プロパン-2-イル}カルバメート (3)
固体を減圧下、外温40 ℃にて乾燥し、表記化合物(3)(1.65 kg, 94.1%(グロス重量))を取得した。
1H NMR(500 MHz, CDCl3): δ=1.32 (d, J=7.0 Hz, 3 H), 1.47 (s, 9 H), 4.00 (d, J=4.0 Hz, 2 H), 4.10 (brs, 1H), 4.80 (brs, 1H), 6.87 (d, J=7.6 Hz, 1 H), 7.02-7.08 (m, 2H), 7.92-7.97 (m, 2H), 8.00 (s, 1H), 8.06 (dd, J=7.6, 6.0 Hz, 1H)
tertブチル{(2R)-1-[4-(6-{[(1R)-1-(3-フルオロフェニル)エチル]アミノ}イミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ]プロパン-2-イル}カルバメート 塩酸塩 (4)
得られた溶液から5/8の量を抜き出し、以降の反応に用いた。溶液にシクロペンチルメチルエーテル(0.25 L)、テトラヒドロフラン(3 L )、水(0.05 L) を順次加え、内温23 ℃にて濃塩酸(74.9 g, 1.15 mol, 0.4 equiv.)を加えた。25 ℃で1.5時間撹拌した後、シクロペンチルメチルエーテル(1.5 L)、テトラヒドロフラン(1.5 L)の混合液を加えた。さらに1.5時間撹拌した後、濃塩酸(112 g, 1.72 mol, 0.6 equiv.)を3回に分けて1時間おきに添加した。内温25 ℃にて18時間撹拌した後、析出した固体をろ過し、シクロペンチルメチルエーテル(1.25 L)、テトラヒドロフラン(1.25 L)、水(0.025 L)の混合液で洗浄した。減圧下、外温40 ℃にて乾燥し、表記化合物(4)(808.0 g) を得た。
3-{4-[(2R)-2-アミノプロポキシ]フェニル}-N-[(1R)-1-(3-フルオロフェニル)エチルイミダゾ[1,2-b]ピリダジン-6-アミン 2塩酸塩 (5)
3-{4-[(2R)-2-アミノプロポキシ]フェニル}-N-[(1R)-1-(3-フルオロフェニル)エチルイミダゾ[1,2-b]ピリダジン-6-アミン(V)
窒素雰囲気下、式(5)の化合物(75.5 g, 0.17 mol)とエタノール(604 mL)、水(604 mL)を混合した後、内温50 ℃に加温し溶解した。内温50 ℃にて25%水酸化ナトリウム水溶液(68.1 g)を3分間で添加した。その後内温1 ℃まで1.5時間かけて冷却し、18.5時間攪拌した。析出した固体をろ過し、冷却したエタノール(151 mL)と水(151 mL)の混合液にて洗浄した。減圧下、外温40 ℃にて乾燥し、表記化合物(V)(58.8 g)を得た。
3-{4-[(2R)-2-アミノプロポキシ]フェニル}-N-[(1R)-1-(3-フルオロフェニル)エチルイミダゾ[1,2-b]ピリダジン-6-アミン アジピン酸塩 (6)
*結晶は反応液を長時間攪拌すれば自然と析出するが、ここでは結晶析出までの時間短縮のため、予め同様の実験で取得してあった結晶を種結晶として加えた。
tert-ブチル{(2R)-1-[4-(6-クロロイミダゾ[1,2-b]ピリダジン-3-イル)フェノキシ]プロパン-2-イル}カルバメート (7)
[1]式(I):
で表される化合物またはその塩と、
式(II):
(式中、PGは、窒素原子の保護基を示す。)で表される化合物またはその塩を、溶媒中でパラジウム触媒及び塩基の存在下で反応させる工程を包含することを特徴とする、
式(III):
(式中の各記号は前述したとおり。)で表される化合物またはその塩の製造方法。
[2]上記式(II)及び(III)において、PGがtert-ブトキシカルボニル基である、[1]に記載の製造方法。
[3]パラジウム触媒が、酢酸パラジウム及びトリス(2-メチルフェニル)ホスフィンからなる触媒である、[1]または[2]のいずれかに記載の製造方法。
[4]塩基が、炭酸カリウムである、[1]乃至[3]のいずれか1項に記載の製造方法。
[5]溶媒がジエチレングリコールジメチルエーテルである、[1]乃至[4]のいずれか1項に記載の製造方法。
[6][1]乃至[5]のいずれか1項に記載の製造方法を用いて式(III)で表される化合物またはその塩を製造し、
式(IV):
で表される化合物またはその塩と反応させる工程:及び
窒素原子上のPGを脱保護する工程を包含することを特徴とする、式(V):
で表される化合物またはその塩の製造方法。
[7][6]に記載の製造方法を用いて式(V)で表される化合物を製造し、次いで、アジピン酸を用いて塩化する工程を包含することを特徴とする、式(V)で表される化合物のアジピン酸塩の製造方法。
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023143544A JP2023171735A (ja) | 2017-03-14 | 2023-09-05 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017049138 | 2017-03-14 | ||
JP2017049138 | 2017-03-14 | ||
JP2019506027A JP7082608B2 (ja) | 2017-03-14 | 2018-03-13 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
PCT/JP2018/009596 WO2018168815A1 (ja) | 2017-03-14 | 2018-03-13 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019506027A Division JP7082608B2 (ja) | 2017-03-14 | 2018-03-13 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023143544A Division JP2023171735A (ja) | 2017-03-14 | 2023-09-05 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022105746A JP2022105746A (ja) | 2022-07-14 |
JP7384963B2 true JP7384963B2 (ja) | 2023-11-21 |
Family
ID=63523451
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019506027A Active JP7082608B2 (ja) | 2017-03-14 | 2018-03-13 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
JP2022086917A Active JP7384963B2 (ja) | 2017-03-14 | 2022-05-27 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
JP2023143544A Pending JP2023171735A (ja) | 2017-03-14 | 2023-09-05 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019506027A Active JP7082608B2 (ja) | 2017-03-14 | 2018-03-13 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023143544A Pending JP2023171735A (ja) | 2017-03-14 | 2023-09-05 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Country Status (12)
Country | Link |
---|---|
US (3) | US11028091B2 (ja) |
EP (2) | EP4101853A1 (ja) |
JP (3) | JP7082608B2 (ja) |
CN (2) | CN110418792B (ja) |
AU (1) | AU2018234027B2 (ja) |
CA (1) | CA3055504A1 (ja) |
ES (1) | ES2947326T3 (ja) |
HR (1) | HRP20230764T1 (ja) |
HU (1) | HUE063830T2 (ja) |
PL (1) | PL3597648T3 (ja) |
RS (1) | RS64354B1 (ja) |
WO (1) | WO2018168815A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2018234027B2 (en) * | 2017-03-14 | 2021-12-09 | Daiichi Sankyo Company, Limited | Method for producing 3, 6-disubstituted imidazo[1, 2-b]pyridazine derivative |
AU2021453749A1 (en) * | 2021-07-01 | 2023-12-21 | Anheart Therapeutics (Hangzhou) Co., Ltd. | Crystalline forms of 3-{4-[(2r)-2-aminopropoxy]phenyl}-n-[(1r)- 1-(3-fluorophenyl) ethyl]imidazo[1,2-b]pyridazin-6-amine and salts thereof |
WO2023220967A1 (en) * | 2022-05-18 | 2023-11-23 | Anheart Therapeutics (Hangzhou) Co., Ltd. | Method for producing 3,6-disubstituted-imidazo[1,2-b]pyridazine compounds |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013183578A1 (ja) | 2012-06-04 | 2013-12-12 | 第一三共株式会社 | キナーゼ阻害剤としてのイミダゾ[1,2-b]ピリダジン誘導体 |
WO2018168815A1 (ja) | 2017-03-14 | 2018-09-20 | 第一三共株式会社 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60197640A (ja) * | 1984-03-19 | 1985-10-07 | Ihara Chem Ind Co Ltd | ハロゲン化ニトロベンゼン類の製造方法 |
JPS61205220A (ja) * | 1985-03-08 | 1986-09-11 | Rikagaku Kenkyusho | 一級アルコ−ル類の選択的フツ素化方法 |
JP3551493B2 (ja) * | 1994-10-21 | 2004-08-04 | 三菱化学株式会社 | 新規ビスオキサゾリン化合物 |
JP2002193914A (ja) * | 2000-05-24 | 2002-07-10 | Nissan Chem Ind Ltd | ニトリル化合物およびその製造方法 |
AU2001260607A1 (en) * | 2000-05-24 | 2001-12-03 | Nissan Chemical Industries Ltd. | Nitrile compounds and process for their preparation |
FR2918061B1 (fr) * | 2007-06-28 | 2010-10-22 | Sanofi Aventis | Derives de 6-cycloamino-3-(pyridin-4-yl)imidazo°1,2-b!- pyridazine,leur preparation et leur application en therapeutique. |
FR2934994B1 (fr) * | 2008-08-12 | 2010-09-17 | Sanofi Aventis | Derives de 2-alkyl-6cycloamino-3-(pyridin-4-yl)imidaz°1,2-b! pyridazine, leur preparation et leur application en therapeutique |
CN104470523B (zh) * | 2012-03-09 | 2017-07-11 | 莱西肯医药有限公司 | 基于咪唑并[1,2‑b]哒嗪的化合物、包含它们的组合物及其使用方法 |
WO2014138692A1 (en) * | 2013-03-07 | 2014-09-12 | Califia Bio, Inc. | Mixed lineage kinase inhibitors and method of treatments |
WO2014200882A1 (en) * | 2013-06-11 | 2014-12-18 | Janssen Pharmaceutica Nv | PDE10a INHIBITORS FOR THE TREATMENT OF TYPE II DIABETES |
-
2018
- 2018-03-13 AU AU2018234027A patent/AU2018234027B2/en active Active
- 2018-03-13 US US16/494,116 patent/US11028091B2/en active Active
- 2018-03-13 PL PL18766623.5T patent/PL3597648T3/pl unknown
- 2018-03-13 HU HUE18766623A patent/HUE063830T2/hu unknown
- 2018-03-13 CA CA3055504A patent/CA3055504A1/en active Pending
- 2018-03-13 EP EP22186787.2A patent/EP4101853A1/en not_active Withdrawn
- 2018-03-13 CN CN201880017847.7A patent/CN110418792B/zh active Active
- 2018-03-13 EP EP18766623.5A patent/EP3597648B1/en active Active
- 2018-03-13 JP JP2019506027A patent/JP7082608B2/ja active Active
- 2018-03-13 WO PCT/JP2018/009596 patent/WO2018168815A1/ja unknown
- 2018-03-13 CN CN202210636460.8A patent/CN114773351A/zh active Pending
- 2018-03-13 ES ES18766623T patent/ES2947326T3/es active Active
- 2018-03-13 RS RS20230550A patent/RS64354B1/sr unknown
- 2018-03-13 HR HRP20230764TT patent/HRP20230764T1/hr unknown
-
2021
- 2021-02-01 US US17/164,684 patent/US11667642B2/en active Active
-
2022
- 2022-05-27 JP JP2022086917A patent/JP7384963B2/ja active Active
-
2023
- 2023-03-13 US US18/183,039 patent/US20230227459A1/en active Pending
- 2023-09-05 JP JP2023143544A patent/JP2023171735A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013183578A1 (ja) | 2012-06-04 | 2013-12-12 | 第一三共株式会社 | キナーゼ阻害剤としてのイミダゾ[1,2-b]ピリダジン誘導体 |
WO2018168815A1 (ja) | 2017-03-14 | 2018-09-20 | 第一三共株式会社 | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 |
Non-Patent Citations (2)
Title |
---|
川口洋子ら,医薬品と結晶多形,生活工学研究,2002年,Vol.4, No.2,p.310-317 |
平山令明,有機化合物結晶作製ハンドブック,2008年,p.17-23,37-40,45-51,57-65 |
Also Published As
Publication number | Publication date |
---|---|
EP3597648A4 (en) | 2020-10-14 |
WO2018168815A1 (ja) | 2018-09-20 |
HRP20230764T1 (hr) | 2023-10-13 |
CN114773351A (zh) | 2022-07-22 |
US11028091B2 (en) | 2021-06-08 |
CN110418792B (zh) | 2022-07-05 |
PL3597648T3 (pl) | 2023-07-24 |
US11667642B2 (en) | 2023-06-06 |
ES2947326T3 (es) | 2023-08-04 |
EP3597648C0 (en) | 2023-06-07 |
JP7082608B2 (ja) | 2022-06-08 |
AU2018234027A1 (en) | 2019-10-31 |
US20200062765A1 (en) | 2020-02-27 |
JPWO2018168815A1 (ja) | 2020-04-23 |
CA3055504A1 (en) | 2018-09-20 |
US20210171532A1 (en) | 2021-06-10 |
AU2018234027B2 (en) | 2021-12-09 |
RS64354B1 (sr) | 2023-08-31 |
EP3597648A1 (en) | 2020-01-22 |
EP4101853A1 (en) | 2022-12-14 |
HUE063830T2 (hu) | 2024-02-28 |
JP2022105746A (ja) | 2022-07-14 |
US20230227459A1 (en) | 2023-07-20 |
CN110418792A (zh) | 2019-11-05 |
EP3597648B1 (en) | 2023-06-07 |
JP2023171735A (ja) | 2023-12-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7384963B2 (ja) | 3,6-ジ置換イミダゾ[1,2-b]ピリダジン誘導体の製造方法 | |
JP2019048859A (ja) | Ask1阻害剤を調製するプロセス | |
JP5197645B2 (ja) | イミダゾ[1,2−b]ピリダジン類の新規な製造法 | |
MX2012009473A (es) | Procesos para preparar derivados de ciclopropilamidas e intermedios asociados con estas. | |
CN116102615A (zh) | 制备细胞毒性苯二氮䓬衍生物的方法 | |
JP2010512379A (ja) | プロセス | |
WO2009104520A1 (ja) | フェノキシピリジン誘導体の製造方法(2) | |
EP1619179A1 (en) | Production method of O-substituted tyrosine compound | |
TWI785660B (zh) | 嘧啶基-3,8-二氮雜雙環[3.2.1]辛烷基甲酮衍生物及其鹽之製備 | |
JP2016198736A (ja) | アミノサリチルアルジミン配位子を金属に配位させた触媒及びこれを用いたヨード環化体の製造方法 | |
KR20150066777A (ko) | 광학활성 인돌린 유도체 및 이의 제조방법 | |
CN115093397B (zh) | 一种用于治疗肿瘤的化合物、合成方法及应用 | |
WO2022009911A1 (ja) | 1,3-ベンゾジオキソール誘導体の製造方法 | |
JP4418430B2 (ja) | スルホンアミド含有インドール化合物の製造方法 | |
KR102032877B1 (ko) | 피롤로인돌리디온 유도체, 및 이의 제조방법 | |
US10590136B2 (en) | Processes for the preparation of cis-4-[2-{[(3S,4R)-3-fluorooxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide | |
EP4330229A1 (en) | Method for producing pyrrolidine compound | |
WO2023143605A1 (en) | Process for the synthesis of pyrazolyl derivatives useful as anti-cancer agents | |
CN113801062A (zh) | 3-氨基-5-(3,5-二氟苄基)-1h-吲唑的制备方法 | |
CN110831915A (zh) | 方法 | |
JP2019001716A (ja) | アミノグリコシド系抗生物質の製造方法 | |
JP2007284416A (ja) | 光学活性なピペラジン化合物の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220601 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230222 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230227 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230427 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230613 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230905 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230914 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231019 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231109 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7384963 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |