TR2021020001T2 - METHOD FOR PREPARING INDOLE OR INDAZole COMPOUND - Google Patents
METHOD FOR PREPARING INDOLE OR INDAZole COMPOUNDInfo
- Publication number
- TR2021020001T2 TR2021020001T2 TR2021/020001 TR2021020001T2 TR 2021020001 T2 TR2021020001 T2 TR 2021020001T2 TR 2021/020001 TR2021/020001 TR 2021/020001 TR 2021020001 T2 TR2021020001 T2 TR 2021020001T2
- Authority
- TR
- Turkey
- Prior art keywords
- alkyl
- formula
- hydrogen
- atoms
- heterocycle
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- -1 INDAZole COMPOUND Chemical class 0.000 title claims abstract description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 33
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 16
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000005842 heteroatom Chemical group 0.000 claims description 27
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 20
- 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 15
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 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
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 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
- 150000003573 thiols Chemical class 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 229910007932 ZrCl4 Inorganic materials 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 1
- 239000012448 Lithium borohydride Substances 0.000 claims 1
- 101100137157 Mus musculus Pou5f1 gene Proteins 0.000 claims 1
- JQGGAELIYHNDQS-UHFFFAOYSA-N Nic 12 Natural products CC(C=CC(=O)C)c1ccc2C3C4OC4C5(O)CC=CC(=O)C5(C)C3CCc2c1 JQGGAELIYHNDQS-UHFFFAOYSA-N 0.000 claims 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims 1
- 229940125898 compound 5 Drugs 0.000 claims 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 claims 1
- 235000011150 stannous chloride Nutrition 0.000 claims 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 12
- 239000003054 catalyst Substances 0.000 abstract description 7
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 8
- 230000017074 necrotic cell death Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000003277 amino 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
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 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
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- 229910000085 borane Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 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
- 230000007423 decrease Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000002473 indoazoles Chemical class 0.000 description 2
- 208000027866 inflammatory disease Diseases 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
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 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
- 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000167 toxic agent Toxicity 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 125000006274 (C1-C3)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
- UOMTVKMKHZMFMQ-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide;hydrochloride Chemical compound Cl.O=S1(=O)CCNCC1 UOMTVKMKHZMFMQ-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
- 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
- ZFYNVJTUGXRIAI-UHFFFAOYSA-N 4-[(7-nitro-2-phenyl-1h-indol-5-yl)methyl]-1,4-thiazinane 1,1-dioxide Chemical compound C=1C=2C=C(C=3C=CC=CC=3)NC=2C([N+](=O)[O-])=CC=1CN1CCS(=O)(=O)CC1 ZFYNVJTUGXRIAI-UHFFFAOYSA-N 0.000 description 1
- VJPDDMKAPSYDDQ-UHFFFAOYSA-N 7-nitro-2-phenyl-1h-indole-5-carboxylic acid Chemical compound C=1C2=CC(C(=O)O)=CC([N+]([O-])=O)=C2NC=1C1=CC=CC=C1 VJPDDMKAPSYDDQ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 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
- 229910020667 PBr3 Inorganic materials 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
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical group 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
- 229910052796 boron Inorganic materials 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
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation 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
- 125000001153 fluoro group Chemical group F* 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
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 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
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052742 iron Inorganic materials 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-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 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
- 229940098779 methanesulfonic acid Drugs 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
- 239000012044 organic layer 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
- 239000002245 particle Substances 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 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
- 238000000746 purification Methods 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
- 230000035484 reaction time Effects 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 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
Abstract
Mevcut buluş, güvenlik sağlayabilen, prosesin basitleştirilmesi sayesinde verimi arttırabilen ve bir demir (Fe) katalizörü kullanılarak geleneksel yöntemin sınırlandırmalarını çözebilen farmasötik olarak faydalı bir indol veya indazol bileşiği hazırlamaya yönelik yeni bir yöntem ile ilgilidir.The present invention relates to a new method for preparing a pharmaceutically useful indole or indazole compound that can provide safety, increase the yield due to simplification of the process, and solve the limitations of the conventional method using an iron (Fe) catalyst.
Description
TARIFNAME INDOL VEYA INDAZOL BILESIGI HAZIRLAMAYA YÖNELIK YÖNTEM TEKNIK ALAN Ilgili Basvurulara Çapraz Referans Bu basvuru, açiklamasinin referans yoluyla buraya bütün olarak dahil edildigi, 0073020 Numarali Kore Patent Basvurusunun rüçhanindan faydalanmayi talep etmektedir. DESCRIPTION FOR PREPARING INDOLE OR NDAZole COMPOUND METHOD TECHNICAL FIELD Cross Reference to Related Applications 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. 0073020 It does.
Teknik Alan Mevcut bulus, farmasötik 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 inIlamatuar hastaliklari içermektedir. 36906119 Hücresel nekroz, morbid kosullar altinda kontrolsüz, kaza sonucu meydana gelen 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. Technical Field The present invention provides a novel synthesis of a pharmaceutically useful indole or indazole compound. It is about the method of preparation. BACKGROUND ART Typical diseases caused by cellular necrosis are ischemic (e.g. myocardial infarction, stroke, renal infarction), neurodegenerative and inflammatory diseases. 36906119 Cellular necrosis is an uncontrolled, accidental occurrence under morbid conditions. 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 aktiviteye sahip oldugunu rapor eden WOZOOÖ/ 112549 Numarali PCT Uluslararasi Yayini, bilesiklerin, kardiyovasküler sistemin üretimine karsi tümör önleyici ajanlar ve inhibitörler olarak faydali oldugunu rapor eden WO95/07276 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 bir indol Uluslararasi Yayini bulunmaktadir. 36906119 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 hazirlamaya yönelik yeni 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. WOZOOÖ/ PCT No. 112549, which reported that it has activity International Publication, compounds against the production of the cardiovascular system, tumor WO95/07276 reporting usefulness as preventive agents and inhibitors PCT International Publication No. and its compounds as antibiotics It has a publication. In addition, cellular necrosis and necrosis-related diseases A new indole useful for prevention or treatment and healing effect It has an international publication. 36906119 Among these, the present invention provides treatment for cellular necrosis and necrosis-related diseases. An indole or It concerns a new method for preparing the compound indazole.
Geleneksel olarak, boran dimetilsülfür (BHgsMez), indol veya indazol bilesiklerinin sentez prosesinde kullanilmistir ancak boran dimetilsülfür (BH3SMe2), zehirli bir maddedir, dolayisiyla bir güvenlik sorununa ve proses çok fazla sayida adim araciligiyla karmasik bir prosedür halinde gerçeklestirildigi için kötü bir verim sorununa yol açmaktadir. Traditionally, borane dimethylsulfide (BHgsMez), indole or indazole has been used in the synthesis process of compounds, but borane dimethylsulfide (BH3SMe2) is a toxic substance, thus causing a safety issue and the process being very because it is carried out as a complex procedure through a large number of steps It causes a bad efficiency problem.
Ek olarak, bir demir (Fe) katalizörü kullanilarak bir nitro gmbunu ihtiva eden bir indol veya indazol bilesiginin, bir amin grubunu ihtiva eden bir indol veya indazol bilesigine indirgenmesinin bir hazirlama yöntemi geleneksel olarak kullanilmaktadir. Bununla birlikte, bu durumda, demirin (Fe) çesitli partikül büyüklüklerinden dolayi yeniden üretilebilirligin kötülesmesi, karistirmanin reaksiyon sirasinda pürüzsüz olmamasi veya reaksiyon süresi uzatildiginda reaksiyonda olusan safsizliklardan dolayi verimin düsmesi bakimindan sinirlandinnalar bulunmaktaydi. Ek olarak, bir reaktörün, reaksiyondan sonra üretilen demir oksit ile kaplanmasi ve reaktörün temizlenmesi için maliyet ve 3690609 zamanin gerekli olmasi bakimindan bir sinirlandirma bulunmaktaydi. Additionally, a nitro-containing enzyme using an iron (Fe) catalyst was produced. indole or indazole compound, an indole or indazole containing an amine group A method of preparation of reduction to the compound is traditionally is used. However, in this case, various particulate matter of iron (Fe) deterioration of reproducibility due to their size, mixing not smooth during the reaction or when the reaction time is extended In terms of the decrease in efficiency due to impurities formed in the reaction There were limitations. In addition, after the reaction of a reactor cost and cost for coating the produced iron oxide and cleaning the reactor. 3690609 There was a limitation in terms of time required.
Bu yüzden, geleneksel hazirlama prosesinde meydana gelen sinirlandirmalari çözen ve verimi ve benzerini arttiran yeni bir hazirlama yönteminin gelistirilmesine ihtiyaç duyulmaktadir. Therefore, it avoids the limitations of the traditional preparation process. of a new method of preparation that dissolves and increases yield etc. needs to be developed.
BULUSUN AÇIKLAMASI TEKNIK SORUN Mevcut bulusun bir yönü, güvenlik saglayabilen, prosesin basitlestirilmesi sayesinde verimi arttirabilen ve bir demir (Fe) katalizör kullanilarak geleneksel yöntemin sinirlandirmalarini Çözebilen farmasötik olarak faydali bir inclol veya 36906.09 indazol bilesigi hazirlamaya yönelik yeni bir yöntem saglamaktadir. DESCRIPTION OF THE INVENTION TECHNICAL PROBLEM One aspect of the present invention is the simplification of the process, which can provide safety which can increase the efficiency by using an iron (Fe) catalyst A pharmaceutically useful inclol that can overcome the limitations of the method or 36906.09 It provides a new method for preparing the indazole compound.
TEKNIK çÖZÜM 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. TECHNICAL SOLUTION 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.
[Formül 2] R6 R7' burada, yukaridaki F ormüllerde, n, 1 ile 3 arasinda bir tam sayidir, 36906119 in 0 veya ladir, 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 veya istege bagli olarak hidroksi veya amino ile sübstitüe edilmis Ci-C4-alkili temsil etmektedir, X, X”in N olmasi durumunda m”nin 0 olmasi ve X°in C olmasi durumunda m”nin 1 olmasi sartiyla, C veya N,yi temsil etmektedir, R1, hidrojen, Ci-CÖ-alkil veya I(CH2)rNR8R9”u temsil etmektedir, burada r, 2 ile arasinda bir tam sayidir, R8 ve R9”un her biri bagimsiz olarak, X”in N olmasi durumunda Rhin hidrojen olmasi sartiyla, hidrojen veya Ci-C3-alkili temsil etmektedir, R2, hidrojen, halojen veya Ci-Ce-alkoksiyi temsil etmektedir veya -(CH2)pC02RS, -(CH2)pOR8, -(CH2)pNRR1°°u temsil etmektedir veya I(CH2)p-heterosikl-Rw”u temsil etmektedir, burada heterosikl kismi, N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden -6 üyeli bir halkadir, burada p, 0 ile 3 arasinda bir tam sayidir, R8 ve R9 yukarida tanimlanan sekildedir ve RIO, hidrojen, okso, Ci-Cg-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, 36906119 R3, hidrojen, halojen, Ci-Cé-alkil veya fenili temsil etmektedir veya I(CH2)S- heterosikli temsil etmektedir, burada heterosikl, N ve O atomlar] arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir halkadir, burada s, X°in N olmasi durumunda R3°ün hidrojen veya fenil olmasi sartiyla, 1 ile 3 arasinda bir tam sayidir. [Formula 2] R6 R7' here, in the above formulas, n is an integer between 1 and 3, 36906119 in is 0 or less, 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 represents heteroaryl or heterocycle, where R represents hydrogen or optional represents C1-C4-alkyl substituted with hydroxy or amino, 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-CO-alkyl or I(CH2)rNR8R9 where r is 2 is an integer between, R8 and R9 each independently, so that X is N represents hydrogen or C1-C3-alkyl, provided that Rh is hydrogen. is doing, R2 represents hydrogen, halogen or C1-C6-alkoxy or -(CH2)pCO2RS, -(CH2)pOR8 represents -(CH2)pNRR1°° or represents "I(CH2)p-heterocycle-Rw" where the heterocycle containing one or two heteroatoms selected among N, O and S atoms. -It is a 6-membered ring, where p is an integer between 0 and 3, R8 and R9 above as defined and RIO, hydrogen, oxo, Ci-C8-alkylcarbonyl, Ci-C8-alkoxy or represents Ci-C6-alkyl or one or two nitrogens as a heteroatom It represents a 5-6 membered heterocycle containing the atom, 36906119 R3 represents hydrogen, halogen, C1-C6-alkyl or phenyl or I(CH2)S- represents the heterocycle, where heterocycle is selected from N and O atoms] is a 5-6 membered ring containing one or two heteroatoms where s is is between 1 and 3, provided that R3 is hydrogen or phenyl is an integer.
R4, -YR”°i temsil etmektedir, burada Y, bir dogrudan bagdir veya -(CR8R9)g-'yi temsil etmektedir, burada g, 0 ile 3 arasinda bir tam sayidir, R8 ve R9, yukarida tanimlanan ile aynidir, R”, hidrojen, halojen, C i-Cß-alkil ve I(CH2)tBýRl3”ten olusan gruptan seçilmektedir, t, 0 ile 3 arasinda bir tam sayidir, E; N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir veya Cs-Cin-arili temsil etmektedir, RB, X`in N olmasi durumunda R4”ün hidrojen veya Ci-Ca-alkili temsil etmesi sartiyla, hidrojen, siyano, halojen, hidroksi, okso, tiyol, karboksi veya karboksi-Ci-Ca- alkili temsil etmektedir. R4 represents -YR” where Y is a direct bond or -(CR8R9)g- represents, where g is an integer between 0 and 3, R8 and R9 above same as defined, R” consists of hydrogen, halogen, C i-Cß-alkyl and I(CH2)tBýRl3” is selected from the group consisting of, t is an integer between 0 and 3, E; N, O and S It is a 5-6 membered compound containing one or two heteroatoms selected from among represents heterocycle or represents Cs-Cin-aryl, RB, X represents N provided that R4 represents hydrogen or Ci-Ca-alkyl, hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy-Ci-Ca- represents alkyl.
R5, -Y'RH °i temsil etmektedir, burada Y”, bir dogrudan bagdir veya -(CRSR°)hY"- ”yi temsil etmektedir, burada h, 0 ile 3 arasinda bir tam sayidir ve R8, R9 ve R11 yukarida tanimlanan ile aynidir, Y”, X,in N olmasi durumunda R59in hidrojen veya Ci-Ca-alkili temsil etmesi sartiyla, -O-, -C(O)- ve -C(O)O-”den olusan gruptan seçilmektedir. 36906119 R6, hidrojen, Ci-Cg-alkil, C3-C6-sikloalkil, heterosikl veya heterosiklil-C1-C6-alkili temsil etmektedir, burada heterosikl, X”in N olmasi durumunda R6°nin hidrojen olmasi sartiyla, N ve O atomlari arasindan seçilen bir ila üç heteroatom ihtiva R7, -(CRSR9)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”dan olusan gruptan seçilmektedir, D, bir dogrudan bagi, C4-C6-sikloalkili veya bir veya iki N atomu ihtiva eden 5-6 üyeli bir heteroarili temsil etmektedir veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir, W, bir dogrudan bagi veya -NRR-, -C(O)-, -C(O)O-, -C(O)NR12- veya -S(O)y-”yi temsil etmektedir, RU, hidrojen, Ci-Cs-alkil veya C6' Cio-arili temsil etmektedir, y 1 veya 2 degerinde bir tam sayidir ve R”; hidrojen, hidroksi, Ci-Ca-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 R7'nin C4-C6- 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-Cö-alkilamino, di(Ci-C6- 36906119 alkil)amin0, karboksi, Ci-Cg-alkil, Ci-Cé-alkoksi, karboksi-Ci-CÖ-alkil ve oksodan olusan gruptan seçilen biri veya daha fazlasidir. R5 represents -Y'RH° where Y" is a direct bond or -(CRSR°)hY"- represents ”, where h is an integer between 0 and 3 and R8, R9 and R11 is the same as described above, Y”, where X is N, R59 represents hydrogen or Ci-Ca-alkyl provided that it is selected from the group consisting of -O-, -C(O)- and -C(O)O-. 36906119 R6 is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, heterocycle or heterocyclyl-C1-C6-alkyl represents, where the heterocycle means R6 is hydrogen if X is N contains one to three heteroatoms selected from N and O atoms, provided that R7 represents -(CRSR9)u-Z-D-W-R14“, where u is an integer between 0 and 3. is the number, Z represents a direct bond or a combination of -C(O)- and -C(O)O” selected from the group D, a direct bond, C4-C6-cycloalkyl or one or two N represents a 5-6 membered heteroaryl containing atoms or N, O and S It is a 5-6 membered compound containing one or two heteroatoms selected from among represents the heterocycle, W represents a direct bond or -NRR-, -C(O)-, -C(O)O-, represents -C(O)NR12- or -S(O)y-", RU represents hydrogen, C1-C8-alkyl or C6' represents cio-aryl, y is an integer of 1 or 2, and R”; hydrogen, One to three heteroatoms selected from hydroxy, C1-Ca-alkyl, N, O, and S atoms containing a 5-6 membered heterocycle or where X is N, R7 is C4-C6- C0-Cio-Ar-Ci-CG-alkyl or N, O and S atoms, provided that it represents cycloalkyl A 5-6 membered heterocycle containing one or two heteroatoms selected from represents and where alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl are optionally can be substituted and the substituents include hydroxy, Ci-C6-alkylamino, di(Ci-C6- 36906119 alkyl)amine0, carboxy, Ci-C6-alkyl, Ci-C6-alkoxy, carboxy-C1-CO-alkyl and oxodane One or more selected from the group.
AVANTAJL] ETKILER Mevcut bulusa göre, güvenlik, boran dimetilsülfürün (BH3SMe2) kullanilmamasindan dolayi saglanabilmektedir, verim, prosesin kolaylastirilmasi sayesinde arttirilabilmektedir, bir indol veya indazol bilesigi, geleneksel bir demir (Fe) katalizörünün sinirlandirmalarrnrn çözülmesi suretiyle yeniden üretilebilirlik ile mükemmel verimde hazirlanabilmektedir ve reaktörün temizlenmesi için gereken maliyetler ve zaman, reaktön'in demir oksit kaplamasinin sinirlandirmalarinin çözülmesi suretiyle azaltilabilmektedir. ADVANTAGES] EFFECTS According to the present invention, safety is provided by borane dimethylsulfide (BH3SMe2) can be achieved due to not being used, efficiency, facilitation of the process An indole or indazole compound, a conventional iron Reproducibility by solving the limitations of the (Fe) catalyst It can be prepared with excellent efficiency and is used for cleaning the reactor. the costs and time required, the iron oxide coating of the reactor can be reduced by resolving its limitations.
BULUSU GERÇEKLESTIRMEYE YÖNELIK MOD Bundan sonra, mevcut bulus, daha ayrintili olarak açiklanacaktir. Bu durumda, 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 36906119 olarak yorumlanmalidir. MODE FOR REALIZING THE INVENTION Hereinafter, the present invention will be described in more detail. In this situation, 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 36906119 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. The alkyl group can be medium-sized alkyl having 1 to 10 carbon atoms.
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. 36906.09 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. ihtiva eden ve aksi tanimlanmadikça benzo veya C3-C3 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, 36906119 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 Cs-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, pirrolidin, imidazolin, imidazolidin, pirazolin, pirazolidin, piran, piperidin, morfolin, tiyomorfolin, piperazin, hidrofuran ve benzerini içermektedir. 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. 36906.09 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. containing and with benzo or C3-C3 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, 36906119 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 Cs-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, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, including morpholine, thiomorpholine, piperazine, hydrofuran and the like.
Aksi tanimlanmadikça, burada kullanilan terimler ve kisaltmalar, mevcut bulusun ilgili oldugu teknikte uzman kisilerce yaygin olarak anlasilan anlamlari olarak yorumlanabilmektedir. 36906119 Mevcut bulus, farmasötik olarak faydali bir indol veya indazol bilesigi hazirlamaya yönelik bir yöntem ile ilgilidir ve bir reaksiyon ara ürünü olarak asagidaki Formül 1 ile temsil edilen bir bilesigin dahil edilmesi suretiyle asagidaki Formül 2 ile temsil edilen bir bilesigi hazirlamaya yönelik yöntem saglamaktadir: burada, yukaridaki Formül 1`de, n, 1 ile 3 arasinda bir tam sayidir, m 0 veya 1”dir, 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 veya istege bagli olarak hidroksi veya amino ile sübstitüe edilmis Ci-C4-alkili temsil etmektedir, X, X'in N olmasi durumunda m'nin 0 olmasi ve X°in C olmasi durumunda minin 1 olmasi sartiyla, C veya N,yi temsil etmektedir, 36906119 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)pCOzR8, -(CH2)pOR8, _(CH2)pNRR10°u temsil etmektedir veya _(CH2)p-heterosikl-R'Ü'u temsil etmektedir, burada heterosikl kismi, N, O ve S atomlari arasindan seçilen bir veya iki heteroatornu ihtiva eden -6 üyeli bir halkadir, burada p, 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)S- heterosikli temsil etmektedir, burada heterosikl, N ve O atoinlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir halkadir, burada 5, X°in N olmasi durumunda R3”ün hidrojen veya fenil olmasi sartiyla, 1 ile 3 arasinda bir tam sayidir. Unless otherwise defined, terms and abbreviations used herein are the meanings of the present invention. as the meanings commonly understood by those skilled in the art to which it relates. can be interpreted. 36906119 The present invention provides a pharmaceutically useful indole or indazole compound. relates to a method for preparing and as a reaction intermediate By incorporating a compound represented by Formula 1 below, It provides a method for preparing a compound represented by formula 2: where, in Formula 1 above, n is an integer between 1 and 3, m is 0 or 1”, 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 represents heteroaryl or heterocycle, where R represents hydrogen or optional represents C1-C4-alkyl substituted with hydroxy or amino, If X is N then m is 0 and if X is C then mi is Provided that it is 1, it represents C or N, 36906119 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)pCO2R8, -(CH2)pOR8 represents _(CH2)pNRR10° or represents _(CH2)p-heterocycle-R'U, where the heterocycle containing one or two heteroatrons selected from among N, O and S atoms. -It is a 6-membered ring, where p 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)S- represents the heterocycle, where the heterocycle is selected from the atoms N and O. is a 5-6 membered ring containing one or two heteroatoms where 5, X°in N between 1 and 3, provided that R3 is hydrogen or phenyl is an integer.
R4, -YR””i temsil etmektedir, burada Y, bir dogrudan bagdir veya -(CR8R9)g-'yi temsil etmektedir, burada g, 0 ile 3 arasinda bir tam sayidir, R8 ve R9, yukarida 36906119 tanimlanan ile aynidir, R”, hidrojen, halojen, Ci-Cö-alkil ve I(CH2)tBýR'3°ten olusan gruptan seçilmektedir, t, 0 ile 3 arasinda bir tani sayidir, B; N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir veya Cs-Cio-arili temsil etmektedir, R'3, X`in N olmasi durumunda R4°ün hidrojen veya Ci-Cs-alkili temsil etmesi sartiyla, hidrojen, siyano, halojen, hidroksi, okso, tiyol, karboksi veya karboksi-Ci-Cö- alkili temsil etmektedir. R4 represents -YR” where Y is a direct bond or -(CR8R9)g- represents, where g is an integer between 0 and 3, R8 and R9 above 36906119 Same as defined, R”, hydrogen, halogen, Ci-C6-alkyl and I(CH2)tBýR'3° is selected from the group consisting of, t is a diagnostic number between 0 and 3, B; N, O and S It is a 5-6 membered compound containing one or two heteroatoms selected from among represents heterocycle or represents Cs-Cio-aryl, R'3, X is N provided that R4 represents hydrogen or Ci-C8-alkyl, hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy-Ci-Co- represents alkyl.
Yukaridaki Formül 2lde, n, ni, X, A, R, R2 ve R3 yukarida tanimlanan ile aynidir, R5, -Y'R1 ' ”i temsil etmektedir, burada Y', bir dogrudan bagdir veya -(CR8R9)hY"- ”i temsil etmektedir, burada 11, 0 ile 3 arasinda bir tam sayidir ve R8, R9 ve R11 yukarida tanimlanan ile aynidir, Y”, X'in N olmasi durumunda R57in hidrojen veya Ci-Cs-alkili temsil etmesi 36906119 sartiyla, -O-, -C(O)- ve -C(O)O-,den olusan gruptan seçilmektedir. In Formula 2 above, n, ni, X, A, R, R2 and R3 are the same as defined above, R5 represents -Y'R1'" where Y' is a direct bond or -(CR8R9)hY"- represents ”, where 11 is an integer between 0 and 3 and R8, R9 and R11 is the same as described above, Y”, where X is N, R57 represents hydrogen or Ci-C8-alkyl 36906119 provided that it is selected from the group consisting of -O-, -C(O)- and -C(O)O-.
R6, hidrojen, Ci-Ce-alkil, C3-C6-sikloalki1, heterosikl veya heterosiklil-Ci-Ca-alkili temsil etmektedir, burada heterosikl, X”in N olmasi durumunda R6”nin hidrojen olmasi sartiyla, N ve O atomlari arasindan seçilen bir ila üç heteroatom ihtiva R7, -(CR8R9)u-Z-D-W-Rl4”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-Cû-sikloalkili temsil etmektedir veya bir veya iki N atomu ihtiva eden 5-6 üyeli heteroarili temsil etmektedir veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatomu ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir, W, bir dogrudan bagi veya - NRS-,-C(O)-, -C(O)O-, -C(0)NR12- veya -S(O)y-”yi temsil etmektedir, R'Z, hidrojen, Ci-Cs-alkil veya Cs-Cio-arili temsil etmektedir, y 1 veya 2 degerinde bir tam sayidir ve RM; hidrojen, hidroksi, C 1-C6-alkil, N, O ve S atomlari arasindan seçilen bir ila üç heteroatom ihtiva eden 5-6 üyeli bir heterosikl veya X7in N olmasi durumunda R7`nin C4-C6-sikloalkili temsil etmesi sartiyla, CÖ'CIO'AI'C 1- Cé-alkili veya N, O ve S atomlari arasindan seçilen bir veya iki heteroatom ihtiva eden 5-6 üyeli bir heterosikli temsil etmektedir, burada alkil, alkoksi, aril, sikloalkil, heterosikl ve heteroaril istege bagli olarak 36906119 sübstitüe edilebilmektedir ve sübstitüentler, hidroksi, Ci-Cg-alkilamino, di(C1-C6- alkil)amino, karboksi, Ci-Ca-alkil, Ci-Cs-alkoksi, karboksi-Ci-CÖ-alkil ve oksodan olusan gruptan seçilen biri veya daha fazlasidir. R6 is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, heterocycle or heterocyclyl-C1-C6-alkyl represents the heterocycle, where R6 is hydrogen if X is N. contains one to three heteroatoms selected from N and O atoms, provided that R7 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- D represents a direct bond, C4-Cû-cycloalkyl or represents a 5-6 membered heteroaryl containing one or two N atoms. or one or two heteroatoms selected from N, O and S atoms. represents a 5-6 membered heterocycle containing W, a direct bond or - represents "NRS-, -C(O)-, -C(O)O-, -C(O)NR12- or -S(O)y-", R'Z represents hydrogen, C1-C8-alkyl or C8-Cio-aryl, y is a 1 or 2 is an integer and RM; among hydrogen, hydroxy, C1-C6-alkyl, N, O and S atoms a 5-6 membered heterocycle containing one to three selected heteroatoms or X7inN CÖ'CIO'Al'C 1-, provided that R7 represents C4-C6-cycloalkyl C6-alkyl or containing one or two heteroatoms selected from N, O and S atoms represents a 5-6 membered heterocycle, where alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl are optionally 36906119 can be substituted and the substituents include hydroxy, C1-C8-alkylamino, di(C1-C6- alkyl)amino, carboxy, Ci-Ca-alkyl, Ci-C8-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- Cg-alkil veya di(Ci -C3-alkil)amin0-C2-C3-alkil olabilmektedir. Specifically, in Formula 1 and Formula 2 above, R1 above is hydrogen, Ci- It can be Cg-alkyl or di(C1-C3-alkyl)amine0-C2-C3-alkyl.
Ek olarak, yukaridaki R2, hidrojen, halojen, karboksi, karboksi-Ci-C3-alkil, C1-C3- alkoksikarbonil, Ci-Cs-alkoksikarbonil-Ci-Cs-alkil, istege bagli olarak bir okso grubu ile sübstitüe edilmis hidroksi-Ci-Cg-alkil, Ci-Cg-alkoksi, -(CH2)pNRRR9, - NHRIÜ, -N(H)S(O)2Rl0 veya -NHC(O)2R””u temsil edebilmektedir veya - (CI-[2)p-heterosikl-R10 olabilmektedir, burada heterosikl, p, RS, R9 ve R10 yukarida tanimlanan sekildedir. Additionally, R2 above is hydrogen, halogen, carboxy, carboxy-C1-C3-alkyl, C1-C3- alkoxycarbonyl, Ci-C8-alkoxycarbonyl-Ci-C8-alkyl, optionally an oxo hydroxy-Ci-Cg-alkyl, Ci-Cg-alkoxy, -(CH2)pNRRR9, - NHRIÜ may represent -N(H)S(O)2R10 or -NHC(O)2R" or - (CI-[2)p-heterocycle-R10, where the heterocycle is p, RS, R9 and R10 as defined above.
Ayrica, R3, hidrojen, metil veya halojeni temsil edebilmektedir veya istege bagli olarak C 1-C3-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-Cs-alkilen olabilmektedir. 36906119 Ek olarak, yukaridaki Y, bir dogrudan bag olabilmektedir ve yukaridaki Y”, bir dogrudan bag olabilmektedir veya bir dogrudan bag, -O-, -C(O)- ve -CH2C(O)- Ek olarak, yukaridaki R”, hidrojen, metil, etil, fenil, floro, kloro, 2-karboksi- pirrolidin-l-il, pirrolidin-l-il, 4-asetik asit-1,3-tîyazolin-2-il, -CHz-(1,1-diokso- tiyomorfolin-4-il) -CH2-(2-0ksopiperazin-4-il), -l,l-dîokso-tiyomorfolin-4-il ve - 2-0ksopiperazin-4-il”den olusan gruptan seçilebilmektedir. Additionally, R 3 may represent hydrogen, methyl or halogen or optionally may represent phenyl substituted with C1-C3-alkoxy, or heterocycle, containing one or two heteroatoms selected from N and O atoms and a 5-6 membered ring optionally substituted with one or two oxo groups The heterocycle may be-Ci-Cs-alkylene. 36906119 Additionally, Y above may be a direct bond and Y above may be a can be a direct bond or a direct bond, -O-, -C(O)- and -CH2C(O)- Additionally, R" above can be used as hydrogen, methyl, ethyl, phenyl, fluoro, chloro, 2-carboxy- pyrrolidin-1-yl, pyrrolidin-1-yl, 4-acetic acid-1,3-thiazolin-2-yl, -CH2-(1,1-dioxo- thiomorpholin-4-yl) -CH2-(2-0xopiperazin-4-yl), -1,1-dioxo-thiomorpholin-4-yl and - It can be selected from the group consisting of 2-0xopiperazin-4-yl.
Ayni zamanda, yukaridaki Formül 2°de, yukaridaki R6, hidrojen, metil veya izobütil olabilmektedir. Also, in Formula 2 above, R6 above is hydrogen, methyl or It may be isobutyl.
Yukaridaki R7, 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 -CONRIZ-,yi temsil edebilmektedir, burada R”, yukarida tanimlanan ile aynidir. 36906.09 Mevcut bulusun bir uygulamasi olarak, yukaridaki Formül 1 ile temsil edilen bilesik, ((1,l-dioksidotiyomorfolin0)-(7-nitr0-2-fenil-1H-indol-S-il)metan0n Olabilmektedir ve yukaridaki Formül 2 ile temsil edilen bilesik, 4-((2-fenil-7- ((tetrahidro-ZH-piran-4-il)amin0)-1H-indol-S-il)metil)tiy0m0rfolin 1 , 1 -dioksit olabilmektedir. R7 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 -CONRIZ-, where R”, is the same as described above. 36906.09 As an embodiment of the present invention, represented by Formula 1 above compound, ((1,1-dioxidothiomorpholine0)-(7-nitri0-2-phenyl-1H-indol-S-yl)metan0n and the compound represented by Formula 2 above, 4-((2-phenyl-7- ((tetrahydro-ZH-pyran-4-yl)amine0)-1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide It may happen.
Yukaridaki Formül 1 ile temsil edilen bilesik, asagidaki Formül 3 ile temsil edilen bilesigin amite dönüstürülmesi suretiyle hazirlanabilmektedir: R1 NO2 Yukaridaki Formül 3”te, 11, m, X, A, R1, R2 ve R3 yukarida tanimlanan ile aynidir, Amite dönüstürme adimi, spesifik olarak sinirli degildir ve geleneksel bir sekilde gerçeklestirilebilmektedir. 36906119 Geleneksel olarak, yukaridaki Formül 3 ile temsil edilen bilesigi indirgemeye yönelik bir adim, boran dimetilsülfür (BH3SMe2) kullanilarak gerçeklestirilmistir. The compound represented by Formula 1 above is the compound represented by Formula 3 below. It can be prepared by converting the compound to amide: R1 NO2 In Formula 3 above, 11, m, X, A, R1, R2 and R3 are the same as defined above, The amide conversion step is not specifically limited and can be carried out in a conventional manner. can be realized. 36906119 Traditionally, we try to reduce the compound represented by Formula 3 above. A step towards this was achieved using borane dimethylsulfide (BH3SMe2).
Bu adimda kullanilan boran dimetilsülfür (BH3SMe2) zehirli bir madde oldugu için bir güvenlik sorunu bulunmaktaydi. Bununla birlikte, mevcut bulusa göre, yukaridaki Formül 1 ile temsil edilen bir ara ürünün hazirlanmasi için yukaridaki Formül 3 ile temsil edilen bilesigi amite dönüstürmeye yönelik adim gerçeklestirilmektedir, böylelikle boran dimetilsülfürün (BH3SMe2) kullanilmamasindan dolayi güvenlik saglamaktadir. Borane dimethylsulfide (BH3SMe2) used in this step is a toxic substance. There was a security issue. However, according to the present invention, For the preparation of an intermediate product represented by Formula 1 above, Step to convert the compound represented by formula 3 to amide is carried out, so that borane dimethylsulfide (BH3SMe2) It provides security because it is not used.
Sonrasinda, mevcut bulus, asagidaki Formül 4 ile temsil edilen bir bilesigin hazirlanmasi için yukaridaki Formül 1 ile temsil edilen bilesigin bir birincil indirgemesi ve bir ikincil indirgemesini gerçeklestirmeye yönelik bir adimi içerebilmektedir. 36906119 Yukaridaki Formül 4*te, n, m, X, A, R1, R2, R3 ve R4 yukarida tanimlanan ile aynidir, Bu durumda, birincil indirgeme, bir indirgeme maddesi olarak, sodyum borohidrür (NaBH4), bor triflorür eterat (BF30Et2) ve lityum alüminyum hidrürden (LAH) olusan gruptan seçilen en az birinin kullanilmasi suretiyle gerçeklestirilebilmektedir ve daha tercihen, sodyum borohidrür (NaBH4) ve bor triflon'jr eterat (BF30Et2) birlikte kullanilabilmektedir. Birincil indirgeme, asagidaki Formül 5 ile temsil edilen bir bilesigin üretilmesi için Formül 1 ile temsil edilen bilesigin karbonil grubunu (C=O) indirgemektedir: Yukaridaki Formül 5'te, n, m, X, A, R', R2, R3 ve R4 yukarida tanimlanan ile aynidir, 36906119 Ikincil indirgeme, bir indirgeme maddesi olarak, Pd/C, NiBrz, NiClz, ZnClz, ZrCl4, ve CoClz-6HzOadan olusan gruptan seçilen en az biri ve daha tercihen Pd/C kullanilarak gerçeklestirilebilmektedir. Ikincil indirgeme araciligiyla, yukaridaki Formül 5 ile temsil edilen bilesigin nitro grubu (-NOg), Formül 4 ile temsil edilen bilesigin amin grubuna (-NHz) indirgenebilmektedir. Subsequently, the present invention is based on the preparation of a compound represented by Formula 4 below. For its preparation, the compound represented by Formula 1 above is used as a primary reduction and a step towards performing a secondary reduction may contain. 36906119 In Formula 4 above, n, m, X, A, R1, R2, R3 and R4 are defined above. is the same, In this case, primary reduction uses sodium as a reducing agent. borohydride (NaBH4), boron trifluoride etherate (BF30Et2) and lithium aluminum by using at least one selected from the group consisting of hydride (LAH) can be achieved and, more preferably, sodium borohydride (NaBH4) and boron Triflon etherate (BF30Et2) can be used together. primary reduction, with Formula 1 to produce a compound represented by Formula 5 below. It reduces the carbonyl group (C=O) of the represented compound: In Formula 5 above, n, m, X, A, R', R2, R3 and R4 are defined above. is the same, 36906119 Secondary reduction, as a reducing agent, Pd/C, NiBrz, NiClz, ZnClz, ZrCl4, and at least one selected from the group consisting of CoCl2-6HzO, and more preferably Pd/C. can be achieved using . Through secondary reduction, the above The nitro group (-NOg) of the compound represented by Formula 5 is It can be reduced to the amine group (-NHz) of the compound.
Geleneksel olarak, bir demir (Fe) katalizörü, indol veya indazol bilesiklerinin sentezi sirasinda, nitro grubunu (-NOz) ihtiva eden Formül 5 ile temsil edilen bilesigi, amin grubunu (-NH2) ihtiva eden Formül 4 ile temsil edilen bilesige indirgemeye yönelik adimda kullanilmistir. Bununla birlikte, bu durumda, demirin (Fe) çesitli partikül büyüklüklerinden dolayi yeniden üretilebilirligin kötülesmesi, karistirmanin reaksiyon sirasinda pürüzsüz olmamasi veya reaksiyon süresi uzatildiginda reaksiyonda olusan safsizliklardan dolayi verimin düsmesi bakimindan sinirlandirmalar bulunmaktaydi. Ek olarak, bir reaktörün, reaksiyondan sonra üretilen demir oksit ile kaplanmasi ve reaktörün temizlenmesi için maliyet ve zamanin gerekli olmasi bakimindan bir sinirlandirma bulunmaktaydi. Bununla birlikte, mevcut bulus, mükemmel verimde indol veya 36906119 indazol bilesigini hazirlayabilmektedir ve demir (Fe) katalizörü kullanilmadan yukaridaki sekilde birincil ve ikincil indirgemenin gerçeklestirilmesi suretiyle geleneksel demir (Fe) katalizörün sinirlandirmalarmin çözülmesiyle yeniden üretilebilirlige sahip olabilmektedir ve reaktörün temizlenmesi için gerekli maliyetler ve zaman, reaktörün demir oksit kaplamasinin sinirlandirmasinm çözülmesiyle azaltilabilmektedir. Traditionally, an iron (Fe) catalyst has been used to form indole or indazole compounds. During the synthesis, it is represented by Formula 5 containing the nitro group (-NOz). The compound represented by Formula 4 containing the amine group (-NH2) was used in the reduction step. However, in this case, reproducibility of iron (Fe) due to various particle sizes deterioration, mixing is not smooth during the reaction, or the reaction When the time is extended, the yield decreases due to impurities formed in the reaction. There were limitations in terms of Additionally, a reactor coating with iron oxide produced after the reaction and cleaning the reactor a limitation in terms of cost and time required for There was. However, the present invention provides excellent yields of indole or 36906119 can prepare the indazole compound and without using an iron (Fe) catalyst. by performing primary and secondary reduction as above by solving the limitations of the traditional iron (Fe) catalyst can be produced and required for cleaning the reactor. costs and time limit the reactor's iron oxide coating. can be reduced by dissolving it.
Ek olarak, geleneksel olarak, indol veya indazol bilesiklerinin sentezinde, yukaridaki Formül 5 ile temsil edilen bilesik, yukaridaki Formül 3 ile temsil edilen bilesikten hazirlandiginda, yukaridaki Formül 3 ile temsil edilen bilesik, boran dimetilsültîirün (BHssMez) kullanilmasi suretiyle indirgenmistir (Adim 1), halojenlenmistir (Adim 2) ve tekrar amin sübstitüsyonuna tabi tutulmustur (Adim 3). Bununla birlikte, yukaridaki Formül 5 ile temsil edilen bilesik, yukaridaki Formül 3 ile temsil edilen bilesikten hazirlandiginda, mevcut bulus, Formül 3 ile temsil edilen bilesigi amite dönüstürme-ye yönelik bir adim (Adim 1) ve bir birincil indirgeme araciligiyla bir karbonil grubu (C=O) indirgemeye yönelik bir adim (Adim 2) olmak üzere toplamda iki adimda gerçeklestirilebilmektedir. In addition, traditionally in the synthesis of indole or indazole compounds, The compound represented by Formula 5 above is When prepared from the compound given, the compound represented by Formula 3 above, borane was reduced using dimethyl sulfur (BHssMez) (Step 1), halogenated (Step 2) and subjected to amine substitution again (Step 3). However, the compound represented by Formula 5 above When prepared from the compound represented by Formula 3, the present invention is a step (Step 1) to convert the represented compound to an amide and a a method for reducing a carbonyl group (C=O) via primary reduction It can be accomplished in two steps in total: step (Step 2).
Dolayisiyla, mevcut bulus, prosesin basitlestirilmesi sayesinde sentez etkililigini ve verimini arttirmaktadir. 36906119 Mevcut bulusun hazirlama yöntemi, yukaridaki Formül 2 ile temsil edilen bilesigin hazirlanmasi için yukaridaki Formül 4 ile temsil edilen bilesigin, keton veya aldehit ile reaksiyona sokulmasina yönelik bir adimi içerebilmektedir. Therefore, the present invention improves synthesis efficiency through process simplification. and increases its efficiency. 36906119 The preparation method of the present invention is represented by Formula 2 above. To prepare the compound, the compound represented by Formula 4 above is used as a ketone or a step of reacting with the aldehyde.
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 yorumlanmamalidir. 36906.09 a) Adimi ((1 ,1-dioksidotiyomorfolin0)(7-nitro-2-fenil-1H-indol-S-il)metanon sentezi (DIPEA) (, bir reaktöre ilave edilmistir ve sonrasinda oda sicakliginda karistirilmistir. Reaksiyon karisimi, 75-80 °C”ye isitilmistir ve reaksiyon karisimi, 7-nitro-2-fenil-lH-indol-S- karboksilik asidin tepe noktasinin %1,0 veya daha azinin gösterilmesi için isitmadan sonraki 1 saatten itibaren numune alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. 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 not be interpreted as: 36906.09 a) Step ((1,1-dioxidothiomorpholine0)(7-nitro-2-phenyl-1H-indol-S-yl)methanone synthesis (DIPEA) (, to a reactor was added and then mixed at room temperature. reaction mixture, It was heated to 75-80 °C and the reaction mixture was 7-nitro-2-phenyl-1H-indole-S- to show 1.0% or less of the peak carboxylic acid When analyzed by taking samples from 1 hour after heating The reaction has been terminated.
Reaksiyonun tamamlandigi dogrulandiktan sonra, reaksiyon karisimi, 35-40 °C`ye sogutulmustur, HzO (3,75 L), damlatilarak yavasça ilave edilmistir ve sonrasinda 1 saat boyunca oda sicakliginda karistirilmistir. Reaksiyon karisimi, karistirilmistir, filtrelenmistir ve H20 (0,75 L) ile yikanmistir ve sonrasinda tekrar 36906119 etanol/HzO (1/2, 0,75 L) ile yikanmistir. Reaksiyon karisimi, ham (1,1- satlik: %93,43) sentezlenmesi için N2 basinci altinda kurutulmustur. Ham (1,1- dioksidotiyomorfolino)(7-nitro-Z-fenil-1H-indol-S-il)metanon (336,09 g) ve tetrahidrofuran (THF, 2,69 L) oda sicakliginda buna ilave edilmistir, sonrasinda sicaklik yükseltilmistir ve reaksiyon karisimi, geri akitilmistir ve 1 saat boyunca karistirilmistir. Reaksiyon karisimi, buna damlatilarak ilave edilmistir ve 1 saat boyunca oda sicakliginda karistirilmistir ve THF/HzO (1 L) ile yikanmistir. Ortaya çikan madde, (1,1- dioksidotiyomorfolino)(7-nitro-2-feni1-1 H-indol-S -il)mctanon ”ün (314,1 g, verim: %88,78, saflik: %95,87) sentezlenmesi için N2 basinci altinda kurutulmustur. lH NMR (, 8.02 (m, 4H), 3.30 (m, 411). b) Adimi 4-((7-amino-2-fenil- l H-indol-S-il)metil)tivomorfolin 1,1-dioksit sentezi 36906119 NaBl-I4 (, bir reaktöre ilave edilmistir ve reaktör, 10 °C veya daha az bir sicakliga sogutulmustur ve sonrasinda bor triflorür eterat (BF3OEt2) ( buna yavasça ilave edilmistir. (1,1- dioksidotiyomorfolin0)(7-nitro-Z-fenil-1H-indol-S-il)metan0n (4 g), buna ilave edilmistir ve 40 0Üye isitilmistir ve reaksiyon karisimi, (1,1- deoksitiyomorfo1in0)(7-nitro-2-fenil- 1 H-indol-S-il)metan0n'ün tepe noktasinin %1,0 veya daha azinin gösterilmesi için isitmadan sonraki 1 saatten itibaren numunenin alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. After verifying that the reaction is complete, the reaction mixture is heated to 35-40 °C. was cooled, H2O (3.75 L) was added slowly dropwise, and then It was stirred at room temperature for 1 hour. reaction mixture, was mixed, filtered and washed with H2O (0.75 L) and then again 36906119 washed with ethanol/H2O (1/2, 0.75 L). Reaction mixture, crude (1,1- For sale: 93.43%), it was dried under N2 pressure to synthesize it. Crude (1,1- dioxidothiomorpholino)(7-nitro-Z-phenyl-1H-indol-S-yl)methanone (336.09 g) and tetrahydrofuran (THF, 2.69 L) was added at room temperature, then the temperature was raised and the reaction mixture was refluxed for 1 hour. mixed. reaction mixture, was added dropwise and left at room temperature for 1 hour. was mixed and washed with THF/H2O (1 L). The resulting substance is (1,1- dioxidothiomorpholino)(7-nitro-2-phenyl1-1H-indole-S-yl)mctanone (314.1 g, yield: 88.78%, purity: 95.87%) under N2 pressure to synthesize dried. 1H NMR (, 8.02 (m, 4H), 3.30 (m, 411). b) Step 4-((7-amino-2-phenyl-1H-indol-S-yl)methyl)thivomorpholine 1,1-dioxide synthesis 36906119 NaBl-I4 (, was added to a reactor and the reactor was heated to 10 °C. or cooled to a lower temperature and then boron trifluoride etherate (BF3OEt2) ( was added slowly to this. (1,1- dioxidothiomorpholine0)(7-nitro-Z-phenyl-1H-indol-S-yl)methane (4 g), added and the reaction mixture was heated to 40 0 and the reaction mixture was (1,1- peak of deoxythiomorpho1in0)(7-nitro-2-phenyl-1H-indole-S-yl)metan0n 1 hour after heating to show 1.0% or less of the dot. reaction when analyzed by taking a sample from has been terminated.
Reaktör, 10 oC”1ik bir sicakliga sogutulmustur, agirlikça %10 Pd/C (53 mg) ve NaBH4 (1,137 g) buna ilave edilmistir ve sonrasinda etano] (40 m1), ayni sicaklikta damlatilarak ilave edilmistir. Reaksiyon karisimi, 4-((7-nitr0-2-fenil- 1H-indol-S-i1)meti1)tiyomorf01in 1,1-dioksit'in tepe noktasinin %1,0 veya daha azinin gösterilmesi için etanolün ilavesinden sonraki 0,5 saatten itibaren numune alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. Reaksiyon çözeltisinin sicakligi, ilave edilmistir ve reaksiyon karisimi, 30 dakika boyunca karistirilmistir ve indirgenmis basinç altinda konsantre edilmistir. HzO (80 mL), buna ilave 36906.09 edilmistir ve 80-90 oC'ye isitilmistir ve sonrasinda 1 saat boyunca karistirilmistir ve filtrelenmistir. Reaksiyon karisimi, ilk olarak HzO (20 mL) ile yikanmistir ve ikinci olarak etanol/HzO (1/2, 20 mL) ile yikanmistir ve sonrasinda ham 4-((7- saflik: %98,42) sentezlenmesi için Nz basinci altinda kurutulmustur. The reactor was cooled to a temperature of 10 °C, 10 wt% Pd/C (53 mg) and NaBH4 (1.137 g) was added thereto followed by ethanol (40 m1), the same It was added dropwise at temperature. The reaction mixture was 4-((7-nitrO-2-phenyl- 1.0% or more of the peak of 1H-indole-S-methylthiomorphoin 1,1-dioxide samples from 0.5 hours after the addition of ethanol to show the minimum The reaction was terminated when analyzed by removal. Reaction temperature of the solution, was added and the reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. H2O (80 mL), plus 36906.09 was heated to 80-90 oC and then stirred for 1 hour. and filtered. The reaction mixture was first washed with H2O (20 mL) and Secondly, it was washed with ethanol/H2O (1/2, 20 mL) and then the crude 4-((7- Purity: 98.42%) was dried under Nz pressure to synthesize it.
HzO (52 mL), reaktöre ilave edilmistir, 10 0C veya daha azina scgutulmustur ve metansülfonik asit ( sonrasinda, sicaklik 25 C*C”C1e veya altinda tutulurken pH'i 3-4,e ayarlamak üzere damlatilarak ilave edilmistir. Reaksiyon karisimi, 30 dakika boyunca oda sicakliginda karistirilmistir, selit ile Iiltrelenmistir ve HzO (ll mL) ile yikanmistir. 6N NaOH (5 mL), 9 degerinde bir pH olmasi için filtrata ilave edilmistir ve sonrasinda 30 dakika boyunca Oda sicakliginda karistirilmistir ve filtrelenmistir. Ortaya çikan madde, ilk olarak HzO (11 mL) ile yikanmistir ve ikinci olarak etanol/H20 (1/2, 11 mL) ile yikanmistir ve sonrasinda 4-((7-amino- satlik: %91,31) sentezlenmesi için N2 basinci altinda kurutulmustur. 36906119 2.87 (m, 4H). c) Adimi 4-((2-feni1-7-((tetrahidro-2H-piran-4-il)amino)-lH-indol-S- il)metil)tiyomorfolin 1,1-dioksit sentezi tetrahidro-4H-piran-4-on (1,3 kg), asetik asit (AcOH) (4,6 kg) ve izopropil asetat (23,2 L), bir reaktöre ilave edilmistir ve karistirilrnistir 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-di0ksit5in tepe noktasinin %0,5 veya daha azinin gösterilmesi için analiz edildiginde reaksiyon sonlandirilmistir, Reaksiyonun tamamlandigi dogrulanmistir, bir lN NaOH sulu çözeltisi (23,2 L) reaksiyon karisimina 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 Iiltrelenmistir, su (38,7 L) ve t-bütil metil eter (38,7 L) ile yikanmistir ve 4-((2- 36906119 fenil-7-((tetrahidro-2H-piraii-4-il)amino)- l H-indol-5-il)metil)tiyomorfolin 1,1- boyunca N2 basinci altinda kurutulmustur. HzO (52 mL) was added to the reactor, heated to 10 0C or less, and methanesulfonic acid (subsequently, while keeping the temperature at or below 25°C It was added dropwise to adjust the pH to 3-4. Reaction mixture, 30 minutes at room temperature, filtered with celite and H2O (11 mL). Add 6N NaOH (5 mL) to the filtrate to achieve a pH of 9. was added and then stirred at room temperature for 30 minutes. and filtered. The resulting material was first washed with H2O (11 mL) and Secondly, it was washed with ethanol/H2O (1/2, 11 mL) and then 4-((7-amino- for sale: 91.31%) was dried under N2 pressure to synthesize it. 36906119 2.87 (m, 4H). c) Step 4-((2-phenyl1-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indole-S- Synthesis of il)methyl)thiomorpholine 1,1-dioxide tetrahydro-4H-pyran-4-one (1.3 kg), acetic acid (AcOH) (4.6 kg) 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% of the peak of phenyl-1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide5 or When analyzed to show less, the reaction was terminated, The reaction was confirmed to be complete, a lN NaOH aqueous solution (23.2 L). was added to the reaction mixture, then continued for 1 hour or longer. and then the organic solvent was added under reduced pressure. distilled. The solid substance in the remaining aqueous solution It was filtered, washed with water (38.7 L) and t-butyl methyl ether (38.7 L) and 4-((2- 36906119 phenyl-7-((tetrahydro-2H-pyrayl-4-yl)amino)-1H-indol-5-yl)methyl)thiomorpholine 1,1- It was dried under N2 pressure throughout.
Karsilastirmali Örnek a) Adimi (7-nitro-2-fenil-lH-indol-S-il) metanol sentezi 7-nitro-2-fenil-lH-indol-5-karboksilik asit (, oda sicakliginda bir reaktöre ilave edilmistir ve karistirilmistir ve sonrasinda reaksiyon karisimi, 10-15 °C”ye sogutulmustur ve SM boran dimetilsülîür (BH3SMe2, 12,3 L), iç sicakliginin 40 DC”yi asmamasi için buna yavasça damlatilarak ilave edilmistir. Damlatarak ilave etme isleminin tamamlanmasindan sonra, reaktör, 40 °C”lik bir sicakliga isitilmistir, reaksiyon karisimi, 2 saat boyunca 36906119 karistirilmistir ve sonrasinda reaksiyon karisimi, 7-nitro-2-fenil-lH-indol-S- karboksilik asidin tepe noktasinin %1,0 veya daha azinin gösterilmesi için HPLC ile analiz edildiginde reaksiyon tamamlanmistir. Comparative Example a) Step (7-nitro-2-phenyl-1H-indol-S-yl) methanol synthesis 7-nitro-2-phenyl-1H-indole-5-carboxylic acid (room was added to a reactor at temperature and stirred, and then the reaction The mixture was cooled to 10-15 °C and SM borane dimethylsulide (BH3SMe2, 12.3 L) is slowly added dropwise so that the internal temperature does not exceed 40 DC. has been done. After completion of the dropwise addition process, the reactor The reaction mixture was heated to a temperature of 40 °C for 2 hours. 36906119 was stirred and then the reaction mixture was 7-nitro-2-phenyl-1H-indole-S- HPLC to show 1.0% or less of peak carboxylic acid When analyzed with , the reaction is complete.
Reaksiyonun tamamlandiginin dogrulanmasindan sonra, HzO (55 L), reaksiyon karisimina yavasça damlatilarak ilave edilmistir ve sonrasinda karisim, organik katrnanin depolanmasi için katmanlara ayrilmistir ve su katmani, etil asetat (EtOAc, 29 L) ile ekstrakte edilmistir, depolanan organik katman ile karistirilmistir ve indirgenmis basinç altinda damitilmistir. EtOH/HzO (6,1 L/12,2 L), elde edilen konsantreye ilave edilmistir, en az 2 saat boyunca karistirilmistir ve sonrasinda Iiltrelenmistir. Ortaya çikan madde, bir yikama çözeltisi (EtOHfHzO : 1/3, 9,0 L) ile yikanmistir ve sonrasinda (7-nitro-2-fenil- lH-indol-S-il)metanol”ün (4,6 kg, verim: %835, saflik: %98,4) sentezlenmesi için 16 saat boyunca N2 basinci altinda kurutulmustur. 3690609 b) Adimi 4-((7-nitro-2-fenil-lH-indol-5-il)metil)tiyom0rfolin 1, l -dioksit sentezi (7-nitro-2-fenil-1H-iridol-S-il)metanol ( bir reaktöre ilave edilmistir ve oda sicakliginda karistirilmistir, reaktör, 0 °C`lik bir sicakliga sogutulmustur ve sonrasinda reaksiyonun iç sicakligi 20 °C7nin altinda tutulurken PBr3 (2,8 kg) ilave edilmistir. Ilave etme isleminin tamamlanmasindan sonra, reaktörün sicakligi, 25 °C`ye yükseltilmistir, karisim 1 saat boyunca karistirilmistir ve reaksiyon karisimi, 5-(hidr0ksimetil)-7-nitr0-2-fenil-lH- indolaün tepe noktasinin %1,0 veya daha azinin gösterilmesi için numune alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. After confirmation that the reaction was complete, H2O (55 L), reaction was added to the mixture slowly dropwise, and then the mixture was mixed with organic The tar is separated into layers for storage and the water layer is ethyl acetate. (EtOAc, 29 L), with the stored organic layer was mixed and distilled under reduced pressure. EtOH/HZO (6.1 L/12.2 L) was added to the resulting concentrate for at least 2 hours. It was mixed and then filtered. The resulting substance is washed solution (EtOHfHZO: 1/3, 9.0 L) and then (7-nitro-2-phenyl- For the synthesis of 1H-indol-S-yl)methanol (4.6 kg, yield: 835%, purity: 98.4%) It was dried under N2 pressure for 16 hours. 3690609 b) Step 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide synthesis (7-nitro-2-phenyl-1H-iridol-S-yl)methanol (addition to a reactor and stirred at room temperature, the reactor was cooled to a temperature of 0 °C. 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-nitri0-2-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 °C*ye sogutulmustur ve reaksiyonun iç sicakligi 20 °C°nin altinda tutulurken 1,1- dioksotiyomorfolin hiroklorür ( (8,0 kg) ilave edilmistir. Ilave etme isleminin tamamlanmasindan sonra, reaktörün sicakligi, 50 °C”ye yükseltilmistir, karisim 4 saat boyunca karistirilmistir ve reaksiyon kansimi, 5-(br0mometil)-7-nitro-2-fenil-lH-indol”ün tepe noktasinin %l,0 veya daha azinin gösterilmesi için numune alinmasi suretiyle analiz edildiginde reaksiyon sonlandirilmistir. 36906.09 Reaksiyonun tamamlandiginin dogrulanrnasindan sonra, reaktör, 0 OC”lik bir sicakliga sogutulmustur, buna su (46,0 L) ilave edilmistir, reaksiyon karisimi karistirilmistir ve organik çözücü, indirgenmis basinç altinda damitilmistir. The reaction was confirmed to be complete, the reaction mixture was heated to 0 °C. was cooled and the internal temperature of the reaction was kept below 20 °C while 1,1- dioxothiomorpholine 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-(br0momethyl)-7-nitro-2-phenyl-1H-indole by taking samples to show 1.0% or less of the point When analyzed, the reaction is terminated. 36906.09 After verification that the reaction is complete, the reactor is kept at 0 °C. 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)tiy0m0rfolin 1,1-di0ksit'in kati madde olarak elde edilmesi için tekrar indirgenmis basinç altinda damitilmistir ve sonrasinda filtrelenmistir. Ortaya sentezlenmesi için 16 saat boyunca N2 basinci altinda kumtulmustur. 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 For synthesis, it was crushed under N2 pressure for 16 hours.
Saflastirma için, yukaridaki ham 4-((7-nitr0-2-fenil- 1 H-indol-S- il)metil)tiy0morfolin karisimina ilave edilmistir, karistirilmistir, 120 °Ciye isitilmistir, 2 saat boyunca karistirilmistir ve sonrasinda oda sicakliginda tekrar 2 saat daha karistirilmistir. 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 for another 2 hours at room temperature.
Toluen (60,0 L) ilaveten buna ilave edilmistir ve 2 saat daha karistirilmistir ve sonrasinda çözeltideki bir kati madde filtrelenmistir ve 4-((7-nitr0-2-fenil-1H- indol-S-il)metil)tiyom0rfolin 1,1-di0ksit'in (5,1 kg, verim: %77,0 toplam, 36906.09 saflik: %98,4) sentezlenmesi için toluen (20,0 L) ile yikanmistir. lH NMR (, 7.49 (t, 2.84 (m, 4H). ilave edilmistir ve karistirilmistir ve sonrasinda buna Fe (480 g) ilave edilmistir. Toluene (60.0 L) was further added and stirred for a further 2 hours. Afterwards, a solid in the solution was filtered and 4-((7-nitrO-2-phenyl-1H- indole-S-yl)methyl)thiomorfoline 1,1-dioxide (5.1 kg, yield: 77.0% total, 36906.09 Purity: 98.4%) was washed with toluene (20.0 L) to synthesize it. 1H NMR (, 7.49 (t, 2.84 (m, 4H). was added and mixed, and then Fe (480 g) was added thereto.
Reaktör, 60 C)C”lik bir sicakliga isitilmistir, reaksiyon karisimi, 1 saat veya daha uzun süre boyunca karistirilmistir ve sonrasinda reaksiyon karisimi, 4-((7-nitr0-2- fenil-1H-indol-S-il)metil)tiyomorfolin 1,1-dioksit”in tepe noktasinin %05 veya daha azinin gösterilmesi için analiz edildiginde reaksiyon sonlandirilmistir, Reaksiyonun tamamlandigi dogrulanmistir, THF (3,0 L) reaksiyon karisimina ilave edilmistir ve 10 dakika boyunca karistirilmistir ve sonrasinda selit ile Iiltrelenmistir ve ortaya çikan madde, THF/HzO (1: 1, 3,0 L) ile yikanmistir. 36906119 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, 1,0 L] ile yikanmistir ve sonrasinda 4-((7-amin0-2-fenil-lH-indol-S- sentezlenmesi için 16 saat boyunca N2 basinci altinda kurutulmustur. lH NMR (, 7.48 (t, J= 7.7 Hz, 2.87 (m, 4H). 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 so of the peak of phenyl-1H-indol-S-yl)methyl)thiomorpholine 1,1-dioxide When analyzed to show less, the reaction was terminated, Confirming 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. It was filtered and the resulting material was washed with THF/H2O (1:1, 3.0 L). 36906119 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 1.0 L] and then 4-((7-amine0-2-phenyl-1H-indole-S- It was dried under N2 pressure for 16 hours to synthesize it. 1H NMR (, 7.48 (t, J= 7.7 Hz, 2.87 (m, 4H).
Sonrasinda, 4-((2-fenil-7-((tetrahidro-2H-piran-4-il)amino)- 1 H-indol-S- c) Adimi ile ayni sekilde hazirlanmistir. Örnek ve Karsilastirmali Ömege referansla, 4-(7-amino-2-fenil-lH-indol-S- il)metil)tiyomorfolin 1,1-dioksit7in toplam verimi, 4-(7-amino-2-fenil-1H-indol-S- il)metil)tiyomorfolin 1,1-dioksit°in, mevcut bulusa göre iki adim araciligiyla 7- 36906119 nitro-Z-fenil-lH-iiidol-S-karboksîlik asitten sentezlendigi Ömekte %78,06”ydi (a) fenil-lH-indol-S-il)metil)tiy0m0rf01in 1,1-di0ksit7in bir toplam verimi, bilesigin üç adim araciligiyla sentezlendigi Karsilastiii-nali Örnekte %52,27 (a) Adiminin %83,5, b) Adiminin %77,0 ve c) Adiminin %81,3”ünün çarpildigi deger) olacak sekilde hesaplanmistir. Baska bir deyisle, mevcut bulusun, prosesin basitlestirilmesi sayesinde verimi büyük ölçüde arttirilabildigi dogrulanabilmektedir. Subsequently, 4-((2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indole-S- It is prepared in the same way as step c) With reference to the Example and Comparative Example, 4-(7-amino-2-phenyl-1H-indole-S- Total yield of yl)methyl)thiomorpholine 1,1-dioxide, 4-(7-amino-2-phenyl-1H-indole-S- yl)methyl)thiomorpholine 1,1-dioxide is converted to 7- by two steps according to the present invention. 36906119 It was 78.06% in the sample where it was synthesized from nitro-Z-phenyl-1H-iiidol-S-carboxylic acid (a) An overall yield of phenyl-1H-indol-S-yl)methyl)thioy0m0rf01in 1,1-dioxide, the compound 52.27% (a) in the Comparative Example where it was synthesized through three steps 83.5% of step b) 77.0% of step and 81.3% of step c) value) was calculated as . In other words, present presence, efficiency can be greatly increased by simplifying the process can be verified.
Claims (4)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2021020001T2 true TR2021020001T2 (en) | 2022-02-21 |
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