TR2021019998T2 - METHOD FOR PREPARING INDOLE OR NDAZOLE COMPOUND - Google Patents
METHOD FOR PREPARING INDOLE OR NDAZOLE COMPOUNDInfo
- Publication number
- TR2021019998T2 TR2021019998T2 TR2021/019998 TR2021019998T2 TR 2021019998 T2 TR2021019998 T2 TR 2021019998T2 TR 2021/019998 TR2021/019998 TR 2021/019998 TR 2021019998 T2 TR2021019998 T2 TR 2021019998T2
- Authority
- TR
- Turkey
- Prior art keywords
- alkyl
- formula
- hydrogen
- atoms
- compound represented
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 42
- 238000000034 method Methods 0.000 title claims description 13
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 27
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 13
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 13
- -1 indazole compound Chemical class 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 125000000623 heterocyclic group Chemical group 0.000 claims description 37
- 150000002431 hydrogen Chemical group 0.000 claims description 32
- 125000005842 heteroatom Chemical group 0.000 claims description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 125000004434 sulfur atom Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910020667 PBr3 Inorganic materials 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000007806 chemical reaction intermediate Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 1
- 101100533890 Hypocrea jecorina (strain QM6a) sor3 gene Proteins 0.000 claims 1
- 101100533874 Hypocrea jecorina (strain QM6a) sor5 gene Proteins 0.000 claims 1
- 229940125898 compound 5 Drugs 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000013341 scale-up Methods 0.000 abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 8
- 230000017074 necrotic cell death Effects 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 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 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 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 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000000626 neurodegenerative effect Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- NSKGQURZWSPSBC-VVPCINPTSA-N ribostamycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](N)C[C@@H]1N NSKGQURZWSPSBC-VVPCINPTSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical compound C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- YBFCBQMICVOSRW-UHFFFAOYSA-N 1-phenylindole Chemical compound C1=CC2=CC=CC=C2N1C1=CC=CC=C1 YBFCBQMICVOSRW-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- IAILDDJSLJVCOC-UHFFFAOYSA-N 5-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-2-phenyl-1h-indol-7-amine Chemical compound C=1C=2C=C(C=3C=CC=CC=3)NC=2C(N)=CC=1CN1CCS(=O)(=O)CC1 IAILDDJSLJVCOC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HECJEKMGZGYLFM-UHFFFAOYSA-N BrCC=1C=C2C=C(NC2=C(C1)[N+](=O)[O-])C1=CC=CC=C1 Chemical compound BrCC=1C=C2C=C(NC2=C(C1)[N+](=O)[O-])C1=CC=CC=C1 HECJEKMGZGYLFM-UHFFFAOYSA-N 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010038470 Renal infarct Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 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
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical group OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 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
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The present invention relates to a novel preparation method of a pharmaceutically useful indole or indazole compound by introducing a stable intermediate. Thus, it is possible to solve the limitations caused by conventional unstable intermediates to reduce the generation of impurities, prepare an indole or indazole compound in excellent yield, and be stably applied to scale up.The present invention relates to a novel preparation method of a pharmaceutically useful indole or indazole compound by introducing a stable intermediate. Thus, it is possible to solve the limitations caused by conventional unstable intermediates to reduce the generation of impurities, prepare an indole or indazole compound in excellent yield, and be stably applied to scale up.
Description
TARIENAME INDOL VEYA INDAZOL BILESIGI HAZIRLAMAYA YÖNELIK YÖNTEM TEKNIK ALAN Bu basvuru, açiklamasinin referans yoluyla buraya bütün olarak dahil edildigi, 0073018 Numarali Kore Patent Basvurusunun rüçhanindan faydalanmayi talep etmektedir. TARIENAME FOR PREPARING INDOLE OR NDAZole COMPOUND METHOD TECHNICAL FIELD This application, the description of which is incorporated herein in its entirety by reference, Request to benefit from the priority of Korean Patent Application No. 0073018 It does.
TeknikAlan Mevcut bulus, stabil bir ara ürünün uygulanmasi suretiyle farrnasötik olarak faydali bir indol veya indazol bilesiginin yeni bir hazirlanma yöntemi ile ilgilidir. ÖNCEKI TEKNIK Hücresel nekrozun yol açtigi tipik hastaliklar, iskemik (ör. miyokard enfarktüsü, inme, renal enfarktüs), nörodejeneratif ve inflamatuar hastaliklari içermektedir. TechnicalField The present invention is pharmaceutically effective by administering a stable intermediate. It relates to a new method of preparation of a useful indole or indazole compound. BACKGROUND ART Typical diseases caused by cellular necrosis are ischemic (e.g. myocardial infarction, stroke, renal infarction), neurodegenerative and inflammatory diseases.
Hücresel nekroz, morbid kosullar altinda kontrolsüz, kaza sonucu meydana gelen 36906.08 bir hücre ölümüdür ve iskemik, nörodejeneratif ve inflamatuar hastaliklarin tedavi edilmesi ve hücresel nekrozun biyolojik, patolojik nedenlerinin açikliga kavusturulmasi amaciyla nekroz önleyici maddelerin kesfedilmesi ve gelistirilmesi üzerine çalismalar gerçeklestirilmektedir. Cellular necrosis is an uncontrolled, accidental occurrence under morbid conditions. 36906.08 It is a form of cell death and is used in the treatment of ischemic, neurodegenerative and inflammatory diseases. and clarification of biological and pathological causes of cellular necrosis discovery and discovery of anti-necrosis agents for the purpose of Work is being carried out on its development.
Indol türevleri, tibbi bir bakis açisindan, hücresel nekrozun inhibisyonuna yönelik çok faydali yapiya sahiptir ve bu yapilar üzerine birçok çalisma sonucu rapor edilmistir. Temsili örnekler arasinda, örnegin, bilesiklerin glukokinaza yönelik Uluslararasi Yayini, bilesiklerin, kardiyovasküler sistemin üretimine karsi tümör önleyici ajanlar ve inhibitörler olarak faydali oldugunu rapor eden W095f07276 Numarali PCT Uluslararasi Yayini ve bilesiklerin antibiyotikler olarak Yayini bulunmaktadir. Ek olarak, hücresel nekroz ve nekroz ile iliskili hastaliklara yönelik bir önleme veya tedavi ve iyilestirme etkisi için faydali yeni Uluslararasi Yayini bulunmaktadir. 36906.08 Bunlarin arasinda, mevcut bulus, hücresel nekroz ve nekroz ile iliskili hastaliklara yönelik bir önleme veya tedavi ve iyilestirme etkisi sergileyen bir indol veya indazol bilesigini yeni bir ara ürünün uygulanmasi suretiyle hazirlamaya yönelik bir yöntem ile ilgilidir. Indole derivatives, from a medical point of view, are useful for the inhibition of cellular necrosis. It has a very useful structure and many studies have reported on these structures. has been done. Representative examples include, for example, the effects of compounds on glucokinase. International Publication, compounds against the production of the cardiovascular system, tumor WO95f07276 reporting usefulness as preventive agents and inhibitors PCT International Publication No. and its compounds as antibiotics It has a publication. Additionally, it is associated with cellular necrosis and necrosis. useful for a prevention or treatment of diseases and a healing effect It has an international publication. 36906.08 Among these, the present invention provides treatment for cellular necrosis and necrosis-related diseases. An indole or To prepare the compound indazole by application of a new intermediate It is about a method.
Geleneksel olarak, indol veya indazol bilesiklerinin sentez prosesi sirasinda üretilen ara ürünler stabil olmadigi için birçok safsizlik olusmustur, verim düsürülmüstür ve ölçek büyütme için stabil olarak uygulanmasi zordur. Traditionally, during the synthesis process of indole or indazole compounds Since the intermediate products produced were not stable, many impurities were formed, the yield has been reduced and is difficult to apply stably for scale-up.
Dolayisiyla, geleneksel stabil olmayan ara ürünün yol açtigi sinirlandirmalari çözen ve daha stabil ara ün'inler uygulayan yeni bir hazirlama yönteminin gelistirilmesine ihtiyaç duyulmaktadir. 36906.08 BULUSUN AÇIKLAMASI TEKNIK SORUN Mevcut bulusun bir yönü, safsizliklarin olusumunun azaltilmasi, verimin arttirilmasi ve ölçek büyütme için stabil olarak uygulanmasi amaciyla daha stabil yeni bir ara ürünün uygulanmasi suretiyle farmasötik olarak faydali bir indol veya indazol bilesigi hazirlamaya yönelik bir yöntem saglamaktadir. Therefore, the limitations caused by the traditional unstable intermediate A new preparation method that solves and implements more stable intermediates needs to be developed. 36906.08 DESCRIPTION OF THE INVENTION TECHNICAL PROBLEM One aspect of the present invention is the reduction of the formation of impurities, improving efficiency more stable in order to be increased and applied stably for scale-up. a pharmaceutically useful indole or provides a method for preparing the indazole compound.
TEKNIK gözÜM Mevcut bulusun bir yönüne göre, bir reaksiyon ara ürünü olarak asagidaki Formül 1 ile temsil edilen bir bilesigin dahil edilmesi suretiyle Formül 2 ile temsil edilen bir bilesigi hazirlamaya yönelik bir yöntem saglanmaktadir. 36906.08 Yukaridaki formüllerde, n, 1 ile 3 arasinda bir tam sayidir, m 0 veya 1”dir, p, 1 ile 3 arasinda bir tam sayidir, A, fenili temsil etmektedir veya her biri, N, O ve S atomlari arasindan seçilen 1 ila 3 heteroatom ihtiva eden ve istege bagli olarak R ile sübstitüe edilen 5-üyeli heteroaril veya heterosikli temsil etmektedir, burada R, hidrojeni temsil etmektedir veya istege bagli olarak hidroksi veya amino ile sübstitüe edilmis C1- C4-alkili temsil etmektedir, X, X”in N olmasi durumunda mlnin 0 olmasi ve X'in C olmasi durumunda m7nin 1 olmasi sartiyla, C veya N”yi temsil etmektedir, 36906.08 R', hidrojen, Ci-Ce-alkil veya I(CH2)iNRSR9'u temsil etmektedir, burada r, 2 ile arasinda bir tam sayidir, R8 ve R9”un her biri bagimsiz olarak, X,in N olmasi durumunda Rl'in hidrojen olmasi sartiyla, hidrojen veya Ci-Cs-alkili temsil etmektedir, R2, hidrojen, halojen veya Ci-Ce-alkoksiyi temsil etmektedir veya -(CH2)5C02RR, -(CH2)SOR8, -(CH2)SNRR””u temsil etmektedir veya -(CH2)s-heterosikl-R10`u temsil etmektedir, burada heterosikl kismi, N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden -6 üyeli bir halkadir, burada 5, 0 ile 3 arasinda bir tam sayidir, R8 ve R9 yukarida tanimlanan sekildedir ve RIO, hidrojen, okso, Ci-Cö-alkilkarbonil, Ci-Cg-alkoksi veya Ci-Ce- alkili temsil etmektedir veya bir heteroatom olarak bir veya iki azot atomunu ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir, R3, hidrojen, halojen, Ci-Ce-alkil veya fenili temsil etmektedir veya _(CH2)g' heterosikli temsil etmektedir, burada heterosikl, N ve O atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir halkadir, burada g, X7in N olmasi durumunda R3”ün hidrojen veya fenil olmasi sartiyla, 1 ile 3 arasinda bir tam sayidir, 36906.08 R4, -YR””i temsil etmektedir, burada Y, bir dogrudan bagdir veya -(CR8R9)eY,-°i temsil etmektedir, burada e, 0 ile 3 arasinda bir tam sayidir ve R8 ve R9, yukarida tanimlanan sekildedir, Y,, -O-, -C(O)- ve -C(O)O-`den olusan gruptan seçilmektedir, R”, hidrojen, halojen, Ci-Cö-alkil ve -(CH2)iB-R'3'ten olusan gruptan seçilmektedir, t 0 ile 3 arasinda bir tam sayidir, B; N, O ve S atomlari arasindan seçilen bir veya iki heteroatom ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir veya Cö-Cio-arili temsil etmektedir, RH, Xlin N olmasi durumunda R47ün hidrojen veya Ci-Cö-alkil olmasi sartiyla, hidrojen, siyano, halojen, hidroksi, okso, tiyol, karboksi veya karboksi-Ci-Cö-alkili temsil etmektedir, R5, hidrojen, Ci -Cs-alkil, Cs-Ca-sikloalkil, heterosikl veya heterosiklil-Ci-Ca-alkili temsil etmektedir, burada heterosikl, Xlin N olmasi durumunda R55in hidrojen olmasi sartiyla, N ve O atomlari arasindan seçilen bir ila üç heteroatom ihtiva eden 3-8 üyeli bir halkadir, R6, -(CR8R9)u-Z-D-W-R14,ü temsil etmektedir, burada u, 0 ile 3 arasinda bir tam sayidir, Z, bir dogrudan bagi temsil etmektedir veya -C(O)- ve -C(O)O-”den olusan gruptan seçilmektedir, D, bir dogrudan bagi, C4-C6-sikloalkili, bir veya iki N atomu ihtiva eden 5-6 üyeli heteroarili veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir heterosikli temsil 36906.08 etmektedir, W, bir dogrudan bagi veya -NRS-,-C(O)-, -C(O)O-, -C(O)NR12- veya - S(O)y-,yi temsil etmektedir, R”, hidrojen, Ci-C3-alkil veya Cs-Cio-arili temsil etmektedir, y 1 veya 2 degerinde bir tam sayidir ve R”; hidrojen, hidroksi, Ci-Cs- alkil, N, O ve S atomlari arasindan seçilen bir ila üç heteroatom ihtiva eden 5-6 üyeli bir heterosikl, veya X7in N olmasi durumunda R67nin C4-C5-sikloalkili temsil etmesi sartiyla, Cg-Cio-Ar-Ci-Cö-alkili temsil etmektedir veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatom ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir ve burada alkil, alkoksi, aril, sikloalkil, heterosikl ve heteroaril istege bagli olarak sübstitüe edilebilmektedir ve sübstitüentler, hidroksi, Ci-Cg-alkilamino, di(C1-C6- alkil)amin0, karboksi, Ci-Cs-alkil, Ci-Cs-alkoksi, karboksi-Ci-Ca-alkil ve oksodan olusan gruptan seçilen biri veya daha fazlasidir. MY TECHNICAL EYE According to one aspect of the present invention, as a reaction intermediate the following Formula represented by Formula 2 by incorporating a compound represented by 1 A method for preparing a compound is provided. 36906.08 In the above formulas, n is an integer between 1 and 3, m is 0 or 1”, p is an integer between 1 and 3, A represents phenyl, or 1 to 1 each selected from N, O and S atoms. 5-membered compound containing 3 heteroatoms and optionally substituted with R heteroaryl or heterocycle where R represents hydrogen or C1- optionally substituted with hydroxy or amino represents C4-alkyl, If X is N, mln is 0 and if X is C, m7nin Provided that it is 1, it represents C or N, 36906.08 R' represents hydrogen, C1-C6-alkyl or I(CH2)iNRSR9 where r is 2 to is an integer between, R8 and R9 each independently, so that X is N represents hydrogen or Ci-C8-alkyl, provided that R1 is hydrogen in the is doing, R2 represents hydrogen, halogen or C1-C6-alkoxy or -(CH2)5CO2RR, -(CH2)SOR8 represents -(CH2)SNRR” or represents -(CH2)s-heterocycle-R10, where the heterocycle containing one or two heteroatoms selected among N, O and S atoms. -It is a 6-membered ring, where 5 is an integer between 0 and 3, R8 and R9 above as defined and RIO, hydrogen, oxo, Ci-C6-alkylcarbonyl, Ci-C6-alkoxy or represents Ci-C6-alkyl or one or two nitrogens as a heteroatom It represents a 5-6 membered heterocycle containing the atom, R3 represents hydrogen, halogen, C1-C6-alkyl or phenyl or _(CH2)g' represents the heterocycle, where the heterocycle is selected from N and O atoms. is a 5-6 membered ring containing one or two heteroatoms where g is X7inN between 1 and 3, provided that R3 is hydrogen or phenyl is an integer, 36906.08 R4 represents -YR” where Y is a direct bond or -(CR8R9)eY,-°i where e is an integer between 0 and 3 and R8 and R9 are is as defined, Y is selected from the group consisting of -O-, -C(O)- and -C(O)O-, R" is hydrogen, halogen is selected from the group consisting of C1-C6-alkyl and -(CH2)iB-R'3, t 0 to 3 is an integer between, B; One or two atoms selected from among N, O and S atoms represents a 5-6 membered heterocycle containing heteroatoms or C6-Cio-aryl represents RH, where X is N, R47 is hydrogen or C1-C6-alkyl. provided that hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or represents carboxy-C1-C6-alkyl, R5 is hydrogen, C1-C8-alkyl, Cs-Ca-cycloalkyl, heterocycle or heterocyclyl-C1-Ca-alkyl represents the heterocycle, where R55 is hydrogen if X is N contains one to three heteroatoms selected from N and O atoms, provided that It is a ring with 3-8 members, R6 represents -(CR8R9)u-Z-D-W-R14, where u is an integer between 0 and 3. is the number, Z represents a direct bond or from -C(O)- and -C(O)O- is selected from the group consisting of, D, a direct bond, C4-C6-cycloalkyl, one or two 5-6 membered heteroaryl containing N atoms or between N, O and S atoms represents a 5-6 membered heterocycle containing one or two selected heteroatoms 36906.08 W is a direct bond or -NRS-, -C(O)-, -C(O)O-, -C(O)NR12- or - S represents (O)y-, R” represents hydrogen, C1-C3-alkyl or C8-Cio-aryl. is, y is an integer of value 1 or 2 and R”; hydrogen, hydroxy, Ci-Cs- alkyl, 5-6 atoms containing one to three heteroatoms selected from N, O and S atoms. -membered heterocycle, or C4-C5-cycloalkyl of R67 when X7 is N represents Cg-Cio-Ar-Ci-C6-alkyl or N, O and S It is a 5-6 membered compound containing one or two heteroatoms selected from among represents the heterocycle and where alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl are optionally can be substituted and the substituents include hydroxy, C1-C8-alkylamino, di(C1-C6- alkyl)amine0, carboxy, Ci-C8-alkyl, Ci-C8-alkoxy, carboxy-C1-Ca-alkyl and oxodane One or more selected from the group.
AVANTAJLI ETKILER Mevcut bulusa göre, safsizliklarin olusumunun azaltilmasi, bir indol veya indazol bilesiginin mükemmel verimde hazirlanmasi ve ölçek büyütme için stabil olarak uygulanmasi için geleneksel stabil olmayan ara ürünlerin yol açtigi sinirlandirmalann çözülmesi mümkündür. 36906.08 BULUSU GERCEKLESTIRMEYE YÖNELIK MOD Bundan sonra, mevcut bulus, daha ayrintili olarak açiklanacaktir. Burada, tarifnamede ve istemlerde kullanilan terimler veya kelimeler, geleneksel veya sözlük anlami ile sinirli olarak yorumlanmamalidir ve bulus sahibinin, bulusu en iyi sekilde açiklayabilmesi amaciyla terimin kavramini uygun bir sekilde tanimlayabilecegi prensibe dayanarak teknik öze uygun olan anlam ve kavram olarak yorumlanmalidir. ADVANTAGEOUS EFFECTS According to the present invention, reducing the formation of impurities is achieved by an indole or indazole compound in excellent yield and stably for scale-up. caused by conventionally unstable intermediates for its application. It is possible to resolve the limitations. 36906.08 MODE FOR REALIZING THE INVENTION Hereinafter, the present invention will be described in more detail. Here, terms or words used in the specification and claims are not customary or It should not be interpreted as limited to the dictionary meaning and the inventor is responsible for the invention. to explain the concept of the term appropriately in order to explain it well. meaning and concept in accordance with the technical essence based on the principle that can be defined should be interpreted as .
Mevcut bulusa göre Formüllerin sübstitüentlerine yönelik tanimda, “alkil” terimi, bir alifatik hidrokarbon radikalini ifade etmektedir. Alkil, bir alkenil veya alkinil kismi içermeyen “doymus alkil” veya en az bir alkenil veya alkinil kismini içeren bagini ihtiva eden bir grubu ifade etmektedir ve “alkinil” terimi, en az bir karbon- karbon üçlü bagini ihtiva eden bir grubu ifade etmektedir. Alkil, tek basina veya alkoksi gibi bir kompozit form halinde kullanildiginda dallanmis veya lineer olabilmektedir. In the definition of substituents of the Formulas according to the present invention, the term "alkyl" means It refers to an aliphatic hydrocarbon radical. Alkyl, an alkenyl or alkynyl “saturated alkyl” containing no moiety or containing at least one alkenyl or alkynyl moiety. refers to a group containing a bond and the term "alkynyl" refers to a group containing at least one carbon- It refers to a group containing a carbon triple bond. Alkyl, alone or branched or linear when used in a composite form such as alkoxy It may happen.
Alkil grubu, aksi tanimlanmadikça, 1 ila 20 karbon atomuna sahip olabilmektedir. The alkyl group can have from 1 to 20 carbon atoms unless otherwise defined.
Alkil grubu, 1 ila 10 karbon atomuna sahip orta büyüklükte alkil olabilmektedir. 36906.08 Alkil grubu, 1 ila 6 karbon atomuna sahip düsük alkil olabilmektedir. Tipik bir alkil grubu, bunlarla sinirli olmamak üzere, metil, etil, propil, izopropil, bütil, izobütil, t-bütil, pentil, heksil, etenil, propenil, bütenil ve benzerini içermektedir. Örnegin, Ci-C4-alkil, alkil zincirinde 1 ila 4 karbon atomuna sahiptir ve metil, etil, propil, izo-propil, n-bütil, izo-bütil, sec-bütil ve t-bütilden olusan gruptan seçilmektedir. ifade etmektedir. ifade etmektedir. Tipik bir sikloalkil grubu, bunlarla sinirli olmamak üzere, siklopropil, siklobütil, siklopentil, sikloheksil ve benzerini içermektedir. monosiklik veya kaynasik polisiklik (baska bir deyisle, bitisik karbon çiftleri paylasan halkalar) grubu içermektedir. Baska bir deyisle, burada aksi tanimlanmadikça, aril; fenil, naftil ve benzerini içeren aromatik bir 4-10 üyeli, tercihen 6-10 üyeli monosiklik veya multisiklik halkayi ifade etmektedir. 36906.08 ihtiva eden ve aksi tanimlanmadikça benzo veya C3-Cg sikloalkil ile kaynastirilabilen aromatik bir 3-10 üyeli halkayi, tercihen 4-8 üyeli halkayi, daha tercihen 5-6 üyeli halkayi ifade etmektedir. Monosiklik heteroarilin örnekleri, bunlarla sinirli olmamak üzere, tiyazol, oksazol, tiyofen, furan, pirrol, imidazol, izoksazol, izotiyazol, pirazol, triazol, triazin, tiyadiazol, tetrazol, oksadiazol, piridin, piridazin, pirimidin, pirazin ve benzerini içermektedir. Bisiklik heteroarilin örnekleri, bunlarla sinirli olmamak üzere, indol, indolin, benzotiyofen, benzofuran, benzimidazol, benzoksazol, benzisoksazol, benztiyazol, benztiyadiazol, benztriazol, kuinolin, izokuinolin, purin, furopiridin ve benzerini içermektedir. ihtiva eden ve aksi tanimlanmadikça benzo veya C3-Cg sikloalkil ile kaynastirilabilen ve doyurulan veya 1 veya 2 çift bagi ihtiva eden 3-10 üyeli bir halkayi, tercihen 4-8 üyeli halkayi, daha tercihen 5-6 üyeli halkayi ifade etmektedir. Heterosiklin örnekleri, bunlarla sinirli olmamak üzere, pirrolin, 36906.08 pirrolidin, imidazolin, imidazolidin, pirazolin, pirazolidin, piran, piperidin, morfolin, tiyomorfolin, piperazin, hidrofuran ve benzerini içermektedir. The alkyl group can be medium-sized alkyl having 1 to 10 carbon atoms. 36906.08 The alkyl group can be lower alkyl having 1 to 6 carbon atoms. a typical alkyl group including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, include isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like. For example, C1-C4-alkyl has 1 to 4 carbon atoms in the alkyl chain and is methyl, ethyl, from the group consisting of propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl is selected. expresses. expresses. A typical cycloalkyl group includes, but is not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. monocyclic or fused polycyclic (i.e., adjacent pairs of carbons sharing rings) group. In other words, here the opposite aryl unless defined; an aromatic 4-10 membered, containing phenyl, naphthyl and the like It preferably refers to a 6-10 membered monocyclic or multicyclic ring. 36906.08 containing benzo or C3-C8 cycloalkyl unless otherwise specified. a fused aromatic 3-10 membered ring, preferably a 4-8 membered ring, more preferably refers to a 5-6 membered ring. Examples of monocyclic heteroaryl, including, but not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. bicyclic Examples of heteroaryl include, but are not limited to, indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine and the like Contains. containing benzo or C3-C8 cycloalkyl unless otherwise specified. It is a 3-10 membered compound that can be fused and saturated or contains 1 or 2 double bonds. ring, preferably a 4-8 membered ring, more preferably a 5-6 membered ring It does. Examples of heterocycles include, but are not limited to, pyrroline, 36906.08 pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, including morpholine, thiomorpholine, piperazine, hydrofuran and the like.
Aksi tanimlanmadikça, burada kullanilan terimler ve kisaltmalar, mevcut bulusun ait oldugu teknikte uzman kisilerce yaygin olarak anlasilan anlamlari olarak yorumlanabilmektedir. Unless otherwise defined, terms and abbreviations used herein are the meanings of the present invention. as its meanings commonly understood by those skilled in the art to which it belongs. can be interpreted.
Mevcut bulus, farmasötik olarak faydali bir indol veya indazol bilesigi hazirlamaya yönelik bir yöntem ile ilgili olup, yöntem, bir reaksiyon ara ürünü 1D olarak asagidaki Formül 1 ile temsil edilen bir bilesigin dahil edilmesi suretiyle asagidaki Formül 2 ile temsil edilen bir bilesigin hazirlanmasidir: burada, yukaridaki Formül 1`de, 36906.08 n, 1 ile 3 arasinda bir tam sayidir, m 0 veya 1”dir, p, 1 ile 3 arasinda bir tam sayidir, A, fenili temsil etmektedir veya her biri, N, O ve S atomlari arasindan seçilen 1 ila 3 heteroatom ihtiva eden ve istege bagli olarak R ile sübstitüe edilen 5-üyeli heteroaril veya heterosikli temsil etmektedir, burada R, hidrojeni temsil etmektedir veya istege bagli olarak hidroksi veya amino ile sübstitüe edilmis Ci- C4-alki1i temsil etmektedir, X, X`in N olmasi durumunda m`nin 0 olmasi ve X'in C olmasi dummunda m”nin 1 olmasi sartiyla, C veya N°yi temsil etmektedir, R1, hidrojen, Ci-Ca-alkil veya _(CH2)rNR8R9”u temsil etmektedir, burada r, 2 ile arasinda bir tam sayidir, Rg ve R9”un her biri bagimsiz olarak, X'in N olmasi durumunda R“in hidrojen olmasi sartiyla, hidrojen veya Ci-C3-alkili temsil etmektedir, R2, hidrojen, halojen veya Ci-Ca-alkoksiyi temsil etmektedir veya -(CH2)SC02RS, etmektedir veya I(CH2)5-heterosikl-Rlû”u temsil etmektedir, burada heterosikl kismi, N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva 5-6 üyeli bir halkadir, burada 5, 0 ile 3 arasinda bir tam sayidir, R8 ve R9 yukarida 36906.08 tanimlanan sekildedir ve RIO, hidrojen, okso, Ci-Ca-alkilkarbonil, Ci-Cg-alkoksi veya Ci-Ca- alkili temsil etmektedir veya bir heteroatom olarak bir veya iki azot atomunu ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir, ve R3, hidrojen, halojen, Ci-Ca-alkil veya fenili temsil etmektedir veya _(CH2)g' heterosikli temsil etmektedir, burada heterosikl, N ve O atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir halkadir, burada g, X”in N olmasi durumunda R3”ün hidrojen veya fenil olmasi sartiyla, 1 ile 3 arasinda bir tam sayidir. The present invention provides a pharmaceutically useful indole or indazole compound. Pertaining to a method for preparing a reaction intermediate By incorporating a compound represented in 1D by Formula 1 below It is the preparation of a compound represented by the following Formula 2: where, in Formula 1 above, 36906.08 n is an integer between 1 and 3, m is 0 or 1”, p is an integer between 1 and 3, A represents phenyl, or 1 to 1 each selected from N, O and S atoms. 5-membered compound containing 3 heteroatoms and optionally substituted with R heteroaryl or heterocycle where R represents hydrogen or C- optionally substituted with hydroxy or amino It represents C4-alkyl, X is 0 if X is N and m is 0 if X is C Provided that it is 1, it represents C or N°, R1 represents hydrogen, C1-C-alkyl or _(CH2)rNR8R9" where r is 2 is an integer between, Rg and R9” each independently, X being N represents hydrogen or C1-C3-alkyl, provided that R is hydrogen in is doing, R2 represents hydrogen, halogen or C1-Ca-alkoxy or -(CH2)SC02RS, or represents I(CH2)5-heterocycle-R11, where the heterocycle part contains one or two heteroatoms selected among N, O and S atoms 5-6 is a membered ring, where 5 is an integer between 0 and 3, R8 and R9 above 36906.08 as defined and RIO, hydrogen, oxo, Ci-C6-alkylcarbonyl, Ci-C6-alkoxy or C1-Ca- represents alkyl or one or two nitrogens as a heteroatom represents a 5-6 membered heterocycle containing the atom, and R3 represents hydrogen, halogen, C1-C6-alkyl or phenyl or _(CH2)g' represents the heterocycle, where the heterocycle is selected from N and O atoms. is a 5-6 membered ring containing one or two heteroatoms, where g is between 1 and 3, provided that R3 is hydrogen or phenyl is an integer.
Yukaridaki Formül 2”de, n, m, X, A, R1, R:2 ve R3 yukarida tanimlanan ile aynidir, 36906.08 R4, -YR””i temsil etmektedir, burada Y, bir dogrudan bagdir veya -(CR8R9)eY,-°i temsil etmektedir, burada e, 0 ile 3 arasinda bir tam sayidir ve R8 ve R9, yukarida tanimlanan ile aynidir, Y,, -O-, -C(O)- ve -C(O)O-`den olusan gruptan seçilmektedir, R”, hidrojen, halojen, Ci-Cö-alkil ve -(CH2)iB-R'3'ten olusan gruptan seçilmektedir, t 0 ile 3 arasinda bir tam sayidir, B; N, O ve S atomlari arasindan seçilen bir veya iki heteroatom ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir veya Cö-Cio-arili temsil etmektedir, RH, Xlin N olmasi durumunda R47ün hidrojen veya Ci-Cö-alkil olmasi sartiyla, hidrojen, siyano, halojen, hidroksi, okso, tiyol, karboksi veya karboksi-Ci-Cö-alkili temsil etmektedir, R5, hidrojen, Ci -Cs-alkil, Cs-Ca-sikloalkil, heterosikl veya heterosiklil-Ci-Ca-alkili temsil etmektedir, burada heterosikl, Xlin N olmasi durumunda R55in hidrojen olmasi sartiyla, N ve O atomlari arasindan seçilen bir ila üç heteroatom ihtiva eden 3-8 üyeli bir halkadir, R6, -(CR8R9)u-Z-D-W-R14,ü temsil etmektedir, burada u, 0 ile 3 arasinda bir tam sayidir, Z, bir dogrudan bagi temsil etmektedir veya -C(O)- ve -C(O)O-”den olusan gruptan seçilmektedir, D, bir dogrudan bagi, C4-C6-sikloalkili, bir veya iki N atomu ihtiva eden 5-6 üyeli heteroarili veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir heterosikli temsil 36906.08 etmektedir, W, bir dogrudan bagi veya -NRS-,-C(O)-, -C(O)O-, -C(O)NR12- veya - S(O)y-,yi temsil etmektedir, R”, hidrojen, Ci-C3-alkil veya Cs-Cio-arili temsil etmektedir, y 1 veya 2 degerinde bir tam sayidir ve R”; hidrojen, hidroksi, Ci-Cs- alkil, N, O ve S atomlari arasindan seçilen bir ila üç heteroatom ihtiva eden 5-6 üyeli bir heterosikl veya X”in N olmasi durumunda R6“nin C4-C5-sikloalkili temsil etmesi sartiyla, Cö-Cio-Ar-Ci-Cg-alkili veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatom ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir ve burada alkil, alkoksi, aril, sikloalkil, heterosikl ve heteroaril istege bagli olarak sübstitüe edilebilmektedir ve sübstitüentler, hidroksi, Ci-Cs-alkilamino, dl(C1-C6- alkil)a.mino, karboksi, Cl-Cg-alkil, Ci-CÖ-alkoksi, karboksi-Ci-CÖ-alkil ve oksodan olusan gruptan seçilen biri veya daha fazlasidir. In Formula 2 above, n, m, X, A, R1, R:2 and R3 are the same as defined above, 36906.08 R4 represents -YR” where Y is a direct bond or -(CR8R9)eY,-°i where e is an integer between 0 and 3 and R8 and R9 are is the same as defined, Y is selected from the group consisting of -O-, -C(O)- and -C(O)O-, R" is hydrogen, halogen is selected from the group consisting of C1-C6-alkyl and -(CH2)iB-R'3, t 0 to 3 is an integer between, B; One or two atoms selected from among N, O and S atoms represents a 5-6 membered heterocycle containing heteroatoms or C6-Cio-aryl represents RH, where X is N, R47 is hydrogen or C1-C6-alkyl. provided that hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or represents carboxy-C1-C6-alkyl, R5 is hydrogen, C1-C8-alkyl, Cs-Ca-cycloalkyl, heterocycle or heterocyclyl-C1-Ca-alkyl represents the heterocycle, where R55 is hydrogen if X is N contains one to three heteroatoms selected from N and O atoms, provided that It is a ring with 3-8 members, R6 represents -(CR8R9)u-Z-D-W-R14, where u is an integer between 0 and 3. is the number, Z represents a direct bond or from -C(O)- and -C(O)O- is selected from the group consisting of, D, a direct bond, C4-C6-cycloalkyl, one or two 5-6 membered heteroaryl containing N atoms or between N, O and S atoms represents a 5-6 membered heterocycle containing one or two selected heteroatoms 36906.08 W is a direct bond or -NRS-, -C(O)-, -C(O)O-, -C(O)NR12- or - S represents (O)y-, R” represents hydrogen, C1-C3-alkyl or C8-Cio-aryl. is, y is an integer of value 1 or 2 and R”; hydrogen, hydroxy, Ci-Cs- alkyl, 5-6 atoms containing one to three heteroatoms selected from N, O and S atoms. In case of a three-membered heterocycle or where X is N, R6 represents C4-C5-cycloalkyl. C6-Cio-Ar-Ci-Cg-alkyl or selected from N, O and S atoms, provided that represents a 5-6 membered heterocycle containing one or two heteroatoms and where alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl are optionally can be substituted and the substituents include hydroxy, C1-C8-alkylamino, dl(C1-C6- alkyl)a.mino, carboxy, Cl-C8-alkyl, Ci-CO-alkoxy, carboxy-C1-CO-alkyl and oxodane One or more selected from the group.
Spesifik olarak, yukaridaki Formül 1 ve Formül 2°de, yukaridaki R1, hidrojen, Ci- CÖ-alkil veya di(C1-Cg-alkil)amin0-C2-C3-alkil olabilmektedir. Specifically, in Formula 1 and Formula 2 above, R1 above is hydrogen, Ci- It can be C6-alkyl or di(C1-C8-alkyl)amine0-C2-C3-alkyl.
Ek olarak, yukaridaki R2, hidrojen, halojen, karboksi, karboksi-Ci-C3-alkil, C1-C3- alkoksikarbonil, Ci-C3-alkoksikarbonil-Ci-Cg-alkil, istege bagli olarak bir okso grubu ile sübstitüe edilmis hidroksi-Ci-Cs-alkil, Ci-Cs-alkoksi, -(CH2)SNR3R9, - NHRIÜ, -N(H)S(O)2R'°'u temsil edebilmektedir veya 7 36906.08 (Cl-[2)s-heterosiklýRIÜ olabilmektedir, burada heterosikl, s, R8, R9 ve R'0 yukarida tanimlanan sekildedir. Additionally, R2 above is hydrogen, halogen, carboxy, carboxy-C1-C3-alkyl, C1-C3- alkoxycarbonyl, C1-C3-alkoxycarbonyl-C1-C8-alkyl, optionally an oxo hydroxy-Ci-Cs-alkyl, Ci-Cs-alkoxy, -(CH2)SNR3R9, - NHRIÜ may represent -N(H)S(O)2R'° or 7 36906.08 It can be (Cl-[2)s-heterocycleRIU, where the heterocycle is s, R8, R9 and R'0 as defined above.
Ayrica, R3, hidrojen, metil veya halojen, istege bagli olarak Ci-Cg-alkoksi ile sübstitüe edilmis fenili temsil edebilmektedir veya heterosiklin, N ve O atomlarindan seçilen bir veya iki heteroatom ihtiva eden ve istege bagli olarak bir veya iki okso grubu ile sübstitüe edilen 5-6 üyeli bir halka oldugu heterosikl-Ci- C3-alki1en olabilmektedir. Additionally, R3 is hydrogen, methyl or halogen, optionally with C1-C8-alkoxy. may represent substituted phenyl or heterocycline, N and O containing one or two heteroatoms selected from atoms and optionally a or heterocycle-Ci-, which is a 5-6 membered ring substituted with two oxo groups. It can be C3-alky1ene.
Ek olarak, yukaridaki Y, bir dogrudan bag, -O-, -C(O)- ve -CH2C(O)-°den olusan gruptan seçilebilmektedir. In addition, Y above is a direct bond consisting of -O-, -C(O)- and -CH2C(O)-. can be selected from the group.
Ek olarak, yukaridaki R”, hidrojen, metil, etil, fenil, Iloro, kloro, 2-karboksi- pirrolidin-l-il, pirrolidin-l-il, 4-asetik asit-1,3-tiyazolin-2-il, -CHz-(1,1-di0kso- tiyomorfolin-4-il) ve -CHg-(2-oksopiperazin-4-il),den olusan gruptan seçilebilmekte dir. Additionally, R" above refers to hydrogen, methyl, ethyl, phenyl, chloro, chloro, 2-carboxy- pyrrolidin-1-yl, pyrrolidin-1-yl, 4-acetic acid-1,3-thiazolin-2-yl, -CH2-(1,1-di0xo- thiomorpholin-4-yl) and -CHg-(2-oxopiperazin-4-yl) can be selected.
Ayni zamanda, yukaridaki Formül 2”de, yukaridaki R5, hidrojen, metil veya izobütil olabilmektedir. 36906.08 Yukaridaki R6, siklobütil, siklopentil, sikloheksil, 4-metil-siklopentil, 4,4- diflorosikloheksilden olusan gruptan seçilebilmektedir veya D, sikopentil, sikloheksil, pirrolidin, tetrahidropiran, tetrahidrofuran ve piperidinden olusan gruptan seçilebilmektedir ve W, bir dogrudan bagi temsil edebilmektedir veya - 802-, -CO-, -C(O)O- veya -CONR12-°yi temsil edebilmektedir, burada R”, yukarida tanimlanan ile aynidir. Also, in Formula 2 above, R5 above is hydrogen, methyl or It may be isobutyl. 36906.08 R6 above is cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl-cyclopentyl, 4,4- difluorocyclohexyl or D, cyclopentyl, consisting of cyclohexyl, pyrrolidine, tetrahydropyran, tetrahydrofuran and piperidine. can be selected from the group where W represents a direct bond, or - 802- may represent -CO-, -C(O)O- or -CONR12-° where R", is the same as described above.
Mevcut bulusun bir uygulamasi olarak, yukaridaki Formül 1 ile temsil edilen bilesik, 5-(bromometil)-7-nitr0-2-fenil-lH-indol olabilmektedir ve yukaridaki Formül 2 ile temsil edilen bilesik, 4-((2-fenil-7-((tetrahidr0-2H-piran-4-il)amin0)- lH-indol-S -il)metil)tiy0morfolin l, 1 -dioksit olabilmektedir. As an embodiment of the present invention, represented by Formula 1 above The compound may be 5-(bromomethyl)-7-nitro-2-phenyl-1H-indole and The compound represented by formula 2 is 4-((2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amine0)- It can be 1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide.
Yukaridaki Formül 1 ile temsil edilen bilesik, asagidaki Formül 3 ile temsil edilen bilesigin brom ile birlestirilmesi suretiyle hazirlanabilmektedir: 36906.08 R1 NO2 HR lrAim- OH Yukaridaki Formül 3'te, n, ni, p, X, A, R', R2 ve R3 yukarida tanimlanan ile aynidir. The compound represented by Formula 1 above is the compound represented by Formula 3 below. It can be prepared by combining the compound with bromine: 36906.08 R1 NO2 HR lrAim- OH In Formula 3 above, n, ni, p, X, A, R', R2 and R3 are defined above. is the same.
Brom ile birlestirme adimi, spesifik olarak sinirli degildir ve geleneksel bir sekilde gerçeklestirilebilmektedir. The bromine coupling step is not specifically limited and can be carried out in a conventional manner. can be realized.
Yukaridaki Formül 3 ile temsil edilen bilesik, yukaridaki Formül 1 ile temsil edilen daha stabil bir ara ürünün üretilmesi için brorn ile birlestirilmektedir, böylelikle safsizliklarin olusumu azaltilmakta, reaksiyon verimi arttirilmakta ve ölçek büyütme için stabil olarak uygulanmaktadir. The compound represented by Formula 3 above is is combined with brone to produce a more stable intermediate. Thus, the formation of impurities is reduced, the reaction efficiency is increased and It is stably applied for scale-up.
Yukaridaki Fermül 1 ile temsil edilen bilesik, PBr3, SOBrz, HBr ve LiBr ve daha tercihen Pbr3`ten olusan gruptan seçilen en az bir bilesigin varliginda yukaridaki 36906.08 Formül 3 ile temsil edilen bilesigin reaksiyona sokulmasi suretiyle hazirlanabilmektedir. The compound represented by Fermule 1 above is PBr3, SOBrz, HBr and LiBr and more. preferably in the presence of at least one compound selected from the group consisting of Pbr3. 36906.08 By reacting the compound represented by formula 3 can be prepared.
Mevcut bulusun hazirlama yöntemi, yukaridaki Formül 1`in ara ürününün olusturulmasindan sonra, asagidaki Formül 4 ile temsil edilen bir bilesigin hazirlanmasi için yukaridaki Formül 1 ile temsil edilen bilesigin sübstitüe edilmesi; Formül 5 ile temsil edilen bir bilesigin hazirlanmasi için Formül 4 ile temsil edilen bilesigin indirgenmesi ve yukaridaki Formül 2 ile temsil edilen bir bilesigin hazirlanmasi için Formül 5 ile temsil edilen bilesigin, keton veya aldehit ile reaksiyona sokulmasi adimlarini içerebilmektedir. 36906.08 Yukaridaki Formül 4 ve Fermül 5”tc, n, m, X, A, R1, R2, R3 ve R4 yukarida tanimlanan ile aynidir, Bundan sonra, mevcut bulusun uygulamalari, teknikte orta derecede uzman bir kisinin mevcut bulusu kolaylikla uygulayabilmesi için ayrintili olarak açiklanacaktir. Bununla birlikte, mevcut bulus, farkli formlarda somutlastirilabilmektedir ve burada belirtilen uygulamalar ile sinirli oldugu seklinde yorumlanmanialidir. 36906.08 a) Adimi 4-((7-nitr0-2-fenil-lH-indol-S-il)metil)tiy0m0rfolin 1,1-di0ksit sentezi -(hidroksimetil)-7-nitr bir reaktöre ilave edilmistir ve oda sicakliginda karistirilmistir, reaktör, 0 0C”lik bir sicakliga sogutulmustur ve sonrasinda reaksiyonun iç sicakligi 20 °C`nin altinda tutulurken PBr3 (2,8 kg) ilave edilmistir. Ilave etrne isleminin tamamlanmasindan sonra, reaktörün sicakligi, 25 °C”ye yükseltilmistir, karisim 1 saat boyunca karistirilmistir ve reaksiyon karisimi, 5-(hidroksimetil)-7-nitr0-2-fenil-lH- indolaün tepe noktasinin %1,0 veya daha azinin gösterilmesi için numune alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. The preparation method of the present invention provides the intermediate product of Formula 1 above. After its formation, a compound represented by Formula 4 below For its preparation, the compound represented by Formula 1 above is substituted. to be done; To prepare a compound represented by Formula 5, use Formula 4. reduction of the represented compound and a compound represented by Formula 2 above To prepare the compound, the compound represented by Formula 5 must be used as a ketone or aldehyde. It may include the steps of reacting with 36906.08 Formula 4 above and Formula 5”tc, n, m, X, A, R1, R2, R3 and R4 above is the same as defined, Thereafter, embodiments of the present invention are available to those of moderate skill in the art. in detail so that one can easily apply the present invention. It will be explained. However, the present invention exists in different forms. can be embodied and is limited to the applications specified here. It should be interpreted as: 36906.08 a) Step 4-((7-nitro-2-phenyl-1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide synthesis -(hydroxymethyl)-7-nitrie into a reactor was added and stirred at room temperature, the reactor was cooled to a temperature of 0 0C. cooled and then kept the internal temperature of the reaction below 20 °C. PBr3 (2.8 kg) was added. After the addition process is completed, The temperature of the reactor was increased to 25 °C, the mixture was stirred for 1 hour. was stirred and the reaction mixture was 5-(hydroxymethyl)-7-nitriO-2-phenyl-1H- Sampling to demonstrate 1.0% or less of the indole peak The reaction was terminated when analyzed by .
Reaksiyonun tamamlandigi dogrulanmistir, reaksiyon karisimi, 0 °C7ye sogutulmustur ve reaksiyonun iç sicakligi 20 °C°nin altinda tutulurken 1,1- dioksotiyornorfolin hiroklorür ( (8,0 kg) ilave edilmistir. Ilave etme isleminin tamamlanmasindan sonra, reaktörün sicakligi, 50 °C”ye yükseltilmistir, karisim 4 saat boyunca karistirilmistir ve reaksiyon karisimi, 5-(br0m0metil)-7-nitr0-2-fenil-1H-indol°ün tepe 36906.08 noktasinin %1,0 veya daha azmin gösterilmesi için numune alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. The reaction was confirmed to be complete, the reaction mixture was returned to 0 °C. was cooled and the internal temperature of the reaction was kept below 20 °C while 1,1- dioxotenorpholine hydrochloride ( (8.0 kg) was added. After completion of the addition, the reactor The temperature was increased to 50 °C, the mixture was stirred for 4 hours and reaction mixture, peak of 5-(br0m0methyl)-7-nitro-2-phenyl-1H-indole 36906.08 by taking a sample to indicate 1.0% or less of the point When analyzed, the reaction is terminated.
Reaksiyonun tamamlandiginin dogrulanmasindan sonra, reaktör, 0 C3C”lik bir sicakliga sogutulmustur, buna su (46,0 L) ilave edilmistir, reaksiyon karisimi karistirilmistir ve organik çözücü, indirgenmis basinç altinda damitilmistir. After verification that the reaction is complete, the reactor is at a temperature of 0 C3C. temperature, water (46.0 L) was added, the reaction mixture was stirred and the organic solvent was distilled off under reduced pressure.
Indirgenmis basinç altinda damitma isleminden sonra, etil asetat (EtOAc) (48,0 L) ilaveten buna ilave edilmistir ve organik çözücü, 4-((7-nitr0-2-fenil-lH-indol-S- il)metil)tiyom0rfolin 1,1-di0ksit'in bir kati madde olarak elde edilmesi için tekrar indirgenmis basinç altinda damitilmistir ve sonrasinda filtrelenrnistir. Ortaya çikan madde, su (26,0 L) ve etanol (26,0 L) ile yikanmistir ve ham 4-((7-nitro-2- fenil-1H-indol-S-il)metil)tiyomorfolin 1,1-di0ksit”in (6,4 kg, satlik: %929) sentezlenmesi için 16 saat boyunca N2 basinci altinda kurutulmustur, Saflastirma için, yukaridaki ham 4-((7-nitro-2-fenil-1H-indol-S- il)metil)tiy0morfolin karisimina ilave edilmistir, karistirilmistir, 120 OClye isitilmistir, 2 saat boyunca karistirilmistir ve sonrasinda tekrar oda sicakliginda 2 saat daha karistirilmistir. After distillation under reduced pressure, ethyl acetate (EtOAc) (48.0 L) was further added thereto and the organic solvent, 4-((7-nitro-2-phenyl-1H-indole-S- again to obtain yl)methyl)thiomorpholine 1,1-dioxide as a solid. It was distilled under reduced pressure and then filtered. emerge The resulting material was washed with water (26.0 L) and ethanol (26.0 L) and crude 4-((7-nitro-2- phenyl-1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide (6.4 kg, sale: 929%) It was dried under N2 pressure for 16 hours to synthesize it, For purification, the above crude 4-((7-nitro-2-phenyl-1H-indole-S- yl)methyl)thiomorpholine mixture added, mixed, heated to 120 °C for 2 hours. It was mixed and then mixed again at room temperature for another 2 hours.
Toluen (60,0 L) ilaveten buna ilave edilmistir ve 2 saat daha karistirilmistir ve 36906.08 sonrasinda çözeltideki bir kati madde tiltrelenmistir ve 4-((7-nitro-2-fenil-1H- indol-S-il)metil)tiyomorfolin 1,1-dioksit'in (5,1 kg, verim: %77,0 toplam, satlik: %98,4) sentezlenmesi için toluen (20,0 L) ile yikanmistir. Toluene (60.0 L) was further added and stirred for a further 2 hours. 36906.08 Afterwards, a solid in the solution was filtered and 4-((7-nitro-2-phenyl-1H- indole-S-yl)methyl)thiomorpholine 1,1-dioxide (5.1 kg, yield: 77.0% total, (sale: 98.4%) was washed with toluene (20.0 L) to synthesize it.
J= 7.7 Hz, 2H) 7.38 (d, J= , 2.84 (m, 4H). b Adimi 4- 7-amin0-2-fenil-1H-indol-5-il metil ti omorfolin 1 l-dioksit sentezi THF/metanol/HQO (1:1:l, 3,0 L) ve NH4C1 (124 g), oda sicakliginda bir reaktöre ilave edilmistir ve karistirilmistir ve sonrasinda buna Fe (480 g) ilave edilmistir. J= 7.7 Hz, 2H) 7.38 (d, J= , 2.84 (m, 4H). b Step 4- 7-amine0-2-phenyl-1H-indol-5-yl methyl thiomorpholine 11-dioxide synthesis THF/methanol/HQO (1:1:1, 3.0 L) and NH4C1 (124 g) were added to a reactor at room temperature. was added and mixed, and then Fe (480 g) was added thereto.
Reaktör, 60 oC'lik bir sicakliga isitilmistir, reaksiyon karisimi, 1 saat veya daha uzun süre boyunca karistirilmistir ve sonrasinda reaksiyon karisimi, 4-((7-nitro-2- fenil-1l-l-indol-S-il)metil)tiyomorfolin 1,1-di0ksit5in tepe noktasinin %05 veya daha azinin gösterilmesi için analiz edildiginde reaksiyon sonlandirilmistir. 36906.08 Reaksiyonun tamamlandigi dogrulanmistir, reaksiyon karisimina THF (3,0 L) ilave edilmistir ve 10 dakika boyunca karistirilmistir ve sonrasinda selit ile filtrelenmistir ve ortaya çikan madde, THF/HzO (lzl, 3,0 L) ile yikanmistir. The reactor was heated to a temperature of 60 °C, the reaction mixture was heated for 1 hour or more. was stirred for a long time and then the reaction mixture was 4-((7-nitro-2- 05% or When analyzed to show less, the reaction was terminated. 36906.08 It was confirmed that the reaction was complete, add THF (3.0 L) to the reaction mixture. was added and mixed for 10 minutes and then mixed with celite. was filtered and the resulting material was washed with THF/H2O (12, 3.0 L).
Filtrat, indirgenmis basinç altindaydi ve THF ve metanol, bir kati maddenin olusturulmasi için damitilmistir ve reaksiyon karisimi 2 saat veya daha uzun bir süre boyunca oda sicakliginda karistirilmistir. Ortaya çikan madde, filtrelenmistir ve yikama çözeltisi [Vinci HzO: 500 mL, 2”nci etanol/HzO = 1/3, sentezlenmesi için 16 saat boyunca N; basinci altinda kurutulmustur. 287 (m, 4H). 4- 2-fenil-7- tetrahidro-ZH- iran-4-il amino -lH-indol-S- illmetilltivomorfolin 1,1-di0ksit sentezi 36906.08 4-((7-amino-2-fenil-lH-indol-5-il)metil)tiy0morfolin l,l-di0ksit (3,8 kg), tetrahidro-4H-piran-4-on ( ve izopropil asetat (23,2 L), bir reaktöre ilave edilmistir ve karistirilmistir ve sonrasinda buna NaBH(OAC)3 (4,6 kg) ilave edilmistir, ardindan 1 saat veya daha uzun süre boyunca oda sicakliginda karistirilmistir ve reaksiyon karisimi 4-((7-amino-2- fenil-1H-indol-S-il)metil)tiyomorfolin 1,1-di0ksit”in tepe noktasinin %0,5 veya daha azinin gösterilmesi için analiz edildiginde reaksiyon sonlandirilmistir. The filtrate was under reduced pressure and THF and methanol formed a solid. distilled to form and the reaction mixture stirred for 2 hours or more. It was stirred at room temperature throughout the period. The resulting substance was filtered and the washing solution [Vinci H2O: 500 mL, 2” ethanol/H2O = 1/3, N for 16 hours to synthesize; dried under pressure. 287 (m, 4H). 4- 2-phenyl-7- tetrahydro-ZH- iran-4-yl amino -1H-indole-S- Synthesis of illmethyltivomorpholine 1,1-dioxide 36906.08 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (3.8 kg), tetrahydro-4H-pyran-4-one (and isopropyl acetate (23.2 L) was added and stirred to a reactor and then NaBH(OAC)3 (4.6 kg) was added, followed by 1 hour or more. The reaction mixture was stirred at room temperature for 4-((7-amino-2- 0.5% or so of the peak of phenyl-1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide When analyzed to show less, the reaction was terminated.
Reaksiyonun tamamlandigi dogrulanmistir, bir lN NaOH sulu çözeltisi (23,2 L) reaksiyon karisimma ilave edilmistir, ardindan 1 saat daha veya daha uzun süre boyunca karistirilmistir ve sonrasinda organik çözücü, indirgenmis basinç altinda damitilmistir. Geriye kalan sulu çözeltinin içinde bulunan kati madde filtrelenmistir, su (38,7 L) ve t-bütil metil eter (38,7 L) ile yikanmistir ve 4-((2- fenil-7-((tetrahidro -2H-piran-4-il)amino)- 1 H-indol-S -il)metil)tiyomorfolin 1,1- boyunca N2 basinci altinda kurutulmustur. 36906.08 Karsilastirmali Örnek a) Adimi 4-( ( 7-nitro-2-fenil-1H-indol-5-illmetilltivomorfolin 1.1-di0ksit sentezi -(hidr0ksimetil)-7-nitr0-2-fenil-lH-indol (804 mg, 3 mmol), oda sicakliginda THF (10 mL) içinde çözündürülmüstür ve imidazol (408 mg, 6 mmol) ve trifenilfosfin (1,52 g, 6 mmol) buna ilave edilmistir. Iyot (453 mg, 3,9 mmol) buna ilave edilmistir ve 2 saat boyunca karistirilmistir. Reaksiyon sonlandirildiginda, reaksiyon karisimi, selit ile filtrelenmistir ve ilaveten saIlastirma olmadan asagidaki reaksiyonda kullanilmistir. mL) içinde çözündürülmüstür ve 1, l-diokso-tiyomorfolin (405 mg, 2,25 mmol) ilave edilmistir ve 2 saat boyunca karistirilmistir. Reaksiyon tamamlandiginda, ortaya çikan madde su ile seyreltilmistir, organik madde, etil asetat (EtOAc) ile ekstrakte edilmistir ve sonrasinda susuz magnezyum sülfat ile kurutulmustur ve 36906.08 filtrelenmistir. Kalinti, 4-((7-nitr0-2-fenil-lH-indol-S-il)metil)tiy0morfolin 1,1- dioksitain (625 mg, verim: %65, saflik: %97,2) elde edilmesi için DCM ve heksan ile yeniden kristalize edilmistir. il)metil)tiy0m0rfolin 1,1-di0ksit, Örnek 1”in b) Adimi ve c) Adimi ile ayni sekilde hazirlanmistir. Örnek ve Karsilastirmali Ömege referansla, mevcut bulusa göre 4-((7-nitr0-2- fenil-lH-indol-5-il)metil)tiy0m0rfolin l,l-di0ksit'in, 5-(brom0metil)-7-nitr0-2- fenil-lH-indol ara ürünü araciligiyla 5-(hidr0ksimetil)-7-nitr0-2-fenil-lH- indol”den sentezlenmesi suretiyle elde edilen Örnegin a) Adiminin veriminin, Karsilastirmali Örnegin a) Adiminin %65 olan verimine kiyasla kayda deger sekilde arttirilmis sekilde %77,0 oldugu dogrulanabilmektedir. The reaction was confirmed to be complete, a lN NaOH aqueous solution (23.2 L). was added to the reaction mixture, then heated for another 1 hour or longer. and then the organic solvent was added under reduced pressure. distilled. The solid substance in the remaining aqueous solution filtered, washed with water (38.7 L) and t-butyl methyl ether (38.7 L) and 4-((2- phenyl-7-((tetrahydro -2H-pyran-4-yl)amino)-1H-indol-S-yl)methyl)thiomorpholine 1,1- It was dried under N2 pressure throughout. 36906.08 Comparative Example a) Step 4-((7-nitro-2-phenyl-1H-indole-5-ylmethyllivomorpholine 1.1-dioxide synthesis -(hydroxymethyl)-7-nitro-2-phenyl-1H-indole (804 mg, 3 mmol), at room temperature dissolved in THF (10 mL) and imidazole (408 mg, 6 mmol) and triphenylphosphine (1.52 g, 6 mmol) was added thereto. Iodine (453 mg, 3.9 mmol) was added thereto and stirred for 2 hours. Reaction When terminated, the reaction mixture was filtered through celite and further It was used in the following reaction without purification. mL) and 1,1-dioxo-thiomorpholine (405 mg, 2.25 mmol) was added and mixed for 2 hours. When the reaction is completed, The resulting material was diluted with water, the organic material was mixed with ethyl acetate (EtOAc). was extracted and then dried with anhydrous magnesium sulfate and 36906.08 has been filtered. Residue, 4-((7-nitro-2-phenyl-1H-indol-S-yl)methyl)thiomorpholine 1,1- DCM and hexane to obtain dioxytaine (625 mg, yield: 65%, purity: 97.2%) It was recrystallized with . il)methyl)thiomorpholine 1,1-dioxide, same as Step b) and Step c) of Example 1 has been prepared. With reference to the Example and Comparative Example, according to the present invention 4-((7-nitr0-2- phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide, 5-(bromomethyl)-7-nitro-2- 5-(hydroxymethyl)-7-nitri0-2-phenyl-1H- via the phenyl-1H-indole intermediate The yield of Example a) Step obtained by synthesizing from indole is, Comparative Example: Significant compared to the 65% efficiency of step a) It can be confirmed that it is 77.0%, increased in the following way.
Claims (4)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2021019998T2 true TR2021019998T2 (en) | 2022-03-21 |
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