KR102765208B1 - one-pot synthesis Method of 1,3-Disubstitued indolizines - Google Patents
one-pot synthesis Method of 1,3-Disubstitued indolizines Download PDFInfo
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- KR102765208B1 KR102765208B1 KR1020220090078A KR20220090078A KR102765208B1 KR 102765208 B1 KR102765208 B1 KR 102765208B1 KR 1020220090078 A KR1020220090078 A KR 1020220090078A KR 20220090078 A KR20220090078 A KR 20220090078A KR 102765208 B1 KR102765208 B1 KR 102765208B1
- Authority
- KR
- South Korea
- Prior art keywords
- chemical formula
- carboxylate
- group
- indolizine
- ethyl
- Prior art date
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- 238000005580 one pot reaction Methods 0.000 title claims abstract description 11
- 150000002478 indolizines Chemical class 0.000 title abstract description 20
- 238000000034 method Methods 0.000 title abstract description 18
- 239000000126 substance Substances 0.000 claims description 66
- -1 Ethyl 3-(2-hydroxy-4-(methylsulfonyl)benzoyl)indolizine-1-carboxylate Chemical compound 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- SKUUQIJFNVBDNS-UHFFFAOYSA-N ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate Chemical compound BrC1=CC=C(C(=O)C2=CC(=C3C=CC=CN23)C(=O)OCC)C=C1 SKUUQIJFNVBDNS-UHFFFAOYSA-N 0.000 claims description 4
- RVHKZXLHVXDZKK-UHFFFAOYSA-N ethyl 3-cyanoindolizine-1-carboxylate Chemical compound C(#N)C1=CC(=C2C=CC=CN12)C(=O)OCC RVHKZXLHVXDZKK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 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 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 6
- 150000007513 acids Chemical class 0.000 abstract description 6
- 239000002585 base Substances 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000007800 oxidant agent Substances 0.000 abstract description 6
- 150000001345 alkine derivatives Chemical class 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 150000002739 metals Chemical class 0.000 abstract description 2
- 238000006452 multicomponent reaction Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 239000007787 solid Substances 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- IUDKTVXSXWAKJO-UHFFFAOYSA-N ethyl 2-pyridin-2-ylacetate Chemical compound CCOC(=O)CC1=CC=CC=N1 IUDKTVXSXWAKJO-UHFFFAOYSA-N 0.000 description 3
- CYCGYQHBFZTOIM-UHFFFAOYSA-N ethyl 3-benzoylindolizine-1-carboxylate Chemical compound N12C=CC=CC2=C(C(=O)OCC)C=C1C(=O)C1=CC=CC=C1 CYCGYQHBFZTOIM-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- BPSNETAIJADFTO-UHFFFAOYSA-N 2-pyridinylacetic acid Chemical compound OC(=O)CC1=CC=CC=N1 BPSNETAIJADFTO-UHFFFAOYSA-N 0.000 description 2
- ZTLNVTLAMWXXFF-UHFFFAOYSA-N 3-benzoylindolizine-1-carbonitrile Chemical compound C=1C(C#N)=C2C=CC=CN2C=1C(=O)C1=CC=CC=C1 ZTLNVTLAMWXXFF-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OFUHMRVPTBVQNE-UHFFFAOYSA-N cyclohexyl 2-pyridin-2-ylacetate Chemical compound C1CCCCC1OC(=O)CC1=CC=CC=N1 OFUHMRVPTBVQNE-UHFFFAOYSA-N 0.000 description 2
- XPEJYNHPQYHYAT-UHFFFAOYSA-N diethyl indolizine-1,3-dicarboxylate Chemical compound C1=CC=CC2=C(C(=O)OCC)C=C(C(=O)OCC)N21 XPEJYNHPQYHYAT-UHFFFAOYSA-N 0.000 description 2
- ZOYZKNRJHFMVDV-UHFFFAOYSA-N ethyl 3-(4-chlorobenzoyl)indolizine-1-carboxylate Chemical compound N12C=CC=CC2=C(C(=O)OCC)C=C1C(=O)C1=CC=C(Cl)C=C1 ZOYZKNRJHFMVDV-UHFFFAOYSA-N 0.000 description 2
- LZXJBYXIPLWNMW-UHFFFAOYSA-N ethyl 3-(4-cyanobenzoyl)indolizine-1-carboxylate Chemical compound N12C=CC=CC2=C(C(=O)OCC)C=C1C(=O)C1=CC=C(C#N)C=C1 LZXJBYXIPLWNMW-UHFFFAOYSA-N 0.000 description 2
- BFHSWJLLCVQEHJ-UHFFFAOYSA-N ethyl 3-(4-methoxybenzoyl)indolizine-1-carboxylate Chemical compound N12C=CC=CC2=C(C(=O)OCC)C=C1C(=O)C1=CC=C(OC)C=C1 BFHSWJLLCVQEHJ-UHFFFAOYSA-N 0.000 description 2
- XOBPSATWKFEZIL-UHFFFAOYSA-N ethyl 3-(4-nitrobenzoyl)indolizine-1-carboxylate Chemical compound N12C=CC=CC2=C(C(=O)OCC)C=C1C(=O)C1=CC=C([N+]([O-])=O)C=C1 XOBPSATWKFEZIL-UHFFFAOYSA-N 0.000 description 2
- BEZNZGODEBOELN-UHFFFAOYSA-N ethyl 3-acetylindolizine-1-carboxylate Chemical compound C1=CC=CC2=C(C(=O)OCC)C=C(C(C)=O)N21 BEZNZGODEBOELN-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- NIAATLPQSKGUBG-UHFFFAOYSA-N methyl 2-(5-bromopyridin-2-yl)acetate Chemical compound COC(=O)CC1=CC=C(Br)C=N1 NIAATLPQSKGUBG-UHFFFAOYSA-N 0.000 description 2
- ORAKNQSHWMHCEY-UHFFFAOYSA-N methyl 2-pyridin-2-ylacetate Chemical compound COC(=O)CC1=CC=CC=N1 ORAKNQSHWMHCEY-UHFFFAOYSA-N 0.000 description 2
- HCNIFXRJBYAJEA-UHFFFAOYSA-N methyl 3-benzoylindolizine-1-carboxylate Chemical compound N12C=CC=CC2=C(C(=O)OC)C=C1C(=O)C1=CC=CC=C1 HCNIFXRJBYAJEA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- QWIGLFXNZSUNPE-UHFFFAOYSA-N tert-butyl 2-pyridin-2-ylacetate Chemical compound CC(C)(C)OC(=O)CC1=CC=CC=N1 QWIGLFXNZSUNPE-UHFFFAOYSA-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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- MQVISALTZUNQSK-UHFFFAOYSA-N 2-pyridin-2-ylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CC1=CC=CC=N1 MQVISALTZUNQSK-UHFFFAOYSA-N 0.000 description 1
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229940115480 Histamine H3 receptor antagonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- OVLSJMKZDXKLEM-UHFFFAOYSA-N benzyl 2-pyridin-2-ylacetate Chemical compound C=1C=CC=CC=1COC(=O)CC1=CC=CC=N1 OVLSJMKZDXKLEM-UHFFFAOYSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- OQQYMAOGIWMABG-UHFFFAOYSA-N ethyl 2-quinolin-2-ylacetate Chemical compound C1=CC=CC2=NC(CC(=O)OCC)=CC=C21 OQQYMAOGIWMABG-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
본 발명은 1,3-치환된 인돌리진의 원팟 합성 방법에 관한 것으로, 원팟 다성분 반응을 통해 다양한 인돌리진 유도체를 산, 염기, 촉매 및 산화제 없이 합성할 수 있다. 인돌리진 합성을 위한 이 새로운 방법은 금속, 산화제 및 값비싼 알킨 없이 생물학적 및 물리화학적 중요한 인돌리진 유도체를 합성하는 간단하고 친환경적인 경로를 제공한다.The present invention relates to a one-pot synthesis method of 1,3-substituted indolizines, which can synthesize various indolizine derivatives through a one-pot multicomponent reaction without acids, bases, catalysts and oxidizing agents. This new method for indolizine synthesis provides a simple and environmentally friendly route for synthesizing biologically and physicochemically important indolizine derivatives without metals, oxidizing agents and expensive alkynes.
Description
본 발명은 1,3-치환된 인돌리진의 원팟 합성 방법에 관한 것이다.The present invention relates to a one-pot synthesis method of 1,3-substituted indolizines.
미국 FDA 승인 약물의 50% 이상이 질소 헤테로고리 시스템을 포함한다. 질소 헤테로고리 화합물 중에서 인돌리진은 주요 구성 성분인 인돌리진 스캐폴드가 다양한 범위의 생물학적 활성을 가지고 있기 때문에, 많은 천연물 및 의약품에서 발견되는 기본적인 구조적 모티프이다. 구조의 관점에서, 인돌리진 코어는 방향족성, 평면성, 생리학적으로 적합한 극성, 형광 및 양성자화 부위를 포함하여 매우 조밀하고 많은 흥미로운 특성을 특징으로 하는 헤테로고리 π-전자가 풍부한 화합물의 부류에 잘 맞다. 또한, 인돌리진 유도체는 혈관 내피 성장 인자(VEGF)의 잠재적 억제제로도 사용될 수 있으며 다양한 생물학적 활성뿐만 아니라 포스포디에스테라제 V 억제제, 히스타민 H3 수용체 길항제를 나타내는 것으로 나타났다. 인돌리진 유도체는 눈에 띄는 광-물리적 특성을 위해 염료감응 태양전지(DSSC) 또는 유기발광소자(OLED)용 염료로도 사용할 수 있다. 이러한 형광 물질은 생명 현상의 탐색, 질병 진단 및 유해 물질 검출에 널리 사용될 수 있다. 인돌리진 유도체는 의약 및 재료 화학 분야에서 광범위하게 유용하다. 일부 인돌리진 유도체는 또한 항염, 항암, 항산화, ACE 억제제, 아로마타제 억제제, 혈당강하 활성과 같은 생물학적 활성을 갖는 것으로 보고되었다. 다른 것들은 중추신경계 억제 활성, 항아세틸콜린, 5HT3 수용체 길항제, 에스트로겐 수용체 결합, 항균 및 진통 활성으로 보고되었다. 인돌리진의 자연적, 생물학적 및 물리화학적 특성으로 인해 합성에 대한 광범위한 연구가 진행되고 있다. 연구자들은 인돌리진의 구조와 활성 관계를 이용하여 새로운 항암제를 개발하기 위해 점점 다양한 시도를 하고 있습니다.More than 50% of US FDA approved drugs contain nitrogen heterocycle systems. Among nitrogen heterocycles, indolizine is a fundamental structural motif found in many natural products and pharmaceuticals because its major constituent, the indolizine scaffold, has a wide range of biological activities. From a structural standpoint, the indolizine core fits well into the class of heterocyclic π-electron-rich compounds that are characterized by a wide range of interesting properties, including aromaticity, planarity, physiologically relevant polarity, fluorescence, and protonation sites. In addition, indolizine derivatives can be used as potential inhibitors of vascular endothelial growth factor (VEGF) and have been shown to exhibit various biological activities as well as phosphodiesterase V inhibitors and histamine H3 receptor antagonists. Indolizine derivatives can also be used as dyes for dye-sensitized solar cells (DSSCs) or organic light-emitting diodes (OLEDs) for their remarkable photo-physical properties. These fluorescent substances can be widely used in the exploration of life phenomena, disease diagnosis, and detection of harmful substances. Indolizine derivatives are widely useful in the fields of pharmaceutical and material chemistry. Some indolizine derivatives have also been reported to have biological activities such as anti-inflammatory, anticancer, antioxidant, ACE inhibitor, aromatase inhibitor, and hypoglycemic activity. Others have been reported to have central nervous system inhibitory activity, antiacetylcholinergic, 5HT3 receptor antagonist, estrogen receptor binding, antimicrobial, and analgesic activities. Due to the natural, biological, and physicochemical properties of indolizines, extensive research has been conducted on their synthesis. Researchers are making increasingly diverse attempts to develop new anticancer agents by utilizing the structure-activity relationship of indolizines.
현재 인돌리진을 합성하는 다양한 방법이 발견되었으며, 산, 염기, 촉매, 산화제, 고가의 알킨을 이용한 합성 방법이 사용되고 있다. 대부분 인돌리진은 피리딘 고리 또는 피롤 고리 형성의 두 가지 접근 방식을 사용하여 합성된다. 이 두 가지 방법 중에서 피리딘 유도체를 출발 물질로 사용하여 피롤 고리를 형성하는 방법이 있다.Currently, various methods for synthesizing indolizines have been discovered, and synthetic methods using acids, bases, catalysts, oxidizing agents, and expensive alkynes are used. Most indolizines are synthesized using two approaches: forming a pyridine ring or a pyrrole ring. Among these two methods, there is a method that uses a pyridine derivative as a starting material to form a pyrrole ring.
현재까지 인돌리진의 합성은 여러 단계로 구성되거나 산, 염기, 산화제 또는 촉매를 사용합니다. 대부분의 반응은 비용이 많이 드는 반응 파트너로 알킨 또는 알켄을 포함하고 합성이 복잡합니다. 다양한 생물학적 활성 및 물질 화학에서 인돌리진의 보급을 고려할 때 인돌리진의 강력한 합성 방법은 여전히 개발되어야 합니다. 우리가 아는 한, 지금까지 촉매(금속 또는 유기) 또는 산 또는 염기의 사용이 배제된 인돌리진의 합성에 대한 보고가 없습니다. 여기에서 우리는 촉매(금속 또는 유기물) 또는 산 또는 염기를 사용하지 않고 3성분 원 포트(one-pot) 반응을 통해 인돌리진을 합성하는 새로운 방법을 개발했습니다.To date, the synthesis of indolizines consists of several steps or uses acids, bases, oxidizing agents, or catalysts. Most reactions involve alkynes or alkenes as costly reaction partners, and the synthesis is complex. Considering the prevalence of indolizines in various biological activities and material chemistry, robust synthetic methods for indolizines still need to be developed. To the best of our knowledge, there has been no report on the synthesis of indolizines so far, excluding the use of catalysts (metallic or organic) or acids or bases. Here, we develop a novel method for the synthesis of indolizines via a three-component one-pot reaction without using catalysts (metallic or organic) or acids or bases.
본 발명자들은 상기한 범위에 적용될 수 있는 유용한 구조인 인돌리진을 쉽게 합성할 수 있는 원팟 합성 방법을 도출하였다.The present inventors have developed a one-pot synthesis method that can easily synthesize indolizine, a useful structure that can be applied in the above-mentioned range.
본 발명은 전술한 종래 기술의 문제점을 해결하기 위한 것으로, 간단하고 경제성이 우수한 인돌리진 합성 방법을 제공하는 것을 목적으로 한다.The present invention is intended to solve the problems of the above-mentioned prior art, and aims to provide a simple and economical method for synthesizing indolizine.
상기와 같은 본 발명의 목적을 달성하기 위하여,In order to achieve the above purpose of the present invention,
디메틸포름아미드(Dimethylformamide, DMF)를 용매로 하여, 하기 화학식 1 및 2를 반응시켜 하기 화학식 7의 화합물을 얻고,By reacting the following chemical formulas 1 and 2 using dimethylformamide (DMF) as a solvent, a compound of the following chemical formula 7 is obtained.
하기 화학식 7의 화합물을 하기 화학식 3 의 화합물과 반응시켜 하기 화학식 4의 화합물을 얻는 것을 포함하는 인돌리진의 제조 방법을 제공한다.A method for producing indolizine is provided, which comprises reacting a compound of the following chemical formula 7 with a compound of the following chemical formula 3 to obtain a compound of the following chemical formula 4.
[화학식 1][Chemical Formula 1]
[화학식 2][Chemical formula 2]
[화학식 7][Chemical formula 7]
[화학식 3][Chemical Formula 3]
[화학식 4][Chemical Formula 4]
상기 화학식에서,In the above chemical formula,
R1은 또는 시아노기이고,R1 is or cyano group,
R2는 C1-C6 알킬기, C4-C6 사이클로알킬기, 또는 하나 이상의 C1-C4 알콕시기로 치환되거나 비 치환된 벤질기이며,R2 is a C1-C6 alkyl group, a C4-C6 cycloalkyl group, or a benzyl group which is unsubstituted or substituted with one or more C1-C4 alkoxy groups,
R6는 또는 시아노기이고,R6 is or cyano group,
R3는 , , C1-C6 알킬기, C1-C4 알콕시기또는 이고,R3 is , , C1-C6 alkyl group, C1-C4 alkoxy group or And,
R4 및 R5는 각각 독립적으로 수소 원자, 할로겐 원자, 하이드록시기, C1-C6 알킬기, C1-C6 알콕시기, 니트로기, C1-C4 할로알킬기, 시아노기 또는 이며,R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a C1-C4 haloalkyl group, a cyano group or And,
X는 할로겐 원자이고,X is a halogen atom,
Y 및 Z는 각각 독립적으로는 수소 원자 또는 할로겐 원자; 이거나,Y and Z are each independently a hydrogen atom or a halogen atom; or
Y 및 Z는 이들이 결합된 탄소 원자가 속한 벤젠 고리와 함께 13-원 삼환식 고리(tricyclic ring)를 형성한다.Y and Z form a 13-membered tricyclic ring together with the benzene ring to which they are attached.
또한, 본 발명은 하기 화학식 4로 표시되는 화합물 또는 이의 염인 화합물을 제공한다.In addition, the present invention provides a compound represented by the following chemical formula 4 or a salt thereof.
[화학식 4][Chemical Formula 4]
상기 화학식 4에서,In the above chemical formula 4,
상기 R1, R6, Y 및 Z는 상기 언급된 바와 같다.The above R1, R6, Y and Z are as mentioned above.
또한, 본 발명은 하기 화학식 7로 표시되는 화합물 또는 이의 염인 화합물을 제공한다.In addition, the present invention provides a compound represented by the following chemical formula 7 or a salt thereof.
[화학식 7][Chemical formula 7]
상기 화학식 7에서,In the above chemical formula 7,
상기 R1, Y 및 Z는 제 1항과 같다.The above R1, Y and Z are as in paragraph 1.
본 발명에 따르면, 상기 합성 방법으로, one-pot 다성분 반응을 통해 다양한 인돌리진 유도체를 산, 염기, 촉매 및 산화제 없이 합성할 수 있다. 인돌리진 합성을 위한 이 새로운 방법은 금속, 산화제 및 값비싼 알킨 없이 생물학적 및 물리화학적 중요한 인돌리진 유도체를 합성하는 간단하고 친환경적인 경로를 제공한다.According to the present invention, by the above synthetic method, various indolizine derivatives can be synthesized without acids, bases, catalysts and oxidizing agents through a one-pot multicomponent reaction. This new method for indolizine synthesis provides a simple and environmentally friendly route for synthesizing biologically and physicochemically important indolizine derivatives without metals, oxidizing agents and expensive alkynes.
본 발명의 효과는 상기한 효과로 한정한 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the composition of the invention described in the detailed description or claims of the present invention.
이하에서는 첨부한 도면을 참조하여 본 발명을 설명하기로 한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며, 따라서 여기에서 설명하는 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described with reference to the attached drawings. However, the present invention can be implemented in various different forms and therefore is not limited to the embodiments described herein.
어떤 부분이 어떤 구성요소를 포함한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 구비할 수 있다는 것을 의미한다.When a part is said to include a certain component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.
본 명세서에 달리 정의되어 있지 않으면, 사용된 모든 기술 및 과학 용어는 당업계에 통상의 기술자가 통상적으로 이해하는 바와 같은 의미를 가진다.Unless otherwise defined herein, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art.
본 명세서에 포함되는 용어를 포함하는 다양한 과학적 사전이 잘 알려져 있고, 당업계에서 이용가능하다. 본 명세서에 설명된 것과 유사 또는 등가인 임의의 방법 및 물질이 본원의 실행 또는 시험에 사용되는 것으로 발견되나, 몇몇 방법 및 물질이 설명되어 있다. 당업자가 사용하는 맥락에 따라, 다양하게 사용될 수 있기 때문에, 특정 방법학, 프로토콜 및 시약으로 본 발명이 제한되는 것은 아니다.Various scientific dictionaries containing terms included in this specification are well known and available in the art. Any methods and materials similar or equivalent to those described herein are found to be useful in the practice or testing of the present invention, but some methods and materials are described. The invention is not limited to specific methodologies, protocols, and reagents, as these can be used in a variety of ways depending on the context in which they are used by those skilled in the art.
본 발명은 디메틸포름아미드(Dimethylformamide, DMF)를 용매로 하여, 하기 화학식 1 및 2를 반응시켜 하기 화학식 7의 화합물을 얻고, 하기 화학식 7의 화합물을 하기 화학식 3 의 화합물과 반응시켜 하기 화학식 4의 화합물을 얻는 것을 포함하는 인돌리진의 제조 방법을 제공할 수 있다.The present invention can provide a method for producing indolizine, which comprises reacting chemical formulas 1 and 2 below using dimethylformamide (DMF) as a solvent to obtain a compound of chemical formula 7 below, and reacting the compound of chemical formula 7 below with a compound of chemical formula 3 below to obtain a compound of chemical formula 4 below.
[화학식 1][Chemical Formula 1]
[화학식 2][Chemical formula 2]
[화학식 7][Chemical formula 7]
[화학식 3][Chemical Formula 3]
[화학식 4][Chemical Formula 4]
상기 화학식에서,In the above chemical formula,
R1은 또는 시아노기이고,R1 is or cyano group,
R2는 C1-C6 알킬기, C4-C6 사이클로알킬기, 또는 하나 이상의 C1-C4 알콕시기로 치환되거나 비 치환된 벤질기이며,R2 is a C1-C6 alkyl group, a C4-C6 cycloalkyl group, or a benzyl group which is unsubstituted or substituted with one or more C1-C4 alkoxy groups,
R6는 또는 시아노기이고,R6 is or cyano group,
R3는 , , C1-C6 알킬기, C1-C4 알콕시기 또는 이고,R3 is , , C1-C6 alkyl group, C1-C4 alkoxy group or And,
R4 및 R5는 각각 독립적으로 수소 원자, 할로겐 원자, 하이드록시기, C1-C6 알킬기, C1-C6 알콕시기, 니트로기, C1-C4 할로알킬기, 시아노기 또는 이며,R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a C1-C4 haloalkyl group, a cyano group or And,
X는 할로겐 원자이고,X is a halogen atom,
Y 및 Z는 각각 독립적으로는 수소 원자 또는 할로겐 원자; 이거나,Y and Z are each independently a hydrogen atom or a halogen atom; or
Y 및 Z는 이들이 결합된 탄소 원자가 속한 벤젠 고리와 함께 13-원 삼환식 고리(tricyclic ring)를 형성한다.Y and Z form a 13-membered tricyclic ring together with the benzene ring to which they are attached.
여기에서, "알킬"은 일반적으로 명시된 수의 탄소원자 (예컨대, 1 내지 12개의 탄소원자)를 갖는 선형 및 분지형 포화 탄화수소 기를 의미한다. 알킬기의 예는 제한 없이 메틸, 에틸, n-프로필, 이소프로필, n-부틸, sec-부틸, 이소부틸, tert-부틸, n-펜틸, n-헥실 및 n-헵틸 등을 포함한다. 알킬은 부착이 원자가 필요조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기(parent group) 또는 기재(substrate)에 부착될 수 있다. 마찬가지로, 알킬기 또는 알케닐기는, 부착이 원자가 요구조건을 위반하지 않는다면 하나 이상의 비수소 치환기를 포함할 수 있다.Herein, "alkyl" generally means a linear or branched saturated hydrocarbon group having a specified number of carbon atoms (e.g., 1 to 12 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl. An alkyl may be attached to the parent group or substrate at any ring atom, provided that such attachment does not violate valence requirements. Likewise, an alkyl or alkenyl group may include one or more non-hydrogen substituents, provided that such attachment does not violate valence requirements.
"할로알킬"은 하나 이상의 할로겐 원자로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)를 의미할 수 있다. 할로알킬의 예는 제한 없이 하나 이상의 할로겐 원자, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소뷰틸 및 N-부틸 등을 포함한다."Haloalkyl" can mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halogen atoms. Examples of haloalkyl include, without limitation, methyl, ethyl, propyl, isopropyl, isobutyl, and N-butyl, all independently substituted with one or more halogen atoms, such as F, Cl, Br, or I.
"사이클로알킬"은 명시된 수의 탄소 원자를 갖는 고리형 탄화수소 기를 의미한다. 사이클로 알킬기의 예는 제한 없이 사이클로프로필, 사이클로뷰틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함한다."Cycloalkyl" means a cyclic hydrocarbon group having the specified number of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
“알콕시”는 산소와 결합된 알킬기이다. (R-O)알콕시기의 범위는 매우 크며, 메톡시, 에톡시, 프로폭시, 부톡시, 펜틸옥시, 헥실옥시가 있다.“Alkoxy” is an alkyl group bonded to oxygen. The range of (R-O) alkoxy groups is very large, including methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.
"할로겐"은 불소, 염소, 브롬, 아이오딘 등일 수 있다."Halogen" can be fluorine, chlorine, bromine, iodine, etc.
본 발명의 또 다른 구현 예로서,As another embodiment of the present invention,
상기 화학식 4에서,In the above chemical formula 4,
Y 및 Z가 수소일 때,When Y and Z are hydrogen,
R1은 , , , , , , , , , , 또는 이고,R1 is , , , , , , , , , , or And,
R6는 또는 이며,R6 is or And,
R3는 -CH3, , , , , , , , , , , , , , 또는 일 수 있다.R3 is -CH 3 , , , , , , , , , , , , , , or It could be.
본 발명의 또 다른 구현 예로서, As another embodiment of the present invention,
상기 화학식 4에서,In the above chemical formula 4,
Y 및 Z가 각각 할로겐 원자 및 수소 원자일 때,When Y and Z are halogen atoms and hydrogen atoms, respectively,
R1은이고,R1 is And,
R6는 이며,R6 is And,
R3는 일 수 있다.R3 is It could be.
본 발명의 또 다른 구현 예로서, As another embodiment of the present invention,
상기 화학식 4에서,In the above chemical formula 4,
Y 및 Z는 이들이 결합된 탄소 원자가 속한 벤젠 고리와 함께 13-원 삼환식 고리(tricyclic ring)를 형성할 때,When Y and Z form a 13-membered tricyclic ring with the benzene ring to which they are attached,
R1은 이고,R1 is And,
R6는 이며,R6 is And,
R3는 일 수 있다.R3 is It could be.
본 발명의 또 다른 구현 예로서, As another embodiment of the present invention,
상기 화학식 4는 하기 화합물 중 하나일 수 있다.The above chemical formula 4 may be one of the following compounds.
본 발명의 또 다른 구현 예로서, 제 1 단계 반응은, 70 내지 150℃에서 3 내지 5시간 교반하여 수행될 수 있다.As another embodiment of the present invention, the first step reaction can be performed by stirring at 70 to 150°C for 3 to 5 hours.
본 발명의 또 다른 구현 예로서, 제 2 단계 반응은, 50 내지 70℃에서 3 내지 5시간 교반하여 수행될 수 있다.As another embodiment of the present invention, the second step reaction can be performed by stirring at 50 to 70°C for 3 to 5 hours.
본 발명의 또 다른 구현 예로서, 제 1 단계; 및 제 2 단계; 반응은 원팟(one-pot)반응으로 수행될 수 있다.As another embodiment of the present invention, the first step; and the second step; reactions can be performed as a one-pot reaction.
본 발명에서 "원팟(one-pot) 반응"은 반응물이 하나의 반응기에서 연속적인 화학 반응을 일으켜 결과물을 얻는 반응을 말하며, 중간 화합물의 분리 또는 정제 과정을 거치지 않을 수 있는 장점이 있다.In the present invention, the “one-pot reaction” refers to a reaction in which reactants undergo continuous chemical reactions in one reactor to obtain a result, and has the advantage of not having to go through a process of separating or purifying intermediate compounds.
본 발명은 하기 화학식 4로 표시되는 화합물 또는 이의 염인 화합물을 제공할 수 있다.The present invention can provide a compound represented by the following chemical formula 4 or a salt thereof.
[화학식 4][Chemical Formula 4]
상기 화학식 4에서,In the above chemical formula 4,
상기 R1, R6, Y 및 Z는 제 1항과 같다.The above R1, R6, Y and Z are as in paragraph 1.
본 발명의 또 다른 구현 예로서,As another embodiment of the present invention,
상기 화학식 4에서,In the above chemical formula 4,
R1은 또는 시아노기이고,R1 is or cyano group,
R2는 C1-C6 알킬기, C4-C6 사이클로알킬기, 또는 하나 이상의 C1-C4 알콕시기로 치환되거나 비 치환된 벤질기이며,R2 is a C1-C6 alkyl group, a C4-C6 cycloalkyl group, or a benzyl group which is unsubstituted or substituted with one or more C1-C4 alkoxy groups,
R6는 또는 시아노기이고,R6 is or cyano group,
R3는 -CH3, , 또는 이고,R3 is -CH 3 , , or And,
R4 및 R5는 각각 독립적으로 수소 원자, 할로겐 원자, 하이드록시기, C1-C6 알콕시기, C1-C4 할로알킬기, 시아노기 또는 이며,R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, a cyano group or And,
Y 및 Z는 각각 독립적으로는 수소 원자 또는 할로겐 원자; 일 수 있다.Y and Z can each independently be a hydrogen atom or a halogen atom;
본 발명의 또 다른 구현 예로서, 상기 화학식 4는 하기 화합물 중 하나일 수 있다;As another embodiment of the present invention, the chemical formula 4 may be one of the following compounds;
, , , , , , , , , , , , , . , , , , , , , , , , , , , .
본 발명의 또 다른 구현 예로서, 상기 화학식 4의 화합물은,As another embodiment of the present invention, the compound of the chemical formula 4 is
에틸 3-(2-하이드록시-4-(메틸술포닐)벤조일)인돌리진-1-카르복실레이트;Ethyl 3-(2-hydroxy-4-(methylsulfonyl)benzoyl)indolizine-1-carboxylate;
에틸 3-(4-(트리플루오로메틸)벤조일)인돌리진-1-카르복실레이트;Ethyl 3-(4-(trifluoromethyl)benzoyl)indolizine-1-carboxylate;
에틸 3-(4-브로모벤조일)인돌리진-1-카르복실레이트;Ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate;
에틸 3-(2-플루오로벤조일)인돌리진-1-카르복실레이트;Ethyl 3-(2-fluorobenzoyl)indolizine-1-carboxylate;
에틸 3-(2,4-디하이드록시벤조일)인돌리진-1-카르복실레이트;Ethyl 3-(2,4-dihydroxybenzoyl)indolizine-1-carboxylate;
에틸 3-(4-하이드록시벤조일)인돌리진-1-카복실레이트;Ethyl 3-(4-hydroxybenzoyl)indolizine-1-carboxylate;
에틸 3-(2-나프토일)인돌리진-1-카르복실레이트;Ethyl 3-(2-naphthoyl)indolizine-1-carboxylate;
프로필 3-벤조일인돌리진-1-카복실레이트;Profile 3-benzoyl indolizine-1-carboxylate;
알릴 3-벤조일인돌리진-1-카르복실레이트;Allyl 3-benzoyl indolizine-1-carboxylate;
시클로헥실 3-벤조일인돌리진-1-카르복실레이트;Cyclohexyl 3-benzoylindolezine-1-carboxylate;
벤질 3-벤조일인돌리진-1-카르복실레이트;Benzyl 3-benzoylindolezine-1-carboxylate;
3,4,5-트리메톡시벤질 3-벤조일인돌리진-1-카르복실레이트;3,4,5-Trimethoxybenzyl 3-benzoylindolezine-1-carboxylate;
메틸 3-벤조일-6-브로모인돌리진-1-카르복실레이트Methyl 3-benzoyl-6-bromoindolizine-1-carboxylate
에틸 3-시아노인돌리진-1-카르복실레이트; 및Ethyl 3-cyanoindolizine-1-carboxylate; and
메틸 3-(3-에톡시-3-옥소프로파노일)인돌리진-1-카복실레이트일 수 있다.It may be methyl 3-(3-ethoxy-3-oxopropanoyl)indolizine-1-carboxylate.
본 발명은 하기 화학식 7로 표시되는 화합물 또는 이의 염인 화합물을 제공할 수 있다.The present invention can provide a compound represented by the following chemical formula 7 or a salt thereof.
[화학식 7][Chemical formula 7]
상기 화학식 7에서,In the above chemical formula 7,
상기 R1, Y 및 Z는 제 1항과 같다.The above R1, Y and Z are as in paragraph 1.
또한, 본 발명에서의 인돌리진의 제조 방법은 하기 반응식 1에 표시된 바와 같이, 화학식 1 및 2를 DMF에 녹인 후 70 내지 150℃에서 3 내지 5시간 교반하는 단계 (단계1);In addition, the method for producing indolizine in the present invention comprises the steps of dissolving chemical formulas 1 and 2 in DMF and stirring at 70 to 150°C for 3 to 5 hours (step 1), as shown in the following reaction scheme 1;
상기 단계 1에서 제조된 화학식 7 및 화학식3을 50 내지 70℃에서 3 내지 5시간을 교반하는 단계 (단계 2)를 포함하는 방법으로 원팟 반응을 통하여 화학식 4의 인돌리진 화합물을 제조할 수 있으나, 이 예에 한정되는 것은 아니다.The indolizine compound of chemical formula 4 can be prepared through a one-pot reaction by a method including a step (step 2) of stirring the chemical formulas 7 and 3 prepared in step 1 at 50 to 70° C. for 3 to 5 hours, but is not limited to this example.
[반응식 1][Reaction Formula 1]
이하, 본 발명의 이해를 돕기 위하여 바람직한 제조예 및 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred manufacturing examples and examples are presented to help understand the present invention. However, the following examples are provided only to help understand the present invention more easily, and the content of the present invention is not limited by the following examples.
<제조예> 2-(피리딘-2-일) 아세테이트(1)의 합성을 위한 일반 절차:<Preparation Example> General procedure for the synthesis of 2-(pyridin-2-yl) acetate (1):
트리에틸 아민(2 eqv) 및 1,3-디시클로헥실카르보디이미드(1eqv), 4-(디메틸아미노)피리딘(0.05eqv)을 디클로로메탄(20mL) 중 2-피리딜아세트산 염산염(1eqv) 및 상응하는 알코올(2.0eqv)의 현탁액에 첨가했다. 실온에서 반응 혼합물을 밤새 교반되도록 두었다. 반응 혼합물을 여과하여 1,3-디시클로헥실우레아를 제거하였다. 여액을 물(3 x 10 mL), 중탄산나트륨 용액(10 mL)으로 세척한 다음 MgSO4로 건조하고 감압 하에 농축하였다. 조 생성물을 실리카겔을 통한 플래시 컬럼 크로마토그래피(용리액 = 헥산:에틸아세테이트)로 정제하여 중간체를 수득하였다.Triethyl amine (2 eqv) and 1,3-dicyclohexylcarbodiimide (1 eqv), 4-(dimethylamino)pyridine (0.05 eqv) were added to a suspension of 2-pyridylacetic acid hydrochloride (1 eqv) and the corresponding alcohol (2.0 eqv) in dichloromethane (20 mL). The reaction mixture was left to stir overnight at room temperature. The reaction mixture was filtered to remove 1,3-dicyclohexyl urea. The filtrate was washed with water (3 x 10 mL) and sodium bicarbonate solution (10 mL), dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography through silica gel (eluent = hexane:ethyl acetate) to give the intermediate.
에틸 2-(피리딘-2-일)아세테이트 (1a): 상업적 입수 가능 Ethyl 2-(pyridin-2-yl)acetate (1a): commercially available
메틸 2-(피리딘-2-일)아세테이트 (1b): 상업적 입수 가능 Methyl 2-(pyridin-2-yl)acetate (1b): commercially available
이소프로필 2-(피리딘-2-일) 아세테이트 (1c)Isopropyl 2-(pyridin-2-yl) acetate (1c)
황색 오일 (233mg, 75% yield), 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.5 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.20 - 7.13 (m, 1H), 5.03 (dt, J = 12.3, 6.1 Hz, 1H), 3.79 (s, 2H), 1.21 (d, J = 6.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 170.2, 154.6, 149.4, 136.5, 123.8, 122, 68.4, 44.2, 36.4, 21.7.Yellow oil (233 mg, 75% yield), 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.5 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.20 - 7.13 (m, 1H), 5.03 (dt, J = 12.3, 6.1 Hz, 1H), 3.79 (s, 2H), 1.21 (d, J = 6.2 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 170.2, 154.6, 149.4, 136.5, 123.8, 122, 68.4, 44.2, 36.4, 21.7.
프로필 2-(피리딘-2-일)아세테이트 (1d)Profile 2-(pyridin-2-yl)acetate (1d)
황색 오일 (190mg, 61% yield), 1 H NMR (600 MHz, CDCl3) δ 8.52 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.61 (td, J = 7.7, 1.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.14 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.81 (s, 2H), 1.61 (h, J = 7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 170.8, 154.6, 149.5, 136.6, 123.9, 122.1, 66.7, 44.1, 22, 10.4.Yellow oil (190 mg, 61% yield), 1H NMR (600 MHz, CDCl3) δ 8.52 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.61 (td, J = 7.7, 1.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.14 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.81 (s, 2H), 1.61 (h, J = 7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 170.8, 154.6, 149.5, 136.6, 123.9, 122.1, 66.7, 44.1, 22, 10.4.
터트-부틸 2-(피리딘-2-일) 아세테이트 (1e)tert-Butyl 2-(pyridin-2-yl) acetate (1e)
황색 오일 (142mg, 46% yield), 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 3.9 Hz, 1H), 7.68 - 7.58 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.20 - 7.12 (m, 1H), 3.75 (s, 2H), 1.44 (s, 9H), 13 C NMR (151 MHz, CDCl3) δ 170.1, 155.1, 149.5, 136.6, 123.9, 122, 81.3, 45.2, 28.1.Yellow oil (142 mg, 46% yield), 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 3.9 Hz, 1H), 7.68 - 7.58 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.20 - 7.12 (m, 1H), 3.75 (s, 2H), 1.44 (s, 9H), 13 C NMR (151 MHz, CDCl3) δ 170.1, 155.1, 149.5, 136.6, 123.9, 122, 81.3, 45.2, 28.1.
프로프-2-인-1-일 2-(피리딘-2-일)아세테이트 (1f)Prop-2-yn-1-yl 2-(pyridin-2-yl)acetate (1f)
황색 오일 (912mg, 90% yield). 1 H NMR (600 MHz, CDCl3) δ 8.56 - 8.53 (m, 1H), 7.65 (tq, J = 7.7, 1.6 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.20 - 7.17 (m, 1H), 4.72 (dt, J = 2.5, 1.3 Hz, 2H), 3.89 (s, 2H), 2.49 - 2.43 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 169.9, 153.9, 149.7, 136.8, 124, 122.3, 77.5, 75.2, 52.5, 43.6.Yellow oil (912 mg, 90% yield). 1 H NMR (600 MHz, CDCl3) δ 8.56 - 8.53 (m, 1H), 7.65 (tq, J = 7.7, 1.6 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.20 - 7.17 (m, 1H), 4.72 (dt, J = 2.5, 1.3 Hz, 2H), 3.89 (s, 2H), 2.49 - 2.43 (m, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 169.9, 153.9, 149.7, 136.8, 124, 122.3, 77.5, 75.2, 52.5, 43.6.
알릴 2-(피리딘-2-일)아세테이트 (1g)Allyl 2-(pyridin-2-yl)acetate (1g)
황색 오일 (210mg, 41% yield). 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.35 - 7.22 (m, 1H), 7.22 - 7.11 (m, 1H), 5.90 (ddt, J = 16.2, 10.5, 5.3 Hz, 1H), 5.27 (d, J = 17.2 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 4.62 (d, J = 4.4 Hz, 2H), 3.87 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 170.3, 154.3, 149.5, 136.6, 131.9, 123.9, 122.1, 118.3, 65.6, 43.9.Yellow oil (210mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.35 - 7.22 (m, 1H), 7.22 - 7.11 (m, 1H), 5.90 (ddt, J = 16.2, 10.5, 5.3 Hz, 1H), 5.27 (d, J = 17.2 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 4.62 (d, J = 4.4 Hz, 2H), 3.87 (s, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 170.3, 154.3, 149.5, 136.6, 131.9, 123.9, 122.1, 118.3, 65.6, 43.9.
사이클로헥실 2-(피리딘-2-일)아세테이트 (1h)Cyclohexyl 2-(pyridin-2-yl)acetate (1h)
황색 (543mg, 86% yield). 1 H NMR (600 MHz, CDCl3) δ 8.52 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.61 (td, J = 7.7, 1.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.14 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 4.78 (ddd, J = 13.0, 9.0, 3.9 Hz, 1H), 3.80 (s, 2H), 1.82 - 1.78 (m, 2H), 1.64 (dt, J = 13.3, 4.4 Hz, 2H), 1.50 - 1.45 (m, 1H), 1.42 - 1.36 (m, 2H), 1.34 - 1.27 (m, 2H), 1.21 (ddd, J = 13.0, 6.6, 3.4 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 170.2, 154.8, 149.5, 136.6, 123.9, 122, 73.3, 44.4, 31.5, 25.4, 23.7.Yellow (543 mg, 86% yield). 1H NMR (600 MHz, CDCl3) δ 8.52 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.61 (td, J = 7.7, 1.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.14 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 4.78 (ddd, J = 13.0, 9.0, 3.9 Hz, 1H), 3.80 (s, 2H), 1.82 - 1.78 (m, 2H), 1.64 (dt, J = 13.3, 4.4 Hz, 2H), 1.50 - 1.45 (m, 1H), 1.42 - 1.36 (m, 2H), 1.34 - 1.27 (m, 2H), 1.21 (ddd, J = 13.0, 6.6, 3.4 Hz, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 170.2, 154.8, 149.5, 136.6, 123.9, 122, 73.3, 44.4, 31.5, 25.4, 23.7.
벤질 2-(피리딘-2-일)아세테이트 (1i)Benzyl 2-(pyridin-2-yl)acetate (1i)
황색 (482mg, 73% yield). 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 3.9 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.33 (s, 4H), 7.29 - 7.25 (m, 2H), 7.20 - 7.17 (m, 1H), 5.17 (s, 2H), 3.90 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 170.5, 154.3, 149.5, 136.6, 135.7, 128.5, 128.2, 123.9, 122.1, 66.8, 43.9.Yellow (482mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 3.9 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.33 (s, 4H), 7.29 - 7.25 (m, 2H), 7.20 - 7.17 (m, 1H), 5.17 (s, 2H), 3.90 (s, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 170.5, 154.3, 149.5, 136.6, 135.7, 128.5, 128.2, 123.9, 122.1, 66.8, 43.9.
3,4,5-트리메톡시벤질 2-(피리딘-2-일)아세테이트 (1j)3,4,5-Trimethoxybenzyl 2-(pyridin-2-yl)acetate (1j)
황색 오일 (562mg, 77% yield). 1 H NMR (600 MHz, CDCl3) δ 8.55 - 8.53 (m, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.17 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.52 (s, 2H), 5.08 (s, 2H), 3.89 (s, 2H), 3.81 - 3.80 (m, 9H). 13 C NMR (151 MHz, CDCl3) δ 170.5, 154.4, 153.4, 149.6, 137.9, 136.7, 131.4, 124, 122.3, 105.3, 67, 60.9, 56.2, 44.Yellow oil (562 mg, 77% yield). 1H NMR (600 MHz, CDCl3) δ 8.55 - 8.53 (m, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.17 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.52 (s, 2H), 5.08 (s, 2H), 3.89 (s, 2H), 3.81 - 3.80 (m, 9H). 13 C NMR (151 MHz, CDCl 3 ) δ 170.5, 154.4, 153.4, 149.6, 137.9, 136.7, 131.4, 124, 122.3, 105.3, 67, 60.9, 56.2, 44.
메틸 2-(5-브로모피리딘-2-일)아세테이트 (1k): 상업적 입수 가능 Methyl 2-(5-bromopyridin-2-yl)acetate (1k): commercially available
에틸 2-(퀴놀린-2-일)아세테이트 (1l): 상업적 입수 가능 Ethyl 2-(quinolin-2-yl)acetate (1l): commercially available
2-(피리딘-2-일)아세토니트릴 (1m): 상업적 입수 가능 2-(Pyridin-2-yl)acetonitrile (1m): commercially available
<실시예> 인돌리진(4) 합성을 위한 일반 절차:<Example> General procedure for synthesis of indolizine (4):
실온에서 에틸 2-(피리딘-2-일)아세테이트(110mg.0.6mmol), DMF-DMA(106μM, 1.2당량) 및 DMF(2mL)로 충전된 바이알을 130℃에서 3-4시간 동안 교반한 후, 반응 바이알을 실온이 되게 하고 DMF(1 mL) 중 2-브로모-1-페닐에탄-1-온(1.2 당량)을 첨가하였다. 혼합물을 60℃에서 3-4시간 동안 가열하였다. 반응 완료 후, 물 및 에틸 아세테이트를 채우고 유기층을 분리하고 수용액을 에틸 아세테이트(2 x 20mL)로 역추출하였다. 합한 추출물을 염수(20mL)로 세척하고, 황산마그네슘 상에서 건조시키고, 여과하고, 진공에서 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피(n-헥산:에틸 아세테이트)로 정제하여 4a(127 mg, 65% 수율)를 백색 고체로 얻었다.A vial containing ethyl 2-(pyridin-2-yl)acetate (110 mg. 0.6 mmol), DMF-DMA (106 μM, 1.2 equiv) and DMF (2 mL) was stirred at 130 °C for 3-4 h, then the reaction vial was allowed to warm to room temperature and 2-bromo-1-phenylethan-1-one (1.2 equiv) in DMF (1 mL) was added. The mixture was heated at 60 °C for 3-4 h. After the reaction was complete, water and ethyl acetate were charged, the organic layer was separated and the aqueous solution was back-extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate) to give 4a (127 mg, 65% yield) as a white solid.
에틸 3-벤조일인돌리진-1-카르복실레이트 (4a)Ethyl 3-benzoylindolizine-1-carboxylate (4a)
백색 고체 (127 mg, 65% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 1.6 Hz, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.49 - 7.43 (m, 1H), 7.10 (td, J = 7.0, 1.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 185.8, 164.2, 140.0, 131.6, 129.4, 129.2, 129.2, 129.1, 128.5, 127.9, 122.65, 119.6, 115.4, 106.4, 60.3, 14.7.White solid (127 mg, 65% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.98 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 1.6 Hz, 2H), 7.81 (d, J = 1.7 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.49 - 7.43 (m, 1H), 7.10 (td, J = 7.0, 1.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 185.8, 164.2, 140.0, 131.6, 129.4, 129.2, 129.2, 129.1, 128.5, 127.9, 122.65, 119.6, 115.4, 106.4, 60.3, 14.7.
에틸 3-(2-니트로벤조일)인돌리진-1-카르복실레이트 (4b) Ethyl 3-(2-nitrobenzoyl)indolizine-1-carboxylate (4b)
황색 고체 (157 mg, 65% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.69 (dd, J = 11.3, 4.4 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.5, 7.4 Hz, 1H), 7.40 (s, 1H), 7.16 (t, J = 6.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 182.0, 163.9, 146.9, 140.3, 136.1, 133.9, 130.6, 129.5, 128.5, 128.2, 125.0, 122.2, 119.9, 116.0, 107.2, 77.5, 77.2, 76.8, 60.4, 14.6. Yellow solid (157 mg, 65% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.98 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.78 (t, J = 7.5) Hz, 1H), 7.69 (dd, J = 11.3, 4.4 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.5, 7.4 Hz, 1H), 7.40 (s, 1H), 7.16 (t, J = 6.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 182.0, 163.9, 146.9, 140.3, 136.1, 133.9, 130.6, 129.5, 128.5, 128.2, 125.0, 122.2, 119.9, 116.0, 107.2, 77.5, 77.2, 76.8, 60.4, 14.6.
에틸 3-(3-니트로벤조일)인돌리진-1-카르복실레이트 (4c)Ethyl 3-(3-nitrobenzoyl)indolizine-1-carboxylate (4c)
황색 고체 (141 mg, 63% yield), 1 H NMR (400 MHz, CDCl3) δ 9.97 (d, J = 7.0 Hz, 1H), 8.64 (s, 1H), 8.44 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 13.7, 5.8 Hz, 2H), 7.53 (dd, J = 8.4, 7.4 Hz, 1H), 7.17 (t, J = 6.9 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 182.5, 163.9, 148.3, 141.5, 140.5, 134.6, 129.8, 129.4, 129.2, 128.7, 126.0, 123.9, 121.8, 119.8, 116.0, 107.3, 77.5, 77.2, 76.8, 60.5, 14.7.Yellow solid (141 mg, 63% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.97 (d, J = 7.0 Hz, 1H), 8.64 (s, 1H), 8.44 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 13.7, 5.8 Hz, 2H), 7.53 (dd, J = 8.4, 7.4 Hz, 1H), 7.17 (t, J = 6.9 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 182.5, 163.9, 148.3, 141.5, 140.5, 134.6, 129.8, 129.4, 129.2, 128.7, 126.0, 123.9, 121.8, 119.8, 116.0, 107.3, 77.5, 77.2, 76.8, 60.5, 14.7.
에틸 3-(4-니트로벤조일)인돌리진-1-카르복실레이트 (4d)Ethyl 3-(4-nitrobenzoyl)indolizine-1-carboxylate (4d)
황색 고체 (178 mg, 79% yield), 1 H NMR (400 MHz, CDCl3) δ 9.99 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.38 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.54 (dd, J = 8.4, 7.4 Hz, 1H), 7.18 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl33) δ 183.0, 163.9, 149.5, 145.5, 140.5, 129.9, 129.4 (d, J = 11.6 Hz), 128.8, 123.8, 122.0, 119.9, 116.1, 107.4, 77.48, 77.2, 76.8, 60.5, 14.7.Yellow solid (178 mg, 79% yield), 1H NMR (400 MHz, CDCl 3 ) δ 9.99 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.38 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.3) Hz, 2H), 7.74 (s, 1H), 7.54 (dd, J = 8.4, 7.4 Hz, 1H), 7.18 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 33 ) δ 183.0, 163.9, 149.5, 145.5, 140.5, 129.9, 129.4 (d, J = 11.6 Hz), 128.8, 123.8, 122.0, 119.9, 116.1, 107.4, 77.48, 77.2, 76.8, 60.5, 14.7.
에틸 3-(2-하이드록시-4-(메틸술포닐)벤조일)인돌리진-1-카르복실레이트 (4e)Ethyl 3-(2-hydroxy-4-(methylsulfonyl)benzoyl)indolizine-1-carboxylate (4e)
백색 고체 (158 mg, 64% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.73 (s, 1H), 7.52 (dd, J = 8.4, 7.4 Hz, 1H), 7.16 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.14 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 183.4, 163.9, 144.8, 142.8, 140.4, 129.8, 129.4, 128.7, 127.7, 122.0, 119.8, 116.0, 107.3, 77.5, 77.2, 76.8, 60.5, 44.6, 14.7.White solid (158 mg, 64% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.98 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.73 (s, 1H), 7.52 (dd, J = 8.4, 7.4 Hz, 1H), 7.16 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.14 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 183.4, 163.9, 144.8, 142.8, 140.4, 129.8, 129.4, 128.7, 127.7, 122.0, 119.8, 116.0, 107.3, 77.5, 77.2, 76.8, 60.5, 44.6, 14.7.
에틸 3-(4-사이아노벤조일)인돌리진-1-카르복실레이트 (4f)Ethyl 3-(4-cyanobenzoyl)indolizine-1-carboxylate (4f)
백색 고체 (150 mg, 71% yield), 1 H NMR (400 MHz, CDCl3) δ 9.97 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.56 - 7.47 (m, 1H), 7.19 - 7.11 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 183.3, 163.9, 143.8, 140.4, 132.4, 129.7 - 129.2 (m), 128.6, 122.0, 119.8, 118.3, 116.0, 115.0, 107.2, 77.5, 77.2, 76.8, 60.5, 14.7.White solid (150 mg, 71% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.97 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.56 - 7.47 (m, 1H), 7.19 - 7.11 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 183.3, 163.9, 143.8, 140.4, 132.4, 129.7 - 129.2 (m), 128.6, 122.0, 119.8, 118.3, 116.0, 115.0, 107.2, 77.5, 77.2, 76.8, 60.5, 14.7.
에틸 3-(4-(트리플루오로메틸)벤조일)인돌리진-1-카르복실레이트 (4g)Ethyl 3-(4-(trifluoromethyl)benzoyl)indolizine-1-carboxylate (4g)
백색 고체 (150 mg, 71% yield), 1 H NMR (400 MHz, CDCl3) δ 9.99 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.85 - 7.73 (m, 3H), 7.56 - 7.46 (m, 1H), 7.18 - 7.11 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 184.1, 164.0, 143.2, 140.4, 129.4 (d, J = 13.3 Hz), 128.4, 125.6 (d, J = 3.7 Hz), 122.2, 119.8, 115.9, 107.0, 77.5, 77.2, 76.8, 60.4, 14.7.White solid (150 mg, 71% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.99 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.85 - 7.73 (m, 3H), 7.56 - 7.46 (m, 1H), 7.18 - 7.11 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 184.1, 164.0, 143.2, 140.4, 129.4 (d, J = 13.3 Hz), 128.4, 125.6 (d, J = 3.7 Hz), 122.2, 119.8, 115.9, 107.0, 77.5, 77.2, 76.8, 60.4, 14.7.
에틸 3-(4-브로모벤조일)인돌리진-1-카르복실레이트 (4h)Ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate (4h)
황색 고체 (151 mg, 61% yield), 1 H NMR (400 MHz, CDCl3) δ 9.94 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.78 (s, 1H), 7.68 (q, J = 8.5 Hz, 4H), 7.48 (dd, J = 8.4, 7.4 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 184.3, 164.1, 140.2, 138.8, 131.8, 130.6, 129.3, 129.0, 128.1, 126.4, 122.3, 119.7, 115.6, 106.7, 77.5, 77.2, 76.8, 60.3, 14.7.Yellow solid (151 mg, 61% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.78 (s, 1H), 7.68 (q, J = 8.5 Hz, 4H), 7.48 (dd, J = 8.4, 7.4 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 184.3, 164.1, 140.2, 138.8, 131.8, 130.6, 129.3, 129.0, 128.1, 126.4, 122.3, 119.7, 115.6, 106.7, 77.5, 77.2, 76.8, 60.3, 14.7.
에틸 3-(3-브로모벤조일)인돌리진-1-카르복실레이트 (4i)Ethyl 3-(3-bromobenzoyl)indolizine-1-carboxylate (4i)
황색 고체 (131 mg, 53% yield), 1 H NMR (400 MHz, CDCl3) δ 9.95 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.71 (t, J = 7.4 Hz, 2H), 7.51 - 7.46 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 4.39 (q, J = 7.3 Hz, 2H), 1.41 (q, J = 6.9 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 183.8, 164.1, 141.9, 140.2, 134.5, 131.8, 130.1, 129.3 (d, J = 17.2 Hz), 128.2, 127.6, 122.8, 122.2, 119.7, 115.7, 106.8, 77.5, 77.2, 76.8, 60.4, 14.7.Yellow solid (131 mg, 53% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.71 (t, J = 7.4 Hz, 2H), 7.51 - 7.46 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 4.39 (q, J = 7.3 Hz, 2H), 1.41 (q, J = 6.9 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 183.8, 164.1, 141.9, 140.2, 134.5, 131.8, 130.1, 129.3 (d, J = 17.2 Hz), 128.2, 127.6, 122.8, 122.2, 119.7, 115.7, 106.8, 77.5, 77.2, 76.8, 60.4, 14.7.
에틸 3-(4-클로로벤조일)인돌리진-1-카르복실레이트 (4j)Ethyl 3-(4-chlorobenzoyl)indolizine-1-carboxylate (4j)
백색 고체 (146 mg, 67% yield), 1 H NMR (400 MHz, CDCl3) δ 9.94 (dd, J = 7.0, 0.9 Hz, 1H), 8.45 - 8.37 (m, 1H), 7.77 (d, J = 9.2 Hz, 3H), 7.55 - 7.44 (m, 3H), 7.10 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 184.2, 164.1, 140.1, 138.3, 137.9, 130.5, 129.3, 128.9 (d, J = 12.6 Hz), 128.1, 122.3, 119.7, 115.6, 106.6, 77.5, 77.2, 76.8, 60.3, 14.7.White solid (146 mg, 67% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (dd, J = 7.0, 0.9 Hz, 1H), 8.45 - 8.37 (m, 1H), 7.77 (d, J = 9.2 Hz, 3H), 7.55 - 7.44 (m, 3H), 7.10 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 184.2, 164.1, 140.1, 138.3, 137.9, 130.5, 129.3, 128.9 (d, J = 12.6 Hz), 128.1, 122.3, 119.7, 115.6, 106.6, 77.5, 77.2, 76.8, 60.3, 14.7.
에틸 3-(2-플루오로벤조일)인돌리진-1-카르복실레이트 (4k)Ethyl 3-(2-fluorobenzoyl)indolizine-1-carboxylate (4k)
녹색 고체 (141 mg, 68% yield), 1 H NMR (400 MHz, CDCl3) δ 10.01 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.25 (dd, J = 6.3, 1.1 Hz, 1H), 7.19 (t, J = 9.1 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 181.5, 164.0, 159.6 (d, J = 251.5 Hz), 140.3, 132.3 (d, J = 8.1 Hz), 130.2 (d, J = 3.0 Hz), 129.5, 129.4, 128.5, 128.3, 124.3, 124.3, 119.7, 116.5 (d, J = 21.2 Hz), 115.8, 107.0, 60.3, 14.7. Green solid (141 mg, 68% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.25 (dd, J = 6.3, 1.1 Hz, 1H), 7.19 (t, J = 9.1 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 181.5, 164.0, 159.6 (d, J = 251.5 Hz), 140.3, 132.3 (d, J = 8.1 Hz), 130.2 (d, J = 3.0 Hz), 129.5, 129.4, 128.5, 128.3, 124.3, 124.3, 119.7, 116.5 (d, J = 21.2 Hz), 115.8, 107.0, 60.3, 14.7.
에틸 3-(2,4-디하이드록시벤조일)인돌리진-1-카르복실레이트 (4l)Ethyl 3-(2,4-dihydroxybenzoyl)indolizine-1-carboxylate (4l)
백색 고체 (111 mg, 51% yield), 1 H NMR (400 MHz, dmso) δ 10.93 (s, 1H), 10.32 (s, 1H), 9.63 (d, J = 7.0 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.26 (t, J = 6.4 Hz, 1H), 6.41 (dd, J = 8.5, 2.2 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, DMSO-D6) δ 184.9, 162.8, 132.6, 128.7, 128.1, 127.0, 118.8, 115.6, 107.6, 102.9, 59.7, 40.2, 39.9, 39.7, 39.3, 39.1, 38.9, 30.7, 14.4.White solid (111 mg, 51% yield), 1H NMR (400 MHz, dmso) δ 10.93 (s, 1H), 10.32 (s, 1H), 9.63 (d, J = 7.0 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.26 (t, J = 6.4 Hz, 1H), 6.41 (dd, J = 8.5, 2.2 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, DMSO-D 6 ) δ 184.9, 162.8, 132.6, 128.7, 128.1, 127.0, 118.8, 115.6, 107.6, 102.9, 59.7, 40.2, 39.9, 39.7, 39.3, 39.1, 38.9, 30.7, 14.4.
에틸 3-(4-하이드록시벤조일)인돌리진-1-카르복실레이트 (4m)Ethyl 3-(4-hydroxybenzoyl)indolizine-1-carboxylate (4m)
백색 고체 (156 mg, 76% yield), 1 H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 9.75 (d, J = 7.1 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.65 - 7.57 (m, 2H), 7.30 - 7.24 (m, 1H), 6.93 (d, J = 8.6 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, DMSO-D6) δ 184.0, 163.6, 161.6, 139.1, 131.7, 130.4, 129.0, 128.6, 127.2, 122.6, 119.2, 116.0, 115.6, 60.2, 40.5, 40.3, 40.1, 39.9, 39.7, 39.5, 39.2, 14.8.White solid (156 mg, 76% yield), 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 9.75 (d, J = 7.1 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.65 - 7.57 (m, 2H), 7.30 - 7.24 (m, 1H), 6.93 (d, J = 8.6 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, DMSO-D 6 ) δ 184.0, 163.6, 161.6, 139.1, 131.7, 130.4, 129.0, 128.6, 127.2, 122.6, 119.2, 116.0, 115.6, 60.2, 40.5, 40.3, 40.1, 39.9, 39.7, 39.5, 39.2, 14.8.
에틸 3-(4-메톡시벤조일)인돌리진-1-카르복실레이트 (4n)Ethyl 3-(4-methoxybenzoyl)indolizine-1-carboxylate (4n)
백색 고체 (114 mg, 53% yield), 1 H NMR (400 MHz, CDCl3) δ 9.90 (d, J = 7.1 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J = 2.5 Hz, 2H), 7.43 (dd, J = 8.5, 7.3 Hz, 1H), 7.05 (ddd, J = 21.8, 10.9, 5.0 Hz, 3H), 4.38 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 184.7, 164.4, 162.7, 139.8, 132.5, 131.4, 129.2, 128.5, 127.5, 122.8, 119.6, 115.2, 113.8, 106.1, 77.5, 77.2, 76.8, 60.2, 55.6, 14.7.White solid (114 mg, 53% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.90 (d, J = 7.1 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J = 2.5 Hz, 2H), 7.43 (dd, J = 8.5, 7.3 Hz, 1H), 7.05 (ddd, J = 21.8, 10.9, 5.0 Hz, 3H), 4.38 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 184.7, 164.4, 162.7, 139.8, 132.5, 131.4, 129.2, 128.5, 127.5, 122.8, 119.6, 115.2, 113.8, 106.1, 77.5, 77.2, 76.8, 60.2, 55.6, 14.7.
에틸 3-(2-메틸벤조일)인돌리진-1-카르복실레이트 (4o)Ethyl 3-(2-methylbenzoyl)indolizine-1-carboxylate (4o)
백색 고체 (139 mg, 68% yield), 1 H NMR (400 MHz, CDCl3) δ 10.07 (d, J = 7.0 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.48 (ddd, J = 8.8, 6.9, 1.0 Hz, 1H), 7.39 (t, J = 7.0 Hz, 2H), 7.30 (dd, J = 7.1, 5.6 Hz, 2H), 7.12 (td, J = 7.0, 1.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 187.6, 164.1, 140.1, 139.8, 136.2, 131.0, 129.9, 129.5, 128.1, 125.4, 123.4, 119.7, 115.6, 106.5, 77.5, 77.2, 76.8, 60.2, 19.71, 14.7.White solid (139 mg, 68% yield), 1H NMR (400 MHz, CDCl 3 ) δ 10.07 (d, J = 7.0 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.48 (ddd, J = 8.8, 6.9, 1.0 Hz, 1H), 7.39 (t, J = 7.0 Hz, 2H), 7.30 (dd, J = 7.1, 5.6 Hz, 2H), 7.12 (td, J = 7.0, 1.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 187.6, 164.1, 140.1, 139.8, 136.2, 131.0, 129.9, 129.5, 128.1, 125.4, 123.4, 119.7, 115.6, 106.5, 77.5, 77.2, 76.8, 60.2, 19.71, 14.7.
에틸 3-(2-나프토일)인돌리진-1-카르복실레이트 (4p)Ethyl 3-(2-naphthoyl)indolizine-1-carboxylate (4p)
백색 고체 (141 mg, 62% yield), 1 H NMR (400 MHz, CDCl3) δ 10.01 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 9.0 Hz, 1H), 8.32 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.96 - 7.90 (m, 2H), 7.89 (s, 1H), 7.63 - 7.55 (m, 2H), 7.47 (dd, J = 8.5, 7.3 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 185.6, 164.2, 140.1, 137.3, 134.9, 132.6, 129.9, 129.6 - 128.8 (m), 128.5, 127.9 (d, J = 8.2 Hz), 126.9, 125.6, 122.8, 119.7, 115.4, 106.5, 77.5, 77.2, 76.8, 60.2, 14.7.White solid (141 mg, 62% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 9.0 Hz, 1H), 8.32 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.96 - 7.90 (m, 2H), 7.89 (s, 1H), 7.63 - 7.55 (m, 2H), 7.47 (dd, J = 8.5, 7.3 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 185.6, 164.2, 140.1, 137.3, 134.9, 132.6, 129.9, 129.6 - 128.8 (m), 128.5, 127.9 (d, J = 8.2 Hz), 126.9, 125.6, 122.8, 119.7, 115.4, 106.5, 77.5, 77.2, 76.8, 60.2, 14.7.
메틸 3-벤조일인돌리진-1-카르복실레이트 (4q)Methyl 3-benzoylindolizine-1-carboxylate (4q)
백색 고체 (144 mg, 71% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.0 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.91-7.7NMR 4 (m, 3H), 7.62-7.41 (m, 4H), 7.11 (dd, J = 9.9, 4.0 Hz, 1H), 3.90 (s, 3H), 13 C NMR (101 MHz, CDCl3) δ 185.8, 164.6, 140.0 (d, J = 6.2 Hz), 131.6, 129.5-128.9, 128.5, 127.9, 122.7, 119.6, 115.5, 106.0, 77.5, 77.2, 76.8, 51.4.White solid (144 mg, 71% yield), 1H NMR (400 MHz, CDCl 3 ) δ 9.98 (d, J = 7.0 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.91-7.7NMR 4 (m, 3H), 7.62-7.41 (m, 4H), 7.11 (dd, J = 9.9, 4.0 Hz, 1H), 3.90 (s, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 185.8, 164.6, 140.0 (d, J = 6.2 Hz), 131.6, 129.5-128.9, 128.5, 127.9, 122.7, 119.6, 115.5, 106.0, 77.5, 77.2, 76.8, 51.4.
이소프로필 3-벤조일인돌리진-1-카르복실레이트 (4r)Isopropyl 3-benzoylindolizine-1-carboxylate (4r)
황색 고체 (114 mg, 51% yield), 1 H NMR (400 MHz, CDCl3) δ 9.97 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 6.9 Hz, 3H), 7.57 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.08 (t, J = 6.9 Hz, 1H), 5.27 (dt, J = 12.4, 6.2 Hz, 1H), 1.37 (d, J = 6.3 Hz, 6H), 13 C NMR (101 MHz, CDCl3) δ 131.5, 129.1, 129, 128.4, 127.6, 122.5, 119.6, 115.2, 67.5, 22.2.Yellow solid (114 mg, 51% yield), 1 H NMR (400 MHz, CDCl3) δ 9.97 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 6.9 Hz, 3H), 7.57 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.08 (t, J = 6.9 Hz, 1H), 5.27 (dt, J = 12.4, 6.2 Hz, 1H), 1.37 (d, J = 6.3 Hz, 6H), 13 C NMR (101 MHz, CDCl 3 ) δ 131.5, 129.1, 129, 128.4, 127.6, 122.5, 119.6, 115.2, 67.5, 22.2.
프로필 3-벤조일인돌리진-1-카르복실레이트 (4s)Profile 3-benzoyl indolizine-1-carboxylate (4s)
백색 고체 (136 mg, 61% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 - 9.90 (m, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 4.4 Hz, 3H), 7.57 - 7.53 (m, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.05 (t, J = 6.8 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 1.78 (q, J = 6.9 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 13 C NMR (101 MHz, CDCl3) δ 185.5, 164.1, 139.9, 139.8, 131.5, 129.2, 129, 128.4, 127.7, 122.5, 119.4, 115.2, 106.3, 65.7, 22.3, 10.6.White solid (136 mg, 61% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 - 9.90 (m, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 4.4 Hz, 3H), 7.57 - 7.53 (m, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.05 (t, J = 6.8 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 1.78 (q, J = 6.9 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 185.5, 164.1, 139.9, 139.8, 131.5, 129.2, 129, 128.4, 127.7, 122.5, 119.4, 115.2, 106.3, 65.7, 22.3, 10.6.
터트-부틸 3-벤조일인돌리진-1-카르복실레이트 (4t)Tert-butyl 3-benzoyl indolizine-1-carboxylate (4t)
황색 고체 (108 mg, 62% yield), 1 H NMR (600 MHz, CDCl3) δ 9.97 (dt, J = 7.0, 1.1 Hz, 1H), 8.34 (dt, J = 9.0, 1.2 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.78 (s, 1H), 7.59 - 7.55 (m, 1H), 7.52 - 7.49 (m, 2H), 7.43 (ddd, J = 8.9, 6.8, 1.2 Hz, 1H), 7.07 (td, J = 6.9, 1.4 Hz, 1H), 1.62 (s, 9H), 13 C NMR (151 MHz, CDCl3) δ 185.7, 163.7, 140.1, 139.7, 131.6, 129.5, 129.3, 129.1, 128.5, 127.6, 122.4, 119.7, 115.2, 108.1, 80.8, 28.6.Yellow solid (108 mg, 62% yield), 1H NMR (600 MHz, CDCl3) δ 9.97 (dt, J = 7.0, 1.1 Hz, 1H), 8.34 (dt, J = 9.0, 1.2 Hz, 1H), 7.83 - 7.80 (m, 2H), 7.78 (s, 1H), 7.59 - 7.55 (m, 1H), 7.52 - 7.49 (m, 2H), 7.43 (ddd, J = 8.9, 6.8, 1.2 Hz, 1H), 7.07 (td, J = 6.9, 1.4 Hz, 1H), 1.62 (s, 9H), 13 C NMR (151 MHz, CDCl 3 ) δ 185.7, 163.7, 140.1, 139.7, 131.6, 129.5, 129.3, 129.1, 128.5, 127.6, 122.4, 119.7, 115.2, 108.1, 80.8, 28.6.
프로프-2-인-1-일 3-벤조일인돌리진-1-카르복실레이트 (4u)Prop-2-yn-1-yl 3-benzoyl indolizine-1-carboxylate (4u)
백색 고체 (93 mg, 42% yield), 1 H NMR (600 MHz, CDCl3) δ 9.97 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.84 (s, 1H), 7.81 (d, J = 6.9 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.48 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.13 - 7.11 (m, 1H), 4.92 (s, 2H), 2.51 (s, 1H), 13 C NMR (151 MHz, CDCl3) δ 185.8, 163.1, 140.2, 139.9, 131.7, 129.4, 129.2, 129.0, 128.6, 128.2, 122.9, 119.6, 115.6, 105, 78.3, 74.9, 51.7.White solid (93 mg, 42% yield), 1H NMR (600 MHz, CDCl3) δ 9.97 (d, J = 7.0 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.84 (s, 1H), 7.81 (d, J = 6.9 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.48 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.13 - 7.11 (m, 1H), 4.92 (s, 2H), 2.51 (s, 1H), 13 C NMR (151 MHz, CDCl 3 ) δ 185.8, 163.1, 140.2, 139.9, 131.7, 129.4, 129.2, 129.0, 128.6, 128.2, 122.9, 119.6, 115.6, 105, 78.3, 74.9, 51.7.
알릴 3-벤조일인돌리진-1-카르복실레이트 (4v)Allyl 3-benzoyl indolizine-1-carboxylate (4v)
백색 고체 (188 mg, 85 yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.1 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.85 - 7.79 (m, 3H), 7.61 - 7.56 (m, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.49 - 7.45 (m, 1H), 7.11 (t, J = 6.9 Hz, 1H), 6.05 (ddd, J = 16.3, 10.9, 5.2 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 5.28 (d, J = 10.2 Hz, 1H), 4.83 (d, J = 5.4 Hz, 2H), 13 C NMR (101 MHz, CDCl3) δ 185.6, 163.7, 140, 139.9, 132.7, 131.5, 129.3, 129.1, 129, 128.4, 127.9, 122.6, 119.50, 118.2, 115.4, 105.8, 64.8.White solid (188 mg, 85 yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.1 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.85 - 7.79 (m, 3H), 7.61 - 7.56 (m, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.49 - 7.45 (m, 1H), 7.11 (t, J = 6.9 Hz, 1H), 6.05 (ddd, J = 16.3, 10.9, 5.2 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 5.28 (d, J = 10.2 Hz, 1H), 4.83 (d, J = 5.4 Hz, 2H), 13 C NMR (101 MHz, CDCl 3 ) δ 185.6, 163.7, 140, 139.9, 132.7, 131.5, 129.3, 129.1, 129, 128.4, 127.9, 122.6, 119.50, 118.2, 115.4, 105.8, 64.8.
사이클로헥실 3-벤조일인돌리진-1-카르복실레이트 (4w)Cyclohexyl 3-benzoylindolizine-1-carboxylate (4w)
황색 오일 (103 mg, 41% yield), 1 H NMR (600 MHz, CDCl3) δ 9.97 (dt, J = 7.0, 1.1 Hz, 1H), 8.38 (dt, J = 8.9, 1.2 Hz, 1H), 7.83 - 7.82 (m, 2H), 7.81 (d, J = 1.4 Hz, 1H), 7.59 - 7.56 (m, 1H), 7.51 (tt, J = 6.6, 1.3 Hz, 2H), 7.44 (ddd, J = 8.9, 6.8, 1.2 Hz, 1H), 7.07 (td, J = 6.9, 1.4 Hz, 1H), 5.03 (td, J = 9.3, 4.6 Hz, 1H), 2.02 - 1.96 (m, 2H), 1.78 (dt, J = 13.4, 4.2 Hz, 2H), 1.57 (qd, J = 12.8, 11.8, 3.4 Hz, 3H), 1.44 (dtt, J = 14.1, 10.7, 3.5 Hz, 2H), 1.32 (ddt, J = 14.0, 10.2, 3.6 Hz, 1H), 13 C NMR (151 MHz, CDCl3) δ 185.6, 163.7, 140, 139.9, 131.6, 129.3, 129.2, 129.1, 128.5, 127.7, 122.6, 119.7, 115.3, 107, 72.6, 32.1, 25.6, 24.1.Yellow oil (103 mg, 41% yield), 1H NMR (600 MHz, CDCl3) δ 9.97 (dt, J = 7.0, 1.1 Hz, 1H), 8.38 (dt, J = 8.9, 1.2 Hz, 1H), 7.83 - 7.82 (m, 2H), 7.81 (d, J = 1.4 Hz, 1H), 7.59 - 7.56 (m, 1H), 7.51 (tt, J = 6.6, 1.3 Hz, 2H), 7.44 (ddd, J = 8.9, 6.8, 1.2 Hz, 1H), 7.07 (td, J = 6.9, 1.4 Hz, 1H), 5.03 (td, J) = 9.3, 4.6 Hz, 1H), 2.02 - 1.96 (m, 2H), 1.78 (dt, J = 13.4, 4.2 Hz, 2H), 1.57 (qd, J = 12.8, 11.8, 3.4 Hz, 3H), 1.44 (dtt, J = 14.1, 10.7, 3.5 Hz, 2H), 1.32 (ddt, J = 14.0, 10.2, 3.6 Hz, 1H), 13 C NMR (151 MHz, CDCl 3 ) δ 185.6, 163.7, 140, 139.9, 131.6, 129.3, 129.2, 129.1, 128.5, 127.7, 122.6, 119.7, 115.3, 107, 72.6, 32.1, 25.6, 24.1.
벤질 3-벤조일인돌리진-1-카르복실레이트 (4x)Benzyl 3-benzoyl indolizine-1-carboxylate (4x)
회색 고체 (140 mg, 54% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 9.8 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.48 - 7.43 (m, 3H), 7.37 (dt, J = 12.9, 6.9 Hz, 3H), 7.10 (t, J = 6.9 Hz, 1H), 5.38 (s, 2H), 13 C NMR (101 MHz, CDCl3) δ 185.7, 163.9, 140, 139.8, 136.4, 131.5, 129.3, 129.1, 129, 128.6, 128.4, 128.2, 128.2, 127.9, 122.7, 119.5, 115.4, 105.8, 65.9.Gray solid (140 mg, 54% yield), 1 H NMR (400 MHz, CDCl3) δ 9.98 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 9.8 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.48 - 7.43 (m, 3H), 7.37 (dt, J = 12.9, 6.9 Hz, 3H), 7.10 (t, J = 6.9 Hz, 1H), 5.38 (s, 2H), 13 C NMR (101 MHz, CDCl 3 ) δ 185.7, 163.9, 140, 139.8, 136.4, 131.5, 129.3, 129.1, 129, 128.6, 128.4, 128.2, 128.2, 127.9, 122.7, 119.5, 115.4, 105.8, 65.9.
3,4,5-트리메톡시벤질 3-벤조일인돌리진-1-카르복실레이트 (4y)3,4,5-Trimethoxybenzyl 3-benzoylindolizine-1-carboxylate (4y)
백색 고체 (220 mg, 85% yield), 1 H NMR (600 MHz, CDCl3) δ 9.98 (dt, J = 7.0, 1.0 Hz, 1H), 8.41 (dt, J = 8.9, 1.2 Hz, 1H), 7.85 (s, 1H), 7.81 (dd, J = 8.1, 1.1 Hz, 2H), 7.60-7.56 (m, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.46 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.11 (td, J = 6.9, 1.4 Hz, 1H), 5.30 (s, 2H), 3.86 (s, 6H), 3.85 (s, 3H), 13 C NMR (151 MHz, CDCl3) δ 185.7, 163.9, 153.5, 140.1, 139.9, 138, 132.1, 131.6, 129.4, 129.2, 129, 128.5, 128, 122.8, 119.6, 115.5, 105.8, 105.4, 66.1, 60.9, 56.2.White solid (220 mg, 85% yield), 1H NMR (600 MHz, CDCl3) δ 9.98 (dt, J = 7.0, 1.0 Hz, 1H), 8.41 (dt, J = 8.9, 1.2 Hz, 1H), 7.85 (s, 1H), 7.81 (dd, J = 8.1, 1.1 Hz, 2H), 7.60-7.56 (m, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.46 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.11 (td, J = 6.9, 1.4 Hz, 1H), 5.30 (s, 2H), 3.86 (s, 6H), 3.85 (s, 3H), 13 C NMR (151 MHz, CDCl 3 ) δ 185.7, 163.9, 153.5, 140.1, 139.9, 138, 132.1, 131.6, 129.4, 129.2, 129, 128.5, 128, 122.8, 119.6, 115.5, 105.8, 105.4, 66.1, 60.9, 56.2.
메틸 3-벤조일-6-브로모인돌리진-1-카르복실레이트 (4z)Methyl 3-benzoyl-6-bromoindolizine-1-carboxylate (4z)
황색 고체 (87 mg, 51% yield), 1 H NMR (600 MHz, CDCl3) δ 10.16 (dd, J = 1.8, 0.9 Hz, 1H), 8.29 (dd, J = 9.4, 0.8 Hz, 1H), 7.81-7.80 (m, 1H), 7.80 (t, J = 1.7 Hz, 2H), 7.78 (s, 1H), 7.61-7.58 (m, 1H), 7.54-7.52 (m, 2H), 7.52-7.50 (m, 1H), 3.90 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 185.8, 164.2, 139.6, 138.0, 131.9, 130.9, 129.3, 129.1, 128.7, 128.6, 122.7, 120.1, 110.6, 106.8, 51.6.Yellow solid (87 mg, 51% yield), 1 H NMR (600 MHz, CDCl 3 ) δ 10.16 (dd, J = 1.8, 0.9 Hz, 1H), 8.29 (dd, J = 9.4, 0.8 Hz, 1H), 7.81-7.80 (m, 1H), 7.80 (t, J = 1.7 Hz, 2H), 7.78 (s, 1H), 7.61-7.58 (m, 1H), 7.54-7.52 (m, 2H), 7.52-7.50 (m, 1H), 3.90 (s, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 185.8, 164.2, 139.6, 138.0, 131.9, 130.9, 129.3, 129.1, 128.7, 128.6, 122.7, 120.1, 110.6, 106.8, 51.6.
에틸 1-벤조일피롤로[1,2-a]퀴놀린e-3-카르복실레이트 (4aa)Ethyl 1-benzoylpyrrol[1,2-a]quinoline e-3-carboxylate (4aa)
갈색 고체 (111 mg, 63% yield), 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 9.3 Hz, 1H), 8.09 (dd, J = 13.9, 8.3 Hz, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.72-7.65 (m, 2H), 7.64 (s, 1H), 7.57 (t, J = 7.2 Hz, 3H), 7.49 (t, J = 7.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 185.1, 164.3, 140.4, 138.6, 133.4, 133.1, 130.3, 129.7, 129.1, 129.0, 128.9, 128.7, 128.3, 125.6, 125.3, 120.4, 117.9, 107.9, 60.4, 14.7.Brown solid (111 mg, 63% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 9.3 Hz, 1H), 8.09 (dd, J = 13.9, 8.3 Hz, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.72-7.65 (m, 2H), 7.64 (s, 1H), 7.57 (t, J = 7.2 Hz, 3H), 7.49 (t, J = 7.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 185.1, 164.3, 140.4, 138.6, 133.4, 133.1, 130.3, 129.7, 129.1, 129.0, 128.9, 128.7, 128.3, 125.6, 125.3, 120.4, 117.9, 107.9, 60.4, 14.7.
3-벤조일인돌리진-1-카르보니트릴 (4ab)3-Benzoylindolizine-1-carbonitrile (4ab)
녹색 고체 (178 mg, 78% yield), 1 H NMR (400 MHz, CDCl3) δ 9.96 (d, J = 7.1 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.82-7.76 (m, 2H), 7.63 (s, 1H), 7.62-7.58 (m, 1H), 7.56-7.47 (m, 3H), 7.16 (t, J = 7.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 185.3, 141.4, 139.3, 132.2, 129.7, 129.4, 129.0, 128.7, 128.0, 123.0, 117.7, 116.0, 115.3, 85.0.Green solid (178 mg, 78% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (d, J = 7.1 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.82-7.76 (m, 2H), 7.63 (s, 1H), 7.62-7.58 (m, 1H), 7.56-7.47 (m, 3H), 7.16 (t, J = 7.0 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 185.3, 141.4, 139.3, 132.2, 129.7, 129.4, 129.0, 128.7, 128.0, 123.0, 117.7, 116.0, 115.3, 85.0.
에틸 3-아세틸인돌리진-1-카르복실레이트 (4ac)Ethyl 3-acetyl indolizine-1-carboxylate (4ac)
백색 고체 (99 mg, 64% yield), 1 H NMR (400 MHz, CDCl3) δ 9.84 (dd, J = 7.0, 0.9 Hz, 1H), 8.33-8.25 (m, 1H), 7.94 (s, 1H), 7.35 (dd, J = 8.4, 7.4 Hz, 1H), 6.97 (t, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.56 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 187.8, 164.1, 139.3, 129.1, 127.2, 126.2, 122.7, 119.4, 115.2, 105.7, 60.2, 27.4, 14.6.White solid (99 mg, 64% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.84 (dd, J = 7.0, 0.9 Hz, 1H), 8.33-8.25 (m, 1H), 7.94 (s, 1H), 7.35 (dd, J = 8.4, 7.4 Hz, 1H), 6.97 (t, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.56 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 187.8, 164.1, 139.3, 129.1, 127.2, 126.2, 122.7, 119.4, 115.2, 105.7, 60.2, 27.4, 14.6.
디에틸 인돌리진-1,3-디카르복실레이트 (4ad)Diethyl indolizine-1,3-dicarboxylate (4ad)
갈색 고체 (122 mg, 70% yield), 1 H NMR (400 MHz, CDCl3) δ 9.55-9.49 (m, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.30 (dd, J = 8.5, 7.4 Hz, 1H), 6.97 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 4H), 1.41 (td, J = 7.1, 3.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 164.4, 161.3, 139.2, 128.0, 125.7, 124.4, 119.7, 114.9, 114.5, 105.3, 60.4, 60.1, 14.7, 14.6.Brown solid (122 mg, 70% yield), 1 H NMR (400 MHz, CDCl 3 ) δ 9.55-9.49 (m, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 7.30 (dd, J = 8.5, 7.4 Hz, 1H), 6.97 (t, J = 6.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 4H), 1.41 (td, J = 7.1, 3.2 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 164.4, 161.3, 139.2, 128.0, 125.7, 124.4, 119.7, 114.9, 114.5, 105.3, 60.4, 60.1, 14.7, 14.6.
에틸 3-사이아노인돌리진-1-카르복실레이트 (4ae)Ethyl 3-cyanoindolizine-1-carboxylate (4ae)
녹색 고체 (90 mg, 63% yield), 1 H NMR (600 MHz, CDCl3) 8.35-8.29 (m, 2H), 7.77 (s, 1H), 7.32 (ddd, J = 8.9, 6.8, 1.3 Hz, 1H), 7.02 (td, J = 6.9, 1.6 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 163.4, 137.9, 126.1, 125.8, 125.3, 120.6, 115.1, 112.8, 106.2, 96.8, 60.4, 14.6.Green solid (90 mg, 63% yield), 1 H NMR (600 MHz, CDCl 3 ) 8.35-8.29 (m, 2H), 7.77 (s, 1H), 7.32 (ddd, J = 8.9, 6.8, 1.3 Hz, 1H), 7.02 (td, J = 6.9, 1.6 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 163.4, 137.9, 126.1, 125.8, 125.3, 120.6, 115.1, 112.8, 106.2, 96.8, 60.4, 14.6.
메틸 3-(3-에톡시-3-옥소프로파노일)인돌리진-1-카르복실레이트 (4af)Methyl 3-(3-ethoxy-3-oxopropanoyl)indolizine-1-carboxylate (4af)
황색 고체 (82 mg, 39% yield), 1 H NMR (400 MHz, CDCl3) 9.85 (dd, J = 7.0, 1.0 Hz, 1H), 8.34 (dd, J = 8.9, 0.9 Hz, 1H), 8.00 (s, 1H), 7.48-7.39 (m, 1H), 7.05 (t, J = 7.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.92 (s, 3H), 1.27 (dd, J = 7.7, 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 181.6, 167.7, 164.3, 139.9, 129.3, 128.1, 126.8, 122.1, 119.5, 115.8, 106.2, 61.7, 51.5, 46.7, 14.2.Yellow solid (82 mg, 39% yield), 1 H NMR (400 MHz, CDCl 3 ) 9.85 (dd, J = 7.0, 1.0 Hz, 1H), 8.34 (dd, J = 8.9, 0.9 Hz, 1H), 8.00 (s, 1H), 7.48-7.39 (m, 1H), 7.05 (t, J = 7.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.92 (s, 3H), 1.27 (dd, J = 7.7, 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 181.6, 167.7, 164.3, 139.9, 129.3, 128.1, 126.8, 122.1, 119.5, 115.8, 106.2, 61.7, 51.5, 46.7, 14.2.
Claims (12)
하기 화학식 7의 화합물을 하기 화학식 3 의 화합물과 반응시켜 하기 화학식 4의 화합물을 얻는 제 2 단계를 포함하는 화학식 4의 화합물의 제조 방법:
[화학식 1]
[화학식 2]
[화학식 7]
[화학식 3]
[화학식 4]
상기 화학식에서,
R1은 또는 시아노기이고,
R2는 C1-C6 알킬기, C4-C6 사이클로알킬기, 또는 하나 이상의 C1-C4 알콕시기로 치환되거나 비 치환된 벤질기이며,
R6는 또는 시아노기이고,
R3는 , , C1-C6 알킬기, C1-C4 알콕시기 또는 이고,
R4 및 R5는 각각 독립적으로 수소 원자, 할로겐 원자, 하이드록시기, C1-C6 알킬기, C1-C6 알콕시기, 니트로기, C1-C4 할로알킬기, 시아노기 또는 이며,
X는 할로겐 원자이고,
Y 및 Z는 각각 독립적으로는 수소 원자 또는 할로겐 원자; 이고,
단, Y 및 Z가 모두 할로겐 원자인 경우는 제외한다.A first step of obtaining a compound of the following chemical formula 7 by reacting a compound of the following chemical formula 1 and a compound of the following chemical formula 2 using dimethylformamide (DMF) as a solvent, and
A method for producing a compound of formula 4, comprising a second step of reacting a compound of formula 7 below with a compound of formula 3 below to obtain a compound of formula 4:
[Chemical Formula 1]
[Chemical formula 2]
[Chemical formula 7]
[Chemical Formula 3]
[Chemical Formula 4]
In the above chemical formula,
R1 is or cyano group,
R2 is a C1-C6 alkyl group, a C4-C6 cycloalkyl group, or a benzyl group which is unsubstituted or substituted with one or more C1-C4 alkoxy groups,
R6 is or cyano group,
R3 is , , C1-C6 alkyl group, C1-C4 alkoxy group or And,
R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a C1-C4 haloalkyl group, a cyano group or And,
X is a halogen atom,
Y and Z are each independently a hydrogen atom or a halogen atom;
Except when Y and Z are both halogen atoms.
상기 화학식 4에서,
Y 및 Z가 수소일 때,
R1은 , , , , , , , , , , 또는 시아노기이고,
R6는 또는 시아노기이며,
R3는 -CH3, , , , , , , , , , , , , , 또는 인, 제조 방법.In paragraph 1,
In the above chemical formula 4,
When Y and Z are hydrogen,
R1 is , , , , , , , , , , or cyano group,
R6 is or cyano group,
R3 is -CH 3 , , , , , , , , , , , , , , or People, manufacturing method.
상기 화학식 4에서,
Y 및 Z가 각각 할로겐 원자 및 수소 원자일 때,
R1은이고,
R6는 이며,
R3는 인, 제조 방법.In paragraph 1,
In the above chemical formula 4,
When Y and Z are halogen atoms and hydrogen atoms, respectively,
R1 is And,
R6 is And,
R3 is People, manufacturing method.
상기 화학식 4는 하기 화합물 중 하나인 제조 방법:
.In paragraph 1,
The above chemical formula 4 is a manufacturing method of one of the following compounds:
.
제 1 단계 반응은, 70 내지 150℃에서 3 내지 5시간 교반하여 수행되는, 제조 방법.In paragraph 1,
A manufacturing method in which the first step reaction is carried out by stirring at 70 to 150°C for 3 to 5 hours.
제 2 단계 반응은, 50 내지 70℃에서 3 내지 5시간 교반하여 수행되는, 제조 방법.In paragraph 1,
A manufacturing method in which the second step reaction is carried out by stirring at 50 to 70°C for 3 to 5 hours.
제 1 단계; 및 제 2 단계; 반응은 원팟(one-pot)반응으로 수행되는, 제조 방법.In paragraph 1,
A manufacturing method wherein the first step; and the second step; reactions are performed as a one-pot reaction.
[화학식 4]
상기 화학식 4에서,
R1은 또는 시아노기이고,
R2는 C1-C6 알킬기, C4-C6 사이클로알킬기, 또는 하나 이상의 C1-C4 알콕시기로 치환되거나 비 치환된 벤질기이며,
R6는 또는 시아노기이고,
R3는 , , C1-C6 알킬기, C1-C4 알콕시기 또는 이고,
R4 및 R5는 각각 독립적으로 수소 원자, 할로겐 원자, 하이드록시기, C1-C6 알킬기, C1-C6 알콕시기, 니트로기, C1-C4 할로알킬기, 시아노기 또는 이며,
Y 및 Z는 각각 독립적으로는 수소 원자 또는 할로겐 원자; 이고,
단, Y 및 Z가 모두 할로겐 원자인 경우는 제외한다.A compound represented by the following chemical formula 4 or a salt thereof:
[Chemical Formula 4]
In the above chemical formula 4,
R1 is or cyano group,
R2 is a C1-C6 alkyl group, a C4-C6 cycloalkyl group, or a benzyl group which is unsubstituted or substituted with one or more C1-C4 alkoxy groups,
R6 is or cyano group,
R3 is , , C1-C6 alkyl group, C1-C4 alkoxy group or And,
R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a nitro group, a C1-C4 haloalkyl group, a cyano group or And,
Y and Z are each independently a hydrogen atom or a halogen atom;
Except when Y and Z are both halogen atoms.
상기 화학식 4에서,
R3는 -CH3, , 또는 이고,
R4 및 R5는 각각 독립적으로 수소 원자, 할로겐 원자, 하이드록시기, C1-C6 알콕시기, C1-C4 할로알킬기, 시아노기 또는 인 화합물.In Article 8,
In the above chemical formula 4,
R3 is -CH 3 , , or And,
R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkoxy group, a C1-C4 haloalkyl group, a cyano group or A compound of phosphorus.
상기 화학식 4의 화합물은,
에틸 3-(2-하이드록시-4-(메틸술포닐)벤조일)인돌리진-1-카르복실레이트;
에틸 3-(4-(트리플루오로메틸)벤조일)인돌리진-1-카르복실레이트;
에틸 3-(4-브로모벤조일)인돌리진-1-카르복실레이트;
에틸 3-(2-플루오로벤조일)인돌리진-1-카르복실레이트;
에틸 3-(2,4-디하이드록시벤조일)인돌리진-1-카르복실레이트;
에틸 3-(4-하이드록시벤조일)인돌리진-1-카복실레이트;
에틸 3-(2-나프토일)인돌리진-1-카르복실레이트;
프로필 3-벤조일인돌리진-1-카복실레이트;
알릴 3-벤조일인돌리진-1-카르복실레이트;
시클로헥실 3-벤조일인돌리진-1-카르복실레이트;
벤질 3-벤조일인돌리진-1-카르복실레이트;
3,4,5-트리메톡시벤질 3-벤조일인돌리진-1-카르복실레이트;
메틸 3-벤조일-6-브로모인돌리진-1-카르복실레이트;
에틸 3-시아노인돌리진-1-카르복실레이트; 및
메틸 3-(3-에톡시-3-옥소프로파노일)인돌리진-1-카르복실레이트인 화합물.In Article 8,
The compound of the above chemical formula 4 is,
Ethyl 3-(2-hydroxy-4-(methylsulfonyl)benzoyl)indolizine-1-carboxylate;
Ethyl 3-(4-(trifluoromethyl)benzoyl)indolizine-1-carboxylate;
Ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate;
Ethyl 3-(2-fluorobenzoyl)indolizine-1-carboxylate;
Ethyl 3-(2,4-dihydroxybenzoyl)indolizine-1-carboxylate;
Ethyl 3-(4-hydroxybenzoyl)indolizine-1-carboxylate;
Ethyl 3-(2-naphthoyl)indolizine-1-carboxylate;
Profile 3-benzoyl indolizine-1-carboxylate;
Allyl 3-benzoyl indolizine-1-carboxylate;
Cyclohexyl 3-benzoylindolezine-1-carboxylate;
Benzyl 3-benzoylindolezine-1-carboxylate;
3,4,5-Trimethoxybenzyl 3-benzoylindolezine-1-carboxylate;
Methyl 3-benzoyl-6-bromoindolizine-1-carboxylate;
Ethyl 3-cyanoindolizine-1-carboxylate; and
A compound which is methyl 3-(3-ethoxy-3-oxopropanoyl)indolizine-1-carboxylate.
[화학식 7]
상기 화학식 7에서,
상기 R1, Y 및 Z는 제 1항과 같다.A compound represented by the following chemical formula 7 or a salt thereof:
[Chemical formula 7]
In the above chemical formula 7,
The above R1, Y and Z are as in paragraph 1.
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| CN1763039A (en) | 2005-09-15 | 2006-04-26 | 南京师范大学 | The synthetic method of indolizine carboxylic acid compound |
| CN101597293A (en) | 2009-07-02 | 2009-12-09 | 绍兴文理学院 | Method for preparing indolizine derivatives by microwave reaction |
| CN102093355A (en) | 2011-02-09 | 2011-06-15 | 浙江大学 | C-3 acylated indolizine compound and preparation method thereof |
| WO2016110821A1 (en) | 2015-01-08 | 2016-07-14 | Advinus Therapeutics Limited | Bicyclic compounds, compositions and medicinal applications thereof |
| WO2019077517A1 (en) | 2017-10-18 | 2019-04-25 | Suven Life Sciences Limited | Heteroaryl compounds as muscarinic m1 receptor positive allosteric modulators |
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| CN1763039A (en) | 2005-09-15 | 2006-04-26 | 南京师范大学 | The synthetic method of indolizine carboxylic acid compound |
| CN101597293A (en) | 2009-07-02 | 2009-12-09 | 绍兴文理学院 | Method for preparing indolizine derivatives by microwave reaction |
| CN102093355A (en) | 2011-02-09 | 2011-06-15 | 浙江大学 | C-3 acylated indolizine compound and preparation method thereof |
| WO2016110821A1 (en) | 2015-01-08 | 2016-07-14 | Advinus Therapeutics Limited | Bicyclic compounds, compositions and medicinal applications thereof |
| WO2019077517A1 (en) | 2017-10-18 | 2019-04-25 | Suven Life Sciences Limited | Heteroaryl compounds as muscarinic m1 receptor positive allosteric modulators |
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