KR20200023167A - Bi-heteroaromatic compounds including phenyl substitute and method for preparing the same - Google Patents
Bi-heteroaromatic compounds including phenyl substitute and method for preparing the same Download PDFInfo
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- KR20200023167A KR20200023167A KR1020190055375A KR20190055375A KR20200023167A KR 20200023167 A KR20200023167 A KR 20200023167A KR 1020190055375 A KR1020190055375 A KR 1020190055375A KR 20190055375 A KR20190055375 A KR 20190055375A KR 20200023167 A KR20200023167 A KR 20200023167A
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- -1 acetoacetic ester compound Chemical class 0.000 claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 20
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 claims abstract description 13
- 238000003381 deacetylation reaction Methods 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 9
- 230000006196 deacetylation Effects 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims description 98
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 75
- 229910052760 oxygen Inorganic materials 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 36
- 239000011572 manganese Substances 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 13
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052748 manganese Inorganic materials 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 43
- 150000002390 heteroarenes Chemical class 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 3
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 abstract description 3
- MMIPFLVOWGHZQD-UHFFFAOYSA-N manganese(3+) Chemical compound [Mn+3] MMIPFLVOWGHZQD-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001766 physiological effect Effects 0.000 abstract description 3
- OHZAHWOAMVVGEL-UHFFFAOYSA-N 2,2'-bithiophene Chemical compound C1=CSC(C=2SC=CC=2)=C1 OHZAHWOAMVVGEL-UHFFFAOYSA-N 0.000 abstract description 2
- UDHZFLBMZZVHRA-UHFFFAOYSA-N 2-(furan-2-yl)furan Chemical compound C1=COC(C=2OC=CC=2)=C1 UDHZFLBMZZVHRA-UHFFFAOYSA-N 0.000 abstract description 2
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 160
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 144
- 239000000203 mixture Substances 0.000 description 82
- 235000019439 ethyl acetate Nutrition 0.000 description 80
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- 238000003818 flash chromatography Methods 0.000 description 50
- 239000000741 silica gel Substances 0.000 description 50
- 229910002027 silica gel Inorganic materials 0.000 description 50
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 46
- 239000007787 solid Substances 0.000 description 36
- 239000000047 product Substances 0.000 description 28
- 229920006395 saturated elastomer Polymers 0.000 description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 14
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical class CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000012300 argon atmosphere Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 7
- 229930192474 thiophene Chemical group 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 6
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DDNPADUKGZMCHV-CMDGGOBGSA-N (e)-3-phenyl-1-thiophen-2-ylprop-2-en-1-one Chemical compound C=1C=CSC=1C(=O)\C=C\C1=CC=CC=C1 DDNPADUKGZMCHV-CMDGGOBGSA-N 0.000 description 3
- QHSCPZNCMULPEF-UHFFFAOYSA-N 1-(furan-2-yl)-3-phenylprop-2-en-1-one Chemical compound C=1C=COC=1C(=O)C=CC1=CC=CC=C1 QHSCPZNCMULPEF-UHFFFAOYSA-N 0.000 description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- GLNFFMZPELBRRR-UHFFFAOYSA-N 3-phenyl-1-(1h-pyrrol-2-yl)prop-2-en-1-one Chemical compound C=1C=CNC=1C(=O)C=CC1=CC=CC=C1 GLNFFMZPELBRRR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000005693 optoelectronics Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- ULUNQYODBKLBOE-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1h-pyrrole Chemical compound C1=CNC(C=2NC=CC=2)=C1 ULUNQYODBKLBOE-UHFFFAOYSA-N 0.000 description 1
- RVYKTPRETIBSPK-UHFFFAOYSA-N 2-(2-Thienyl)furan Chemical compound C1=COC(C=2SC=CC=2)=C1 RVYKTPRETIBSPK-UHFFFAOYSA-N 0.000 description 1
- BYBZIJZNTITRID-UHFFFAOYSA-N 2-(furan-2-yl)-1h-pyrrole Chemical compound C1=CNC(C=2OC=CC=2)=C1 BYBZIJZNTITRID-UHFFFAOYSA-N 0.000 description 1
- IEMMBWWQXVXBEU-UHFFFAOYSA-N 2-acetylfuran Chemical compound CC(=O)C1=CC=CO1 IEMMBWWQXVXBEU-UHFFFAOYSA-N 0.000 description 1
- IGJQUJNPMOYEJY-UHFFFAOYSA-N 2-acetylpyrrole Chemical compound CC(=O)C1=CC=CN1 IGJQUJNPMOYEJY-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FJLPFSLRWNZKIM-UHFFFAOYSA-N ethyl 2-acetyl-3-(4-fluorophenyl)-5-(furan-2-yl)-5-oxopentanoate Chemical compound C(C)(=O)C(C(=O)OCC)C(CC(=O)C=1OC=CC=1)C1=CC=C(C=C1)F FJLPFSLRWNZKIM-UHFFFAOYSA-N 0.000 description 1
- QHPGIZZSTONVNZ-UHFFFAOYSA-N ethyl 2-acetyl-5-(furan-2-yl)-3-(4-methoxyphenyl)-5-oxopentanoate Chemical compound C(C)(=O)C(C(=O)OCC)C(CC(=O)C=1OC=CC=1)C1=CC=C(C=C1)OC QHPGIZZSTONVNZ-UHFFFAOYSA-N 0.000 description 1
- JKZQMHKUQRIDPX-UHFFFAOYSA-N ethyl 2-acetyl-5-(furan-2-yl)-5-oxo-3-phenylpentanoate Chemical compound C(C)(=O)C(C(=O)OCC)C(CC(=O)C=1OC=CC=1)C1=CC=CC=C1 JKZQMHKUQRIDPX-UHFFFAOYSA-N 0.000 description 1
- AUJGTKPIBMJNPH-UHFFFAOYSA-N ethyl 3-(4-cyanophenyl)-5-thiophen-2-yl-1H-pyrrole-2-carboxylate Chemical compound C(#N)C1=CC=C(C=C1)C1=C(NC(=C1)C=1SC=CC=1)C(=O)OCC AUJGTKPIBMJNPH-UHFFFAOYSA-N 0.000 description 1
- QHYAZRKNHWCUEO-UHFFFAOYSA-N ethyl 3-(4-cyanophenyl)-5-thiophen-2-ylthiophene-2-carboxylate Chemical compound C(#N)C1=CC=C(C=C1)C=1C=C(SC=1C(=O)OCC)C=1SC=CC=1 QHYAZRKNHWCUEO-UHFFFAOYSA-N 0.000 description 1
- IPGZMJWUJULKBU-UHFFFAOYSA-N ethyl 3-(4-fluorophenyl)-5-(furan-2-yl)-1H-pyrrole-2-carboxylate Chemical compound FC1=CC=C(C=C1)C1=C(NC(=C1)C=1OC=CC=1)C(=O)OCC IPGZMJWUJULKBU-UHFFFAOYSA-N 0.000 description 1
- PURNCGAOFLGYFE-UHFFFAOYSA-N ethyl 3-(4-fluorophenyl)-5-(furan-2-yl)-2,5-dioxopentanoate Chemical compound FC1=CC=C(C=C1)C(C(C(=O)OCC)=O)CC(=O)C=1OC=CC=1 PURNCGAOFLGYFE-UHFFFAOYSA-N 0.000 description 1
- SNFNWUXCQVNLSR-UHFFFAOYSA-N ethyl 3-(4-fluorophenyl)-5-(furan-2-yl)furan-2-carboxylate Chemical compound FC1=CC=C(C=C1)C=1C=C(OC=1C(=O)OCC)C=1OC=CC=1 SNFNWUXCQVNLSR-UHFFFAOYSA-N 0.000 description 1
- PRZGZMLNPMASKB-UHFFFAOYSA-N ethyl 3-oxobutanoate;3-oxobutanoic acid Chemical compound CC(=O)CC(O)=O.CCOC(=O)CC(C)=O PRZGZMLNPMASKB-UHFFFAOYSA-N 0.000 description 1
- QOVCFFNYGDSVOR-UHFFFAOYSA-N ethyl 3-phenyl-5-thiophen-2-ylthiophene-2-carboxylate Chemical compound C1(=CC=CC=C1)C=1C=C(SC=1C(=O)OCC)C=1SC=CC=1 QOVCFFNYGDSVOR-UHFFFAOYSA-N 0.000 description 1
- RDINNTSSIJKXSP-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-2,5-dioxo-3-phenylpentanoate Chemical compound O1C(=CC=C1)C(CC(C(C(=O)OCC)=O)C1=CC=CC=C1)=O RDINNTSSIJKXSP-UHFFFAOYSA-N 0.000 description 1
- WOBINZADQCLCFO-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate Chemical compound O1C(=CC=C1)C1=CC(=C(N1)C(=O)OCC)C1=CC=C(C=C1)OC WOBINZADQCLCFO-UHFFFAOYSA-N 0.000 description 1
- FHDYSGQUUYKCNE-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-3-(4-methoxyphenyl)-2,5-dioxopentanoate Chemical compound O1C(=CC=C1)C(CC(C(C(=O)OCC)=O)C1=CC=C(C=C1)OC)=O FHDYSGQUUYKCNE-UHFFFAOYSA-N 0.000 description 1
- OECWVQOPXWOVEJ-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-3-(4-methoxyphenyl)furan-2-carboxylate Chemical compound COC1=CC=C(C=C1)C=1C=C(OC=1C(=O)OCC)C=1OC=CC=1 OECWVQOPXWOVEJ-UHFFFAOYSA-N 0.000 description 1
- BUTNTOZMGAKNMZ-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-3-phenyl-1H-pyrrole-2-carboxylate Chemical compound O1C(=CC=C1)C1=CC(=C(N1)C(=O)OCC)C1=CC=CC=C1 BUTNTOZMGAKNMZ-UHFFFAOYSA-N 0.000 description 1
- NCIYZNGKICBGCV-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-3-phenylfuran-2-carboxylate Chemical compound C1(=CC=CC=C1)C=1C=C(OC=1C(=O)OCC)C=1OC=CC=1 NCIYZNGKICBGCV-UHFFFAOYSA-N 0.000 description 1
- NUIDXZBXZXQGNC-UHFFFAOYSA-N ethyl 5-(furan-2-yl)-3-phenylthiophene-2-carboxylate Chemical compound O1C(=CC=C1)C1=CC(=C(S1)C(=O)OCC)C1=CC=CC=C1 NUIDXZBXZXQGNC-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 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
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 2.2′-바이퓨란, 2.2′-바이티오펜, 2.2′-바이피롤 및 이들의 조합으로 이루어지는 2.2′-바이헤테로아로마틱 화합물들과 이들의 효율적인 제조 방법에 관한 것이다. 더욱 상세하게는 농약, 항균제, 항암제 및 OLED, 태양전지 등의 폭넓은 용도로 사용될 수 있는 바이-헤테로아로마틱 화합물의 합성을 위하여, 아세토아세틱 에스테르 화합물을 다양한 치환체의 페닐기와 헤테로아렌을 각각 함유하는 알파,베타-불포화 카르보닐 화합물에 첨가시켜 1,5-디카르보닐을 제조하고, 이 화합물에 망간(III)/코발트(II) 촉매를 이용한 탈아세틸화 반응을 적용하여 1,4-디카로보닐 화합물을 합성한 다음, 여기에 Paal-Knorr 합성법을 연계하여 상기의 바이-헤테로아로마틱 화합물을 합성하는 방법에 관한 것이다.The present invention relates to 2.2'-biheteroaromatic compounds consisting of 2.2'-bifuran, 2.2'-bithiophene, 2.2'-bipyrrole and combinations thereof and to a method for efficiently preparing them. More specifically, for the synthesis of bi-heteroaromatic compounds that can be used in a wide range of applications, such as pesticides, antibacterial agents, anticancer agents and OLEDs, solar cells, acetoacetic ester compounds each containing a phenyl group and heteroarene of various substituents, respectively 1,5-dicarbonyl was prepared by addition to an alpha, beta-unsaturated carbonyl compound, which was subjected to deacetylation using a manganese (III) / cobalt (II) catalyst to apply 1,4-dicarbobo. After synthesize | combining a nil compound, it relates to the method of synthesizing the said bi-heteroaromatic compound by Paal-Knorr synthesis method here.
바이칼코펜(bichalcophene)으로 알려져 있는 2.2′-바이퓨란 (bifuran), 2.2′-바이티오펜 (bithiophene), 및 2,2′-퓨라닐티오펜 (furanylthiophene) 화합물들은 그램-포지티브 (Gram-positive) 박테리아와 그램-네가티브 (Gram-negative) 박테리아에 대한 항균능력이 뛰어나며, 농약 및 항암제로도 사용될 수 있음이 알려져 있다(M. M. Youssef, M. A. Al-Omair, M. A. Ismail, Medicinal Chemistry Research 2011, DOI 10.1007/s00044-011-9964-y; W. A. Hussin, M. A. Ismail, W. M. El-Sayed, Drug Design, Development and Therapy 2013, 7, 185-193). 2.2'-bifuran, 2.2'-bithiophene, and 2,2'-furanylthiophene compounds, known as bichalcophene, are Gram-positive bacteria. It is known to have excellent antibacterial activity against Gram-negative bacteria and can be used as a pesticide and anticancer agent (MM Youssef, MA Al-Omair, MA Ismail, Medicinal Chemistry Research 2011, DOI 10.1007 / s00044- 011-9964-y; WA Hussin, MA Ismail, WM El-Sayed, Drug Design, Development and Therapy 2013, 7 , 185-193).
또한, 바이칼코펜 화합물들은 형광 발광 및 양자점 수율 (quantum yield)이 뛰어나 태양전지, OLED (organic light emitting diode), 트랜지스터, 센서 등의 폭넓은 광전자적 (opto-electronic) 응용이 가능하다(O. Gidron, N. Varsano, L. J. W. Shimon, G. Leitusb, M. Bendikov, Chem. Commun. 2013, DOI: 10.1039/c3cc41795f; C. Song, D. Sun, X. Peng, J. Bai, R. Zhang, S. Hou, J. Wang, Z. Xu, Chem. Commun. 2013, 49, 9167-9169).In addition, bikalcopene compounds have excellent fluorescence emission and quantum yield, which enables a wide range of optoelectronic applications in solar cells, organic light emitting diodes (OLEDs), transistors, and sensors (O. Gidron). , N. Varsano, LJW Shimon, G. Leitusb, M. Bendikov, Chem. Commun. 2013, DOI: 10.1039 / c3cc41795f; C. Song, D. Sun, X. Peng, J. Bai, R. Zhang, S. Hou, J. Wang, Z. Xu, Chem. Commun. 2013, 49, 9167-9169).
이와 같이 의학, 약학, 그리고 전기, 전자적 산업 영역에서 폭 넓게 사용될 수 있는 바이칼코펜 화합물의 합성을 위한 방법으로는 퓨란과 티오펜의 2번 위치의 활성을 통해 각각 할로겐과 주석 화합물을 제조한 다음, 반응식 a에서와 같이 전위금속 촉매를 이용한 결합반응을 이용하고 있다(A. A. Farahat, A. Kumar, A. E. M. Barghash, F. E. Goda, H. M. Eisa, D. W. Boykin, Journal of Heterocyclic Chemistry 2010, 47, 167-170). 이를 위하여 먼저 퓨란과 티오펜 화합물을 제조하여야 하며, 칼코펜의 2번 위치의 활성에 사용되는 반응 조건(알킬리튬과 같은 강한 염기조건)에 병행할 수 있는 치환체만을 함유하거나, 보호기를 이용하는 방법을 사용해야 하는 문제점이 있다.As a method for synthesizing the Baikalcopene compound which can be widely used in the medical, pharmaceutical, and electrical and electronic industries, the halogen and tin compounds are prepared by the activity of the second position of furan and thiophene, respectively. As in Scheme a, a coupling reaction using a dislocation metal catalyst is used (AA Farahat, A. Kumar, AEM Barghash, FE Goda, HM Eisa, DW Boykin, Journal of Heterocyclic Chemistry 2010, 47 , 167-170). To this end, first, furan and thiophene compounds should be prepared, and only a substituent which can be used in parallel with the reaction conditions (a strong base condition such as alkyllithium) used for the activity of position 2 of chalcopene, or using a protecting group There is a problem that must be used.
[반응식 a]Scheme a
X, Y = O 또는 SX, Y = O or S
한편, 퓨란이나 티오펜을 함유하는 1,4-디카르보닐 화합물의 Paal-Knorr 합성법으로도 바이칼코펜 화합물을 제조할 수 있다. Paal-Knorr 합성법은 1,4-디카르보닐 화합물에 산(acid), 로손 시약(Lawesson's Reagent), 및 1급 아민을 가하여 각각 퓨란, 티오펜, 및 피롤을 합성하는 방법으로 지난 100여 년 동안 유기합성 및 제약화학 분야에서 폭 넓게 사용되어 왔다. 본 합성법은 간단한 실험절차와 비교적 높은 수율로 별다른 문제점이 없는 헤테로 아로마틱 화합물의 제조 방법이지만 시작물질인 1,4-디카르보닐 화합물을 제조하는 방법이 까다롭다는 문제점을 가지고 있다(V. F. Ferreira, M. C. B. V. de Souza, A. C. Cunha, L. O. R. Pereira, M. L. G. Ferreira, Org. Perp. Procedures Int. 2001, 33, 411-454; G. Minetto, L. F. Raveglia, M. Taddei, Org. Lett. 2004, 6, 389-392). On the other hand, the Baikal-copene compound can also be manufactured by the Paal-Knorr synthesis method of the 1, 4- dicarbonyl compound containing furan and a thiophene. Paal-Knorr Synthesis is the synthesis of furan, thiophene, and pyrrole by adding acid, Lawson's Reagent, and primary amine to 1,4-dicarbonyl compounds for the last 100 years. Widely used in organic synthesis and pharmaceutical chemistry. This synthesis method is a method for preparing a heteroaromatic compound having no problems with simple experimental procedures and relatively high yields, but has a problem in that a method for preparing a starting material 1,4-dicarbonyl compound is difficult (VF Ferreira, MCBV). de Souza, AC Cunha, LOR Pereira, MLG Ferreira, Org.Perp.Procedures Int. 2001, 33 , 411-454; G. Minetto, LF Raveglia, M. Taddei, Org. Lett. 2004, 6 , 389-392) .
바이칼코펜을 합성하는데 필요한 퓨란이나 티오펜을 함유하는 1,4-디카르보닐 화합물의 제조 방법도 반응식 b에서와 같이 강한 염기 조건을 이용하거나(L. Fajari, E. Brillas, C. Alema, L. Julia, Journal of Organic Chemistry 1998, 63, 5324-5331), 반응식 c에서와 같이 루이스 산을 이용하는 강한 산성조건에서 장시간 반응하여 비교적 낮은 수율로 진행되는 것으로 알려져 있다(M. A. Ismail, Journal of Chemical Research 2006, 733-737).The method for preparing 1,4-dicarbonyl compounds containing furan or thiophene necessary for synthesizing Baikalcopene may also be prepared using strong base conditions as in Scheme b (L. Fajari, E. Brillas, C. Alema, L). Julia, Journal of Organic Chemistry 1998, 63 , 5324-5331), is known to proceed in a relatively low yield for a long time under strong acidic conditions using Lewis acid as in Scheme c (MA Ismail, Journal of Chemical Research 2006). , 733-737).
[반응식 b]Scheme b
X, Y = O 또는 SX, Y = O or S
[반응식 c]Scheme c
X = O 또는 SX = O or S
반응식 d에 나타낸 바와 같이, 아세토아세틱 에스테르를 메틸 비닐 케톤에 첨가시켜(1,4-addition) 얻어지는 1,5-디카르보닐 화합물을 대기 하에서 망간(III)/코발트(II) 촉매와 반응시킬 경우, 온화한 조건에서 효율적으로 라디칼 산화 반응이 진행되어 탈아세틸화 반응을 거쳐 1,4-디카르보닐 화합물이 형성됨과, 여기에 Paal-Knorr 반응을 적용하여 퓨란, 티오펜, 및 다양한 치환체의 피롤을 합성할 수 있음을 보고하였다(Y. Ju, D. Miao, S. Koo, Org. Biomol. Chem. 2015, 13, 2588-2599; 대한민국 특허 등록 10-1623810). As shown in Scheme d, the 1,5-dicarbonyl compound obtained by adding acetoacetic ester to methyl vinyl ketone (1,4-addition) is reacted with a manganese (III) / cobalt (II) catalyst under air. In this case, the radical oxidation reaction proceeds efficiently under mild conditions to form a 1,4-dicarbonyl compound through a deacetylation reaction, and the Paal-Knorr reaction is applied to pyrrole of furan, thiophene, and various substituents. Has been reported (Y. Ju, D. Miao, S. Koo, Org. Biomol. Chem. 2015, 13 , 2588-2599; Korean Patent Registration 10-1623810).
[반응식 d]Scheme d
X = O 또는 S 또는 NHX = O or S or NH
상기의 금속촉매 산화반응은 1,5-디카르보닐 화합물로부터 1,4-디카르보닐 화합물을 효율적으로 제공해 줄 수 있었기 때문에, Paal-Knorr의 합성법으로 비스-헤테로아로마틱 화합물을 제공해 주는데 필요한 1,4-디카르보닐 화합물의 합성을 위해서는 이에 상응하는 1,5-디카르보닐 화합물의 제조가 필요하다. 상기 1,5-디카르보닐 화합물은 각각 퓨란, 티오펜, 또는 피롤을 함유해야하며, 다양한 페닐치환체에 의한 개선된 생리활성과 물질특성을 기대하기 위해, 페닐치환체와 헤테로아렌을 각각 함유하는 알파,베타-불포화 카르보닐 화합물의 제조와 아세토아세틱 에스테르의 첨가 반응을 통해 이들을 합성하도록 계획하였다.Since the metal catalyst oxidation reaction was able to efficiently provide the 1,4-dicarbonyl compound from the 1,5-dicarbonyl compound, it is necessary to provide a bis-heteroaromatic compound by the synthesis method of Paal-Knorr. Synthesis of 4-dicarbonyl compounds requires the preparation of corresponding 1,5-dicarbonyl compounds. The 1,5-dicarbonyl compound should each contain furan, thiophene, or pyrrole, and alpha containing phenyl substituent and heteroarene, respectively, in order to expect improved physiological activity and material properties by various phenyl substituents. It was planned to synthesize these through the preparation of beta-unsaturated carbonyl compounds and the addition reaction of acetoacetic esters.
본 발명은 다양한 페닐 치환체를 포함함으로써 생리활성 및 광전자 공학적 효능이 개선된 바이퓨란, 바이티오펜, 퓨라닐티오펜 등의 바이칼코펜과 더불어 바이피롤, 퓨라닐피롤, 티오페닐피롤 등의 바이-헤테로아로마틱 화합물을 제공하는 것을 목적으로 한다.The present invention is a bi-heteroaromatic, such as bipyrrole, furanylpyrrole, thiophenylpyrrole, as well as bikalcopene, such as bifuran, bithiophene, furanylthiophene improved bioactivity and optoelectronic efficiency by including various phenyl substituents It is an object to provide a compound.
또한, 본 발명은 Paal-Knorr 합성법으로 제조하는데 필요한 1,4-디카르보닐 화합물, 및 이들을 1,5-디카르보닐 화합물의 금속촉매를 이용하는 산화반응으로 제조하는 방법을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a 1,4-dicarbonyl compound, which is required to be prepared by the Paal-Knorr synthesis method, and a method for producing these by an oxidation reaction using a metal catalyst of a 1,5-dicarbonyl compound. .
본 발명의 목적은 이상에서 언급한 목적으로 제한되지 않는다. 본 발명의 목적은 이하의 설명으로 보다 분명해질 것이며, 특허청구범위에 기재된 수단 및 그 조합으로 실현될 것이다.The object of the present invention is not limited to the above-mentioned object. The object of the present invention will become more apparent from the following description, and will be realized by the means described in the claims and combinations thereof.
본 발명의 일 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3로 표시된다.Bi-heteroaromatic compound comprising a phenyl substituent according to an embodiment of the present invention is represented by the following formula (3).
[화학식 3][Formula 3]
상기 화학식 3 중에서, R1, R2, R3는 서로 독립적으로 NO2, OMe, Br, F 또는 CN이고; R4는 탄소수 1~3의 알킬기이며; X 및 Y는 독립적으로 O, S 또는 N-R이고; R은 H 또는 질소의 보호기이다.In Formula 3, R 1 , R 2 , R 3 are independently of each other NO 2 , OMe, Br, F or CN; R 4 is an alkyl group having 1 to 3 carbon atoms; X and Y are independently O, S or NR; R is a protecting group of H or nitrogen.
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3a로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to another embodiment of the present invention is represented by the formula (3a).
[화학식 3a][Formula 3a]
상기 화학식 3a 중에서, In Formula 3a,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3a에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-1로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3a of the present invention is represented by the following Chemical Formula 3-1.
[화학식 3-1][Formula 3-1]
본 발명의 화학식 3a에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-2로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the formula (3a) of the present invention is represented by the formula (3-2).
[화학식 3-2][Formula 3-2]
본 발명의 화학식 3a에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-3로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3a of the present invention is represented by the following Formula 3-3.
[화학식 3-3][Formula 3-3]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3b로 표시된다.Bi-heteroaromatic compound comprising a phenyl substituent according to another embodiment of the present invention is represented by the following formula (3b).
[화학식 3b][Formula 3b]
상기 화학식 3b 중에서, In Formula 3b,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3b에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-4로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3b of the present invention is represented by the following Formula 3-4.
[화학식 3-4][Formula 3-4]
본 발명의 화학식 3b에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-5로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the general formula (3b) of the present invention is represented by the following formula 3-5.
[화학식 3-5][Formula 3-5]
본 발명의 화학식 3b에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-6로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3b of the present invention is represented by the following Formula 3-6.
[화학식 3-6][Formula 3-6]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3c로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to another embodiment of the present invention is represented by the formula (3c).
[화학식 3c][Formula 3c]
상기 화학식 3c 중에서, In Formula 3c,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3c에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-7로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the formula (3c) of the present invention is represented by the following formula (3-7).
[화학식 3-7][Formula 3-7]
본 발명의 화학식 3c에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-8로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the formula (3c) of the present invention is represented by the formula (3-8).
[화학식 3-8][Formula 3-8]
본 발명의 화학식 3c에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-9로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3c of the present invention is represented by the following Formula 3-9.
[화학식 3-9][Formula 3-9]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3d로 표시된다.Bi-heteroaromatic compound comprising a phenyl substituent according to another embodiment of the present invention is represented by the following formula (3d).
[화학식 3d][Formula 3d]
상기 화학식 3d 중에서, In Formula 3d,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3d에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-10으로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3d of the present invention is represented by the following Chemical Formula 3-10.
[화학식 3-10][Formula 3-10]
본 발명의 화학식 3d에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-11로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3d of the present invention is represented by the following Chemical Formula 3-11.
[화학식 3-11][Formula 3-11]
본 발명의 화학식 3d에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-12로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3d of the present invention is represented by the following Formula 3-12.
[화학식 3-12][Formula 3-12]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3e로 표시된다.Bi-heteroaromatic compound comprising a phenyl substituent according to another embodiment of the present invention is represented by the formula (3e).
[화학식 3e][Formula 3e]
상기 화학식 3e 중에서, In Formula 3e,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3e에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-13으로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3e of the present invention is represented by the following Chemical Formula 3-13.
[화학식 3-13][Formula 3-13]
본 발명의 화학식 3e에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-14로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the general formula (3e) of the present invention is represented by the following formula (3-14).
[화학식 3-14][Formula 3-14]
본 발명의 화학식 3e에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-15로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3e of the present invention is represented by the following Formula 3-15.
[화학식 3-15][Formula 3-15]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3f로 표시된다.Bi-heteroaromatic compound comprising a phenyl substituent according to another embodiment of the present invention is represented by the following formula (3f).
[화학식 3f][Formula 3f]
상기 화학식 3f 중에서, In Formula 3f,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3f에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-16으로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the formula (3f) of the present invention is represented by the following formula (3-16).
[화학식 3-16][Formula 3-16]
본 발명의 화학식 3f에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-17로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3f of the present invention is represented by the following Chemical Formula 3-17.
[화학식 3-17][Formula 3-17]
본 발명의 화학식 3f에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-18로 표시된다.Bi-heteroaromatic compounds containing a phenyl substituent according to the general formula (3f) of the present invention are represented by the following formula (3-18).
[화학식 3-18][Formula 3-18]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3g로 표시된다.Bi-heteroaromatic compound comprising a phenyl substituent according to another embodiment of the present invention is represented by the following formula (3g).
[화학식 3g][Formula 3g]
상기 화학식 3g 중에서, In Formula 3g,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3g에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-19로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3g of the present invention is represented by the following Chemical Formula 3-19.
[화학식 3-19][Formula 3-19]
본 발명의 화학식 3g에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-20으로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the general formula (3g) of the present invention is represented by the following formula 3-20.
[화학식 3-20][Formula 3-20]
본 발명의 화학식 3g에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-21로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the formula 3g of the present invention is represented by the following formula 3-21.
[화학식 3-21][Formula 3-21]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3h로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to another embodiment of the present invention is represented by the formula 3h.
[화학식 3h][Formula 3h]
상기 화학식 3h 중에서, In Formula 3h,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3h에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-22로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3h of the present invention is represented by the following Chemical Formula 3-22.
[화학식 3-22][Formula 3-22]
본 발명의 화학식 3h에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-23으로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3h of the present invention is represented by the following Chemical Formula 3-23.
[화학식 3-23][Formula 3-23]
본 발명의 화학식 3h에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-24로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3h of the present invention is represented by the following Chemical Formula 3-24.
[화학식 3-24][Formula 3-24]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3i로 표시된다.A bi-heteroaromatic compound including a phenyl substituent according to another embodiment of the present invention is represented by the following Chemical Formula 3i.
[화학식 3i][Formula 3i]
상기 화학식 3i 중에서, In Formula 3i,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3i에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-25로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the general formula (3i) of the present invention is represented by the following formula 3-25.
[화학식 3-25][Formula 3-25]
본 발명의 화학식 3i에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-26으로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3i of the present invention is represented by the following Formula 3-26.
[화학식 3-26][Formula 3-26]
본 발명의 화학식 3i에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-27로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Formula 3i of the present invention is represented by the following Formula 3-27.
[화학식 3-27][Formula 3-27]
본 발명의 다른 실시예에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3j로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to another embodiment of the present invention is represented by the formula (3j).
[화학식 3j][Formula 3j]
상기 화학식 3j 중에서, In Formula 3j,
Y는 O, S 또는 NH이다.Y is O, S or NH.
본 발명의 화학식 3j에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-28로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3j of the present invention is represented by the following Chemical Formula 3-28.
[화학식 3-28][Formula 3-28]
본 발명의 화학식 3j에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-29로 표시된다.A bi-heteroaromatic compound comprising a phenyl substituent according to Chemical Formula 3j of the present invention is represented by the following Chemical Formula 3-29.
[화학식 3-29][Formula 3-29]
본 발명의 화학식 3j에 따른 페닐치환체를 포함하는 바이-헤테로아로마틱 화합물은 하기 화학식 3-30으로 표시된다.Bi-heteroaromatic compound containing a phenyl substituent according to the general formula (3j) of the present invention is represented by the following formula (3-30).
[화학식 3-30][Formula 3-30]
본 발명의 다른 실시예에 따른 1,4-디카르보닐 화합물은 하기 화학식 2a로 표시된다.1,4-dicarbonyl compound according to another embodiment of the present invention is represented by the formula (2a).
[화학식 2a][Formula 2a]
상기 화학식 2a 중에서, In Formula 2a,
X는 O, S 또는 NBz이다.X is O, S or NBz.
본 발명의 화학식 2a에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-1로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2a of the present invention is represented by the following Chemical Formula 2-1.
[화학식 2-1][Formula 2-1]
본 발명의 화학식 2a에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-2로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2a of the present invention is represented by the following Chemical Formula 2-2.
[화학식 2-2][Formula 2-2]
본 발명의 화학식 2a에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-3로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2a of the present invention is represented by the following Chemical Formula 2-3.
[화학식 2-3][Formula 2-3]
본 발명의 다른 실시예에 따른 1,4-디카르보닐 화합물은 하기 화학식 2b로 표시된다.1,4-dicarbonyl compound according to another embodiment of the present invention is represented by the formula (2b).
[화학식 2b][Formula 2b]
상기 화학식 2b 중에서, In Formula 2b,
R은 NO2, OMe, Br 또는 F이다.R is NO 2 , OMe, Br or F.
본 발명의 화학식 2b에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-4로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2b of the present invention is represented by the following Chemical Formula 2-4.
[화학식 2-4][Formula 2-4]
본 발명의 화학식 2b에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-5로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2b of the present invention is represented by the following Chemical Formula 2-5.
[화학식 2-5][Formula 2-5]
본 발명의 화학식 2b에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-6으로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2b of the present invention is represented by the following Chemical Formula 2-6.
[화학식 2-6][Formula 2-6]
본 발명의 화학식 2b에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-7로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2b of the present invention is represented by the following Chemical Formula 2-7.
[화학식 2-7][Formula 2-7]
본 발명의 다른 실시예에 따른 1,4-디카르보닐 화합물은 하기 화학식 2c로 표시된다.1,4-dicarbonyl compound according to another embodiment of the present invention is represented by the formula (2c).
[화학식 2c][Formula 2c]
상기 화학식 2c 중에서, In Formula 2c,
X는 S 또는 O 이다.X is S or O.
본 발명의 화학식 2c에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-8로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2c of the present invention is represented by the following Chemical Formula 2-8.
[화학식 2-8][Formula 2-8]
본 발명의 화학식 2c에 따른 1,4-디카르보닐 화합물은 하기 화학식 2-9로 표시된다.The 1,4-dicarbonyl compound according to Chemical Formula 2c of the present invention is represented by the following Chemical Formula 2-9.
[화학식 2-9][Formula 2-9]
본 발명의 또 다른 실시예에 따른 1,4-디카르보닐 화합물은 하기 화학식 2d으로 표시된다.1,4-dicarbonyl compound according to another embodiment of the present invention is represented by the following formula (2d).
[화학식 2d][Formula 2d]
본 발명의 또 다른 실시예에 따른 바이-헤테로아로마틱 화합물의 합성방법은 (a) 아세토아세틱 에스테르 화합물 및 페닐치환체를 포함하는 알파,베타-불포화 카르보닐 화합물을 반응시켜 하기 화학식 1로 표시되는 1,5-디카르보닐 화합물을 제조하는 단계;Method for synthesizing a bi-heteroaromatic compound according to another embodiment of the present invention is (a) by reacting an alpha, beta-unsaturated carbonyl compound comprising an acetoacetic ester compound and a phenyl substituent 1 represented by the following formula (1) Preparing a 5-5-dicarbonyl compound;
[화학식 1][Formula 1]
(b) 상기 (a)단계에서 제조된 1,5-디카르보닐 화합물을 망간 및 코발트를 포함하는 금속촉매의 존재 하에서 탈아세틸화 반응시켜 하기 화학식 2로 표시되는 1,4-디카르보닐 화합물을 합성하는 단계; 및(b) The 1,5-dicarbonyl compound represented by the following Chemical Formula 2 by deacetylation of the 1,5-dicarbonyl compound prepared in step (a) in the presence of a metal catalyst containing manganese and cobalt Synthesizing; And
[화학식 2][Formula 2]
(c) 상기 (b)단계에서 합성된 1,4-디카르보닐 화합물을 Paal-Knorr 합성법으로 반응시켜 하기 화학식 3으로 표시되는 화합물을 제조하는 단계를 포함한다.(c) reacting the 1,4-dicarbonyl compound synthesized in step (b) by Paal-Knorr synthesis to prepare a compound represented by the following Chemical Formula 3.
[화학식 3][Formula 3]
상기 화학식 1 내지 화학식 3 중에서, R1, R2, R3는 서로 독립적으로 NO2, OMe, Br, F 또는 CN이고; R4는 탄소수 1~3의 알킬기이며; X 및 Y는 독립적으로 O, S 또는 N-R이고; R은 H 또는 질소의 보호기이다.In Formulas 1 to 3, R 1 , R 2 , R 3 are independently of each other NO 2 , OMe, Br, F or CN; R 4 is an alkyl group having 1 to 3 carbon atoms; X and Y are independently O, S or NR; R is a protecting group of H or nitrogen.
상기 (b)단계에서 탈아세틸화 반응은 1,5-디카르보닐 화합물을 아세트산에 용해시킨 후, 5~10 mol% Mn(OAc)3·2H2O 및 2~5 mol% CoCl2를 첨가하여 실시될 수 있다.In the step (b), the deacetylation reaction is performed by dissolving the 1,5-dicarbonyl compound in acetic acid, and then adding 5-10 mol% Mn (OAc) 3 · 2H 2 O and 2-5 mol% CoCl 2 . It can be carried out by.
상기 (b)단계에서 탈아세틸화 반응은 25~60℃의 온도에서 1~48시간 동안 실시될 수 있다.Deacetylation in step (b) may be carried out for 1 to 48 hours at a temperature of 25 ~ 60 ℃.
상기 (c)단계에서 반응은 50~100℃에서 0.5~10시간 동안 실시될 수 있다.In step (c), the reaction may be carried out at 50 to 100 ° C. for 0.5 to 10 hours.
상기 (c)단계에서 반응 시 황산, 로손 시약(2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide), 암모늄아세테이트(NH4OAc)와 설파믹 산(sulfamic acid) 및 이들의 조합으로부터 선택되는 적어도 1종을 첨가할 수 있다.In the step (c), sulfuric acid, Lawson's reagent (2,4-Bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide), ammonium acetate (NH 4 OAc) and sulfa At least one selected from sulfamic acid and combinations thereof may be added.
상기 (b)단계 및 (c)단계는 원-포트 연속반응방식으로 수행될 수 있다.Steps (b) and (c) may be performed in a one-port continuous reaction method.
본 발명에 따르면, 아세토아세틱 에스테르 화합물을 다양한 페닐치환체와 헤테로아렌을 함유하는 알파,베타-불포화 카르보닐 화합물에 첨가시켜 얻을 수 있는 1,5-디카르보닐 화합물로부터 Mn(III)/Co(II)의 금속 산화 촉매를 이용한 탈아세틸화 반응을 적용하여 Paal-Knorr 합성에 필요한 1,4-디카르보닐 화합물을 효율적으로 합성할 수 있다. 이들 1,4-디카르보닐 화합물에 Paal-Knorr 합성법을 적용하여 다양한 페닐치환체를 함유하는 신규의 2,2′-바이헤테로아로마틱 화합물을 제조할 수 있다. 이들 신규의 2,2′-바이헤테로아로마틱 화합물들은 페닐 치환체의 다양한 작용기에 의하여 기존의 항균, 항암 등의 생리활성, 및 태양전지, OLED에서의 광전자적 특성이 개선된 물질특성을 함유할 것으로 기대된다.According to the present invention, Mn (III) / Co (1) is obtained from a 1,5-dicarbonyl compound obtained by adding an acetoacetic ester compound to an alpha, beta-unsaturated carbonyl compound containing various phenyl substituents and heteroarene. The deacetylation reaction using the metal oxidation catalyst of II) can be applied to efficiently synthesize the 1,4-dicarbonyl compound required for Paal-Knorr synthesis. By applying the Paal-Knorr synthesis method to these 1,4-dicarbonyl compounds, a novel 2,2'-biheteroaromatic compound containing various phenyl substituents can be prepared. These new 2,2′-biheteroaromatic compounds are expected to contain material properties with improved physiological activities such as antibacterial, anticancer, and photoelectric properties in solar cells and OLEDs by various functional groups of phenyl substituents. do.
이하, 실시예를 통하여 본 발명에 대하여 더욱 구체적으로 설명한다. 이는 본 발명이 속하는 기술 분야의 통상의 기술자에게 본 발명이 충분히 전달될 수 있도록 하기 위하여 제공되는 것이 이하의 실시예에 의하여 본 발명에 제한되어서는 안 된다.Hereinafter, the present invention will be described in more detail with reference to Examples. This should not be limited to the present invention by the following examples that are provided to ensure that the present invention to those skilled in the art to which the present invention pertains.
이하에서는 본 발명의 바이-헤테로아로마틱 화합물의 제조방법을 반응식을 이용하여 상세하게 설명한다.Hereinafter, the preparation method of the bi-heteroaromatic compound of the present invention will be described in detail using a reaction scheme.
본 발명의 바이-헤테로아로마틱 화합물의 제조방법은 (a)아세토아세틱 에스테르 화합물을 페닐 치환체와 헤테로아렌을 각각 포함하는 알파,베타-불포화 카르보닐 화합물에 첨가하여 1,5-디카르보닐 화합물을 합성하는 단계, (b) 상기 1,5-디카르보닐 화합물을 대기 하에서의 금속 촉매를 이용한 탈아세틸화 반응을 적용하여 1,4-디카르보닐 화합물을 합성하는 단계 및 (c) 상기 1,4-디카르보닐 화합물에 Paal-Knorr 헤테로아렌 제조 반응을 적용하는 단계를 포함한다. In the method for producing a bi-heteroaromatic compound of the present invention, (a) an acetoacetic ester compound is added to an alpha, beta-unsaturated carbonyl compound each containing a phenyl substituent and a heteroarene, thereby preparing a 1,5-dicarbonyl compound. Synthesizing (b) synthesizing the 1,4-dicarbonyl compound by applying a deacetylation reaction of the 1,5-dicarbonyl compound using a metal catalyst under an atmosphere, and (c) the 1,4 Applying a Paal-Knorr heteroarene preparation reaction to the dicarbonyl compound.
상기 (a)단계에서 페닐 치환체와 헤테로아렌을 함유하는 알파,베타-불포화 카르보닐 화합물은 하기 반응식 1에서와 같이 다양한 치환체의 벤즈알데하이드와 각각 2-아세틸퓨란, 2-아세틸티오펜, 및 2-아세틸피롤의 알돌반응으로부터 제조될 수 있다.In step (a), the alpha, beta-unsaturated carbonyl compound containing a phenyl substituent and heteroarene may be selected from benzaldehyde and 2-acetylfuran, 2-acetylthiophene, and 2- of various substituents, as shown in Scheme 1 below. It can be prepared from the aldol reaction of acetylpyrrole.
[반응식 1]Scheme 1
R1, R2, R3는 각각 NO2, OMe, Br, F CN으로부터 선택되며,R 1 , R 2 , R 3 are each selected from NO 2 , OMe, Br, F CN,
X는 O, S, N-R 중에서 선택되고, R은 H 또는 질소의 보호기이다.X is selected from O, S, N-R, and R is a protecting group of H or nitrogen.
상기 (a)단계는 에틸 아세토아세테이트를 씨내모일 퓨란 (cinnamoyl furan), 씨내모일 티오펜 (cinnamoyl thiophene), 및 씨내모일 피롤 (cinnamoyl pyrrole)과 반응시켜 하기 화학식 1-a로 표시되는 1,5-디카르보닐 화합물을 합성하는 단계일 수 있다. In step (a), ethyl acetoacetate is reacted with cinnamoyl furan, cinnamoyl thiophene, and cinnamoyl pyrrole to represent 1,5- represented by Chemical Formula 1-a. Synthesizing the dicarbonyl compound.
[화학식 1-a][Formula 1-a]
X는 O, S, N-R 중에서 선택되며, R은 H 또는 질소의 보호기X is selected from O, S, N-R, and R is a protecting group of H or nitrogen
상기 (b)단계는 1,5-디카르보닐 화합물을 아세트산에 용해시킨 용액에 5~10 mol% Mn(OAc)3·2H2O 및 2~5 mol% CoCl2를 첨가하여 탈아세틸화 반응을 수행하는 단계일 수 있다. The step (b) 1,5-dicarbonyl 5 ~ 10 mol% of the carbonyl compound dissolved in acetic acid Mn (OAc) 3 · 2H 2 O , and 2 ~ 5 mol% CoCl 2 was added to deacetylation reaction It may be a step of performing.
상기 (b)단계는 25~60℃에서 1~48 시간 동안 수행할 수 있으며, 에틸 아세토아세테이트를 씨내모일 퓨란 (cinnamoyl furan), 씨내모일 티오펜 (cinnamoyl thiophene), 및 씨내모일 피롤 (cinnamoyl pyrrole)과 반응시켜 하기 화학식 2-a로 표시되는 1,4-디카르보닐 화합물을 합성하는 단계일 수 있다. Step (b) may be performed at 25 to 60 ° C. for 1 to 48 hours, and ethyl acetoacetate is cinnamoyl furan, cinnamoyl thiophene, and cinnamoyl pyrrole. It may be a step of synthesizing a 1,4-dicarbonyl compound represented by the following formula 2-a.
[화학식 2-a][Formula 2-a]
X는 O, S, N-R 중에서 선택되며, R은 H 또는 질소의 보호기X is selected from O, S, N-R, and R is a protecting group of H or nitrogen
상기 (c)단계는 Paal-Knorr 헤테로아렌 제조 반응으로 황산을 첨가하여 반응시킬 경우 퓨란을, 로손 시약(Lawesson’s reagent)을 첨가하여 반응시킬 경우 티오펜을, 암모늄아세테이트(NH4OAc)와 설파믹 산(sulfamic acid)을 첨가하여 반응시킬 경우 피롤이 수득할 수 있다.In the step (c), the furan is reacted by adding sulfuric acid in the Paal-Knorr heteroarene reaction, and thiophene is reacted by adding Lawson's reagent, and ammonium acetate (NH 4 OAc) and sulfamic Pyrrole can be obtained by reaction with the addition of sulfamic acid.
상기 (c)단계는 50~100℃에서 0.5~10시간 동안 수행할 수 있다.The step (c) may be performed at 50 to 100 ° C. for 0.5 to 10 hours.
상기 (c)단계는 에틸 아세토아세테이트를 씨내모일 퓨란 (cinnamoyl furan), 씨내모일 티오펜 (cinnamoyl thiophene), 및 씨내모일 피롤 (cinnamoyl pyrrole)과 반응시켜 하기 화학식 3-a으로 표시되는 바이헤테로아렌을 합성하는 단계일 수 있다.In the step (c), ethyl acetoacetate is reacted with cinnamoyl furan, cinnamoyl thiophene, and cinnamoyl pyrrole to obtain biheteroarene represented by the following Chemical Formula 3-a. May be a step of synthesizing.
[화학식 3-a][Formula 3-a]
X는 O, S, N-R 중에서 선택되며, R은 H 또는 질소의 보호기X is selected from O, S, N-R, and R is a protecting group of H or nitrogen
참고예 1. 재료준비 및 실험방법Reference Example 1. Material Preparation and Experimental Method
본 발명은 1H 및 13CNMR 스펙트럼은 각각 테트라메틸실란(TMS)을 포함하는 듀테로화된(deuterated) 클로로포름(CDCl3)에서 400 MHz와 100 MHz의 NMR 분광계에 기록되었다. 추출용매와 크로마토그래피는 시약 등급으로 사용하였다. 컬럼 크로마토그래피는 EtOAc/hexane의 구배 혼합물(gradient mixture)을 이용하였고 실리카겔 60 (70-230 mesh ASTM)을 이용한 Still 법으로 수행되었다. 별도로 언급하지 않은 한, 산화반응을 제외한 반응들은 아르곤 분위기 하 잘 건조된 플라스크에서 수행하였다. 산화 반응은 촉매로 Mn(OAc)3·2H2O 및 CoCl2를 사용하였고 공기 하에서 수행하였다.In the present invention, 1 H and 13 CNMR spectra were recorded on an NMR spectrometer of 400 MHz and 100 MHz in deuterated chloroform (CDCl 3) containing tetramethylsilane (TMS), respectively. Extraction solvents and chromatography were used as reagent grades. Column chromatography was performed using a gradient mixture of EtOAc / hexane and still using Silica gel 60 (70-230 mesh ASTM). Unless stated otherwise, reactions except oxidation were carried out in well-dried flasks under argon atmosphere. The oxidation reaction used Mn (OAc) 3 .2H 2 O and CoCl 2 as catalyst and was carried out under air.
실시예 1: 하기 화학식 1-1로 표시되는 화합물(Ethyl 2-acetyl-5-oxo-3-phenyl-5-(thiophen-2-yl)pentanoate)의 제조Example 1: Preparation of a compound represented by the following formula 1-1 (Ethyl 2-acetyl-5-oxo-3-phenyl-5- (thiophen-2-yl) pentanoate)
[화학식 1-1][Formula 1-1]
아르곤 분위기 하, 25℃에서, 에틸 아세토아세토아세테이트(ethyl acetoacetate, 7.29 g, 56.00 mmol)와 스티레닐 2-티오페닐 케톤 (styrenyl 2-thiophenyl ketone, 4.00 g, 18.67 mmol)의 혼합물에 CeCl3.7H2O(0.70 g, 1.87 mmol) 및 NaI(0.28 g, 1.87 mmol)를 첨가하였다. 혼합물을 12시간 동안 교반하고 EtOAc로 묽힌 다음, 고체를 거름종이로 거르고, 여과액을 감압 하에서 농축하여 정제되지 않은 생성물(crude product)을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피(silica gel flash column chromatography)로 정제하여 1.2:1 입체이성질체의 혼합물로 이루어진 흰색 고체의 화학식 1-1로 표시되는 화합물(6.57 g, 19.00 mmol)을 얻었다(수율 100%).CeCl 3 .7H in a mixture of ethyl acetoacetoacetate (7.29 g, 56.00 mmol) and styrenyl 2-thiophenyl ketone (4.00 g, 18.67 mmol) at 25 ° C. under argon atmosphere. 2 O (0.70 g, 1.87 mmol) and NaI (0.28 g, 1.87 mmol) were added. The mixture was stirred for 12 h and diluted with EtOAc, then the solid was filtered through a filter paper and the filtrate was concentrated under reduced pressure to give a crude product. This was purified by silica gel flash column chromatography to obtain the compound (6.57 g, 19.00 mmol) represented by Chemical Formula 1-1 as a white solid consisting of a mixture of 1.2: 1 stereoisomers (yield 100%). ).
화학식 1-1로 표시되는 화합물의 데이터: Rf = 0.20 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 0.95 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.23 (d of A of ABq, J AB = 16.4, J d = 8.4 Hz, 1H), 3.30 (d of B of ABq, J AB = 16.4, J d = 4.8 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 4.07 (d, J = 10.4 Hz, 1H), 4.14 (ddd, J = 10.4, 8.4, 4.8 Hz, 1H), 7.06 (dd, J = 5.2, 4.0 Hz, 1H), 7.13-7.26 (m, 5H), 7.57 (dd, J = 5.2, 1.2 Hz, 1H), 7.65 (dd, J = 4.0, 1.2 Hz, 1H) ppm; (minor) δ 1.25 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.32 (d of A of ABq, J AB = 16.0, J d = 9.2 Hz, 1H), 3.40 (d of B of ABq, J AB = 16.0, J d = 4.4 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 4.14 (ddd, J = 10.0, 9.2, 4.4 Hz, 1H), 4.20 (dq, J d = 1.2, J q = 7.2 Hz, 2H), 7.07 (dd, J = 5.2, 4.0 Hz, 1H), 7.13-7.26 (m, 5H), 7.57 (dd, J = 5.2, 1.2 Hz, 1H), 7.71 (dd, J = 4.0, 1.2 Hz, 1H) ppm; 13C-NMR (major) δ13.6, 29.5, 40.8, 43.2, 61.3, 65.0, 68.9, 127.2, 128.0, 128.0, 128.6, 132.1, 133.7, 140.2, 144.0, 168.3, 190.7, 201.9 ppm; (minor) δ 13.9, 29.9, 41.1, 43.4, 61.6, 64.5, 127.0, 128.0, 128.0, 128.3, 132.0, 133.6, 139.9, 144.0, 167.8, 190.4, 202.2 ppm.Data for the compound represented by Formula 1-1: R f = 0.20 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 0.95 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.23 (d of A of ABq, J AB = 16.4, J d = 8.4 Hz, 1H), 3.30 (d of B of ABq, J AB = 16.4, J d = 4.8 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 4.07 (d, J = 10.4 Hz, 1H), 4.14 (ddd, J = 10.4, 8.4, 4.8 Hz, 1H), 7.06 (dd, J = 5.2, 4.0 Hz, 1H), 7.13-7.26 (m, 5H), 7.57 (dd, J = 5.2, 1.2 Hz, 1H), 7.65 ( dd, J = 4.0, 1.2 Hz, 1H) ppm; (minor) δ 1.25 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.32 (d of A of ABq, J AB = 16.0, J d = 9.2 Hz, 1H), 3.40 (d of B of ABq, J AB = 16.0, J d = 4.4 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 4.14 (ddd, J = 10.0, 9.2, 4.4 Hz, 1H), 4.20 (dq, J d = 1.2, J q = 7.2 Hz, 2H), 7.07 (dd, J = 5.2, 4.0 Hz, 1H), 7.13-7.26 (m, 5H), 7.57 (dd, J = 5.2, 1.2 Hz, 1H), 7.71 (dd, J = 4.0, 1.2 Hz, 1H) ppm; 13 C-NMR (major) δ 13.6, 29.5, 40.8, 43.2, 61.3, 65.0, 68.9, 127.2, 128.0, 128.0, 128.6, 132.1, 133.7, 140.2, 144.0, 168.3, 190.7, 201.9 ppm; (minor) δ 13.9, 29.9, 41.1, 43.4, 61.6, 64.5, 127.0, 128.0, 128.0, 128.3, 132.0, 133.6, 139.9, 144.0, 167.8, 190.4, 202.2 ppm.
실시예 2: 하기 화학식 2-1로 표시되는 화합물(Ethyl 2,5-dioxo-3-phenyl-5-(thiophen-2-yl)pentanoate) 의 제조Example 2: Preparation of a compound represented by the following formula 2-1 (Ethyl 2,5-dioxo-3-phenyl-5- (thiophen-2-yl) pentanoate)
[화학식 2-1][Formula 2-1]
화학식 1-1로 표시되는 화합물(0.79 g, 2.29 mmol)을 아세트산(10 mL)에 녹이고 Mn(OAc)3·2H2O(60 mg, 0.23 mmol) 및 CoCl2(30 mg, 0.23 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 25℃에서 14시간 동안 격렬하게 교반하고 감압 하에서 용매를 제거하여 정제되지 않은 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 연노랑 오일 타입의 화학식 2-1로 표시되는 화합물(0.52 g, 1.64 mmol)을 얻었다(수율 72%).The compound of Formula 1-1 (0.79 g, 2.29 mmol) was dissolved in acetic acid (10 mL), and Mn (OAc) 3 · 2H 2 O (60 mg, 0.23 mmol) and CoCl 2 (30 mg, 0.23 mmol) were added thereto. Added. The mixture was stirred vigorously at 25 ° C. for 14 hours under air and the solvent was removed under reduced pressure to give the crude product. This was purified by silica gel flash column chromatography to obtain a compound (0.52 g, 1.64 mmol) represented by the formula (2-1) as a light yellow oil type (yield 72%).
화학식 2-1로 표시되는 화합물의 데이터: Rf = 0.42 (hexane:EtOAc = 4:1); 1H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 3.37 (dd, J = 18.0, 4.0 Hz, 1H), 3.97 (dd, J = 18.0, 10.4 Hz, 1H), 4.19-4.33 (m, 2H), 5.14 (dd, J = 10.4, 4.0 Hz, 1H), 7.12 (dd, J = 4.4, 3.6 Hz, 1H), 7.26-7.38 (m, 5H), 7.64 (dd, J = 4.4, 0.8 Hz, 1H), 7.73 (dd, J = 3.6, 0.8 Hz, 1H) ppm; 13C-NMR δ 13.8, 43.2, 48.3, 62.5, 128.0, 128.1, 128.8, 129.1, 132.4, 134.0, 135.1, 142.8, 160.2, 190.1, 191.9 ppm.Data of the compound represented by Formula 2-1: R f = 0.42 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 3.37 (dd, J = 18.0, 4.0 Hz, 1H), 3.97 (dd, J = 18.0, 10.4 Hz, 1H), 4.19-4.33 (m , 2H), 5.14 (dd, J = 10.4, 4.0 Hz, 1H), 7.12 (dd, J = 4.4, 3.6 Hz, 1H), 7.26-7.38 (m, 5H), 7.64 (dd, J = 4.4, 0.8 Hz, 1H), 7.73 (dd, J = 3.6, 0.8 Hz, 1H) ppm; 13 C-NMR δ 13.8, 43.2, 48.3, 62.5, 128.0, 128.1, 128.8, 129.1, 132.4, 134.0, 135.1, 142.8, 160.2, 190.1, 191.9 ppm.
실시예 3: 하기 화학식 3-1로 표시되는 화합물(Ethyl 3-phenyl-5-(thiophen-2-yl)furan-2-carboxylate)의 제조Example 3: Preparation of a compound represented by the following formula 3-1 (Ethyl 3-phenyl-5- (thiophen-2-yl) furan-2-carboxylate)
[화학식 3-1][Formula 3-1]
화학식 2-1로 표시되는 화합물(0.28 g, 0.89 mmol)을 벤젠(10 mL)에 녹인 용액에 농축된 황산(0.24 mL, 4.8 mmol)을 첨가하였다. 이 혼합물을 60℃에서 1.5 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 NaHCO3(saturated NaHCO3)로 중화, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 정제되지 않은 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 고체 타입의 화학식 3-1로 표시되는 화합물(54 mg, 0.18 mmol)을 얻었다(수율 20%).Concentrated sulfuric acid (0.24 mL, 4.8 mmol) was added to a solution of the compound represented by Formula 2-1 (0.28 g, 0.89 mmol) in benzene (10 mL). This mixture was heated at 60 ° C. for 1.5 h and cooled to rt. The mixture was extracted with a neutralized, EtOAc saturated NaHCO 3 (saturated NaHCO 3) was poured into ice water. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography to obtain the compound (54 mg, 0.18 mmol) represented by the formula (3-1) as a yellow solid type (yield 20%).
화학식 3-1로 표시되는 화합물의 데이터: Rf = 0.62 (hexane:EtOAc = 4:1); 1H-NMR δ 1.30 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 6.68 (s, 1H), 7.09 (dd, J = 4.8, 3.6 Hz, 1H), 7.34 (dd, J = 4.8, 1.2 Hz, 1H), 7.36-7.44 (m, 3H), 7.48 (dd, J = 3.6, 1.2 Hz, 1H), 7.58-7.62 (m, 2H) ppm; 13C-NMR δ 14.1, 60.7, 109.2, 125.3, 126.4, 127.9, 127.9, 128.3, 129.3, 131.8, 132.0, 136.4, 137.5, 151.3, 159.0 ppm.Data of the compound represented by Formula 3-1: R f = 0.62 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.30 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 6.68 (s, 1H), 7.09 (dd, J = 4.8, 3.6 Hz, 1H), 7.34 (dd, J = 4.8, 1.2 Hz, 1H), 7.36-7.44 (m, 3H), 7.48 (dd, J = 3.6, 1.2 Hz, 1H), 7.58-7.62 (m, 2H) ppm; 13 C-NMR δ 14.1, 60.7, 109.2, 125.3, 126.4, 127.9, 127.9, 128.3, 129.3, 131.8, 132.0, 136.4, 137.5, 151.3, 159.0 ppm.
실시예 4: 하기 화학식 3-2로 표시되는 화합물(Ethyl 3-phenyl-5-(thiophen-2-yl)-1Example 4: Compound (Ethyl 3-phenyl-5- (thiophen-2-yl) -1 represented by Chemical Formula 3-2 HH -pyrrole-2-carboxylate)의 제조 -pyrrole-2-carboxylate)
[화학식 3-2][Formula 3-2]
화학식 2-1로 표시되는 화합물(0.16 g, 0.51 mmol)을 아세트산(10 mL)에 녹이고 NH4OAc(80 mg, 1.03 mmol)와 sulfamic acid(5 mg, 0.051 mmol)를 첨가하였다. 이 혼합물을 50 ℃에서 8시간 동안 가열하고 실온으로 식힌 다음, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 정제되지 않은 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 고체 타입의 화학식 3-2로 표시되는 화합물(70 mg, 0.25 mmol)을 얻었다(수율 49%). The compound represented by Formula 2-1 (0.16 g, 0.51 mmol) was dissolved in acetic acid (10 mL), and NH 4 OAc (80 mg, 1.03 mmol) and sulfamic acid (5 mg, 0.051 mmol) were added thereto. The mixture was heated at 50 ° C. for 8 hours, cooled to room temperature, and the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product. This was purified by silica gel flash column chromatography to obtain a compound (70 mg, 0.25 mmol) represented by the general formula 3-2 of the yellow solid type (yield 49%).
화학식 3-2로 표시되는 화합물의 데이터: Rf = 0.43 (hexane:EtOAc = 4:1); 1H-NMR δ 1.23 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 3.2 Hz, 1H), 7.05 (dd, J = 5.2, 3.2 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 7.26 (s, 1H), 7.28-7.40 (m, 3H), 7.54-7.60 (m, 2H), 9.46 (br s, 1H) ppm; 13C-NMR δ 14.1, 60.5, 110.4, 118.2, 123.3, 124.7, 127.1, 127.6, 127.8, 129.5, 130.1, 133.3, 134.1, 134.8, 161.2 ppm.Data for the compound represented by Formula 3-2: R f = 0.43 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.23 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 3.2 Hz, 1H), 7.05 (dd, J = 5.2, 3.2 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 7.26 (s, 1H), 7.28-7.40 (m, 3H), 7.54-7.60 (m, 2H), 9.46 (br s, 1H) ppm ; 13 C-NMR δ 14.1, 60.5, 110.4, 118.2, 123.3, 124.7, 127.1, 127.6, 127.8, 129.5, 130.1, 133.3, 134.1, 134.8, 161.2 ppm.
실시예 5: 하기 화학식 3-3으로 표시되는 화합물(Ethyl 4-phenyl-[2,2'-bithiophene]-5-carboxylate)의 제조 Example 5: Preparation of a compound represented by Chemical Formula 3-3 (Ethyl 4-phenyl- [2,2'-bithiophene] -5-carboxylate)
[화학식 3-3][Formula 3-3]
화학식 2-1로 표시되는 화합물(0.24 g, 0.76 mmol)을 벤젠(10 mL)에 녹인 다음 Lawesson’s Reagent(0.637 g, 0.91 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 9 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3(saturated NaHCO3)로 퀀치하고, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 고체 타입의 화학식 3-3으로 표시되는 화합물(0.12 g, 0.38 mmol)을 얻었다(수율 49%). The compound represented by Formula 2-1 (0.24 g, 0.76 mmol) was dissolved in benzene (10 mL), and Lawesson's Reagent (0.637 g, 0.91 mmol) was added thereto. The mixture was heated at 60 ° C. for 9 hours and cooled to room temperature. Quench the mixture with saturated NaHCO 3 (saturated NaHCO 3) and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain a compound (0.12 g, 0.38 mmol) represented by the formula (3-3) as a yellow solid type (yield 49%).
화학식 3-3으로 표시되는 화합물의 데이터: Rf = 0.66 (hexane:EtOAc = 4:1); 1H-NMR δ 1.23 (t,J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 7.03 (dd, J = 5.2, 3.6 Hz, 1H), 7.13 (s, 1H), 7.28 (dd, J = 5.2, 0.8 Hz, 1H), 7.29 (dd, J = 3.6, 0.8 Hz, 1H), 7.34-7.42 (m, 3H), 7.45-7.49 (m, 2H) ppm; 13C-NMR δ 14.0, 60.9, 125.1, 125.2, 126.1, 127.5, 127.7, 128.0, 128.1, 129.1, 135.5, 136.1, 141.3, 149.1, 161.8 ppm.Data for the compound represented by Formula 3-3: R f = 0.66 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.23 (t, J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 7.03 (dd, J = 5.2, 3.6 Hz, 1H), 7.13 (s, 1H), 7.28 (dd, J = 5.2, 0.8 Hz, 1H), 7.29 (dd, J = 3.6, 0.8 Hz, 1H), 7.34-7.42 (m, 3H), 7.45-7.49 (m, 2H) ppm; 13 C-NMR δ 14.0, 60.9, 125.1, 125.2, 126.1, 127.5, 127.7, 128.0, 128.1, 129.1, 135.5, 136.1, 141.3, 149.1, 161.8 ppm.
실시예 6: 하기 화학식 1-2로 표시되는 화합물(Ethyl 2-acetyl-5-(furan-2-yl)-5-oxo-3-phenylpentanoate) 의 제조Example 6: Preparation of a compound represented by the following formula 1-2 (Ethyl 2-acetyl-5- (furan-2-yl) -5-oxo-3-phenylpentanoate)
[화학식 1-2][Formula 1-2]
아르곤 분위기 하, 25℃에서, 에틸 아세토아세토아세테이트(ethyl acetoacetate, 8.78 g, 47.50 mmol)와 스티레닐 2-퓨라닐 케톤 (styrenyl 2-furanyl ketone, 4.46 g, 22.50 mmol)의 혼합물에 CeCl3.7H2O(1.68 g, 4.50 mmol) 및 NaI(0.34 g, 2.25 mmol)를 첨가하였다. 혼합물을 14시간 동안 교반하고 EtOAc로 묽힌 다음, 고체를 거름종이로 거르고, 여과액을 감압 하에서 농축하여 정제되지 않은 생성물(crude product)을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 1.1:1 입체이성질체의 혼합물로 이루어진 흰색 고체의 화학식 1-2로 표시되는 화합물(4.65 g, 14.16 mmol)을 얻었다(수율 63%). CeCl 3 .7H in a mixture of ethyl acetoacetoacetate (8.78 g, 47.50 mmol) and styrenyl 2-furanyl ketone (4.46 g, 22.50 mmol) at 25 ° C. under an argon atmosphere. 2 O (1.68 g, 4.50 mmol) and NaI (0.34 g, 2.25 mmol) were added. The mixture was stirred for 14 h and diluted with EtOAc, then the solid was filtered through a filter paper and the filtrate was concentrated under reduced pressure to give a crude product. This was purified by silica gel flash column chromatography to obtain a compound (4.65 g, 14.16 mmol) represented by formula 1-2 of a white solid composed of a mixture of 1.1: 1 stereoisomers (yield 63%).
화학식 1-2로 표시되는 화합물의 데이터: Rf = 0.18 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 0.95 (t,J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.25 (d of A of ABq, J AB = 16.0, J d = 4.8 Hz, 1H), 3.31 (d of B of ABq, J AB = 16.0, J d = 9.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 4.05 (d, J = 10.8 Hz, 1H), 4.14 (ddd, J = 10.8, 9.2, 4.8 Hz, 1H), 6.46 (dd, J = 4.0, 1.6 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 7.14-7.26 (m, 5H), 7.51 (d, J = 1.6 Hz, 1H) ppm; (minor) δ 1.26 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.16 (d of A of ABq, J AB = 16.0, J d = 4.8 Hz, 1H), 3.21 (d of B of ABq, J AB = 16.0, J d = 7.6 Hz, 1H), 4.02 (d, J = 10.4 Hz, 1H), 4.14 (ddd, J = 10.4, 7.6, 4.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 6.47 (dd, J = 4.0, 1.2 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.14-7.26 (m, 5H), 7.52 (d, J = 1.2 Hz, 1H) ppm; 13C-NMR (major) δ13.6, 29.4, 40.3, 42.3, 61.2, 65.1, 68.9, 112.1, 117.3, 127.0, 128.0, 128.3, 140.2, 146.3, 152.4, 168.2, 186.7, 202.2 ppm; (minor) δ 13.9, 29.9, 40.6, 42.5, 61.5, 64.6, 112.1, 117.2, 127.1, 128.0, 128.5, 140.0, 146.2, 152.4, 167.8, 186.4, 201.9 ppm.Data of compounds represented by formula 1-2: R f = 0.18 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 0.95 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.25 (d of A of ABq, J AB = 16.0, J d = 4.8 Hz, 1H), 3.31 (d of B of ABq, J AB = 16.0, J d = 9.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 4.05 (d, J = 10.8 Hz, 1H), 4.14 (ddd, J = 10.8, 9.2, 4.8 Hz, 1H), 6.46 (dd, J = 4.0, 1.6 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 7.14-7.26 (m, 5H), 7.51 (d, J = 1.6 Hz, 1H) ppm; (minor) δ 1.26 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.16 (d of A of ABq, J AB = 16.0, J d = 4.8 Hz, 1H), 3.21 (d of B of ABq, J AB = 16.0, J d = 7.6 Hz, 1H), 4.02 (d, J = 10.4 Hz, 1H), 4.14 (ddd, J = 10.4, 7.6, 4.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 6.47 (dd, J = 4.0, 1.2 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.14-7.26 (m, 5H), 7.52 (d, J = 1.2 Hz , 1H) ppm; 13 C-NMR (major) δ 13.6, 29.4, 40.3, 42.3, 61.2, 65.1, 68.9, 112.1, 117.3, 127.0, 128.0, 128.3, 140.2, 146.3, 152.4, 168.2, 186.7, 202.2 ppm; (minor) δ 13.9, 29.9, 40.6, 42.5, 61.5, 64.6, 112.1, 117.2, 127.1, 128.0, 128.5, 140.0, 146.2, 152.4, 167.8, 186.4, 201.9 ppm.
실시예 7: 하기 화학식 2-2로 표시되는 화합물(Ethyl 5-(furan-2-yl)-2,5-dioxo-3-phenylpentanoate)의 제조Example 7: Preparation of a compound represented by Chemical Formula 2-2 (Ethyl 5- (furan-2-yl) -2,5-dioxo-3-phenylpentanoate)
[화학식 2-2][Formula 2-2]
화학식 1-2로 표시되는 화합물(2.43 g, 7.40 mmol)을 아세트산(25 mL)에 녹이고 Mn(OAc)3·2H2O(0.20 g, 0.74 mmol) 및 CoCl2(0.10 g, 0.74 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 25 ℃에서 이틀 동안 격렬하게 교반하고 감압 하에서 용매를 제거하여 정제되지 않은 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 연노랑 오일 타입의 화학식 2-2로 표시되는 화합물(0.88 g, 2.96 mmol)을 얻었다(수율 40%).The compound represented by Formula 1-2 (2.43 g, 7.40 mmol) was dissolved in acetic acid (25 mL), and Mn (OAc) 3 .2H 2 O (0.20 g, 0.74 mmol) and CoCl 2 (0.10 g, 0.74 mmol) were added thereto. Added. The mixture was vigorously stirred for 2 days at 25 ° C. under air and the solvent was removed under reduced pressure to give the crude product. This was purified by silica gel flash column chromatography to obtain a compound represented by the formula (2-2) of the light yellow oil type (0.88 g, 2.96 mmol) (yield 40%).
화학식 2-2로 표시되는 화합물의 데이터: Rf= 0.26 (hexane:EtOAc = 4:1); 1H-NMR δ 1.27 (t,J = 7.2 Hz, 3H), 3.29 (dd, J = 18.0, 4.0 Hz, 1H), 3.88 (dd, J = 18.0, 10.4 Hz, 1H), 4.18-4.32 (m, 2H), 5.12 (dd, J = 10.4, 4.0 Hz, 1H), 6.53 (dd, J = 3.2, 2.0 Hz, 1H), 7.20 (dd, J = 3.2, 0.8 Hz, 1H), 7.26-7.37 (m, 5H), 7.57 (dd, J = 2.0, 0.8 Hz, 1H) ppm; 13C-NMR δ 13.8, 42.1, 47.9, 62.4, 112.3, 117.4, 127.9, 128.8, 129.0, 135.0, 146.5, 151.9, 160.2, 186.3, 191.9 ppmData for the compound represented by Formula 2-2: R f = 0.26 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 3.29 (dd, J = 18.0, 4.0 Hz, 1H), 3.88 (dd, J = 18.0, 10.4 Hz, 1H), 4.18-4.32 (m , 2H), 5.12 (dd, J = 10.4, 4.0 Hz, 1H), 6.53 (dd, J = 3.2, 2.0 Hz, 1H), 7.20 (dd, J = 3.2, 0.8 Hz, 1H), 7.26-7.37 ( m, 5H), 7.57 (dd, J = 2.0, 0.8 Hz, 1H) ppm; 13 C-NMR δ 13.8, 42.1, 47.9, 62.4, 112.3, 117.4, 127.9, 128.8, 129.0, 135.0, 146.5, 151.9, 160.2, 186.3, 191.9 ppm
실시예 8: 하기 화학식 3-4로 표시되는 화합물(Ethyl 4-phenyl-[2,2'-bifuran]-5-carboxylate)의 제조Example 8: Preparation of the compound represented by Chemical Formula 3-4 (Ethyl 4-phenyl- [2,2'-bifuran] -5-carboxylate)
[화학식 3-4] [Formula 3-4]
화학식 2-2로 표시되는 화합물(0.39 g, 1.31 mmol)을 벤젠(10 mL)에 녹인 용액에 농축된 황산(0.14 mL, 2.8 mmol)을 첨가하였다. 이 혼합물을 60℃에서 4 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 NaHCO3(saturated NaHCO3)로 중화, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 정제되지 않은 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-4로 표시되는 화합물(0.19 g, 0.67 mmol)을 얻었다(수율 51%).Concentrated sulfuric acid (0.14 mL, 2.8 mmol) was added to a solution of the compound represented by Formula 2-2 (0.39 g, 1.31 mmol) in benzene (10 mL). The mixture was heated at 60 ° C. for 4 hours and cooled to room temperature. The mixture was extracted with a neutralized, EtOAc saturated NaHCO 3 (saturated NaHCO 3) was poured into ice water. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography to obtain the compound represented by the formula (3-4) (0.19 g, 0.67 mmol) (yield 51%).
화학식 3-4로 표시되는 화합물의 데이터: Rf = 0.56 (hexane:EtOAc = 4:1); 1H-NMR δ 1.30 (t, J = 7.2 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 6.52 (dd, J = 3.2, 2.0 Hz, 1H), 6.75 (s, 1H), 6.86 (d, J = 3.2 Hz, 1H), 7.36-7.47 (m, 3H), 7.50 (d, J = 2.0 Hz, 1H), 7.57-7.62 (m, 2H) ppm; 13C-NMR δ 14.2, 60.8, 108.4, 109.2, 111.8, 128.0, 128.4, 129.4, 131.8, 136.2, 137.7, 143.2, 145.2, 148.1, 159.1 ppm.Data for the compound represented by Formula 3-4: R f = 0.56 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.30 (t, J = 7.2 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 6.52 (dd, J = 3.2, 2.0 Hz, 1H), 6.75 (s, 1H), 6.86 (d, J = 3.2 Hz, 1H), 7.36-7.47 (m, 3H), 7.50 (d, J = 2.0 Hz, 1H), 7.57-7.62 (m, 2H) ppm; 13 C-NMR δ 14.2, 60.8, 108.4, 109.2, 111.8, 128.0, 128.4, 129.4, 131.8, 136.2, 137.7, 143.2, 145.2, 148.1, 159.1 ppm.
실시예 9: 하기 화학식 3-5로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-phenyl-1Example 9: Compound represented by Chemical Formula 3-5 (Ethyl 5- (furan-2-yl) -3-phenyl-1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-5][Formula 3-5]
화학식 2-2로 표시되는 화합물(0.36 g, 1.21 mmol)을 아세트산(10 mL)에 녹이고 NH4OAc(0.19 g, 2.42 mmol)와 sulfamic acid(12 mg, 0.12 mmol)를 첨가하였다. 이 혼합물을 50℃에서 3시간 동안 가열하고 실온으로 식힌 다음, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 정제되지 않은 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-5로 표시되는 화합물(0.22 g, 0.79 mmol)을 얻었다(수율 66%). The compound represented by Formula 2-2 (0.36 g, 1.21 mmol) was dissolved in acetic acid (10 mL), and NH 4 OAc (0.19 g, 2.42 mmol) and sulfamic acid (12 mg, 0.12 mmol) were added. The mixture was heated at 50 ° C. for 3 hours and cooled to room temperature, then the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the crude product. This was purified by silica gel flash column chromatography to obtain the compound represented by the formula 3-5 (0.22 g, 0.79 mmol) (66% yield).
화학식 3-5로 표시되는 화합물의 데이터: Rf = 0.43 (hexane:EtOAc = 4:1); 1H-NMR δ 1.23 (t,J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.44 (dd, J = 2.8, 1.6 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 7.27-7.39 (m, 3H), 7.40 (dd, J = 1.6, 0.8 Hz, 1H), 7.54-7.59 (m, 2H), 9.60 (br s, 1H) ppm; 13C-NMR δ 14.1, 60.3, 105.5, 108.8, 111.6, 117.8, 126.9, 127.1, 127.5, 129.5, 133.2, 134.8, 141.8, 146.5, 161.0 ppm.Data of compounds represented by formula 3-5: R f = 0.43 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.23 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.44 (dd, J = 2.8, 1.6 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 7.27-7.39 (m, 3H), 7.40 (dd, J = 1.6, 0.8 Hz, 1H), 7.54-7.59 (m, 2H), 9.60 (br s, 1H) ppm; 13 C-NMR δ 14.1, 60.3, 105.5, 108.8, 111.6, 117.8, 126.9, 127.1, 127.5, 129.5, 133.2, 134.8, 141.8, 146.5, 161.0 ppm.
실시예 10: 하기 화학식 3-6으로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-phenylthiophene-2-carboxylate)의 제조Example 10 Preparation of Compound (Ethyl 5- (furan-2-yl) -3-phenylthiophene-2-carboxylate) represented by Formula 3-6
[화학식 3-6][Formula 3-6]
화학식 2-2로 표시되는 화합물(0.30 g, 1.00 mmol)을 벤젠(10 mL)에 녹인 다음 Lawesson’s Reagent(0.48 g, 1.20 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 3 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3(saturated NaHCO3)로 퀀치하고, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-6으로 표시되는 화합물(0.11 g, 0.36 mmol)을 얻었다(수율 36%).The compound represented by Formula 2-2 (0.30 g, 1.00 mmol) was dissolved in benzene (10 mL), and Lawesson's Reagent (0.48 g, 1.20 mmol) was added thereto. This mixture was heated at 60 ° C. for 3 hours and cooled to room temperature. Quench the mixture with saturated NaHCO 3 (saturated NaHCO 3) and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain a compound represented by the formula (3-6) (0.11 g, 0.36 mmol) (yield 36%).
화학식 3-6으로 표시되는 화합물의 데이터: Rf = 0.63 (hexane:EtOAc = 4:1); 1H-NMR δ 1.23 (t,J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 6.46 (dd, J = 3.6, 1.6 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 7.20 (s, 1H), 7.34-7.42 (m, 3H), 7.44 (dd, J = 1.6, 0.8 Hz, 1H), 7.45-7.49 (m, 2H) ppm; 13C-NMR δ 14.0, 60.9, 107.3, 112.0, 125.0, 126.1, 127.7, 127.9, 129.1, 135.5, 137.2, 142.8, 148.3, 149.0, 161.9 ppm.Data for the compound represented by Formula 3-6: R f = 0.63 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.23 (t, J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 6.46 (dd, J = 3.6, 1.6 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 7.20 (s, 1H), 7.34-7.42 (m, 3H), 7.44 (dd, J = 1.6, 0.8 Hz, 1H), 7.45-7.49 (m, 2H) ppm; 13 C-NMR δ 14.0, 60.9, 107.3, 112.0, 125.0, 126.1, 127.7, 127.9, 129.1, 135.5, 137.2, 142.8, 148.3, 149.0, 161.9 ppm.
실시예 11: 하기 화학식 1-3으로 표시되는 화합물(Ethyl 2-acetyl-5-(1-benzoyl-1Example 11 Compound represented by Chemical Formula 1-3 (Ethyl 2-acetyl-5- (1-benzoyl-1) HH -pyrrol-2-yl)-5-oxo-3-phenylpentanoate)의 제조-pyrrol-2-yl) -5-oxo-3-phenylpentanoate)
[화학식 1-3][Formula 1-3]
아르곤 분위기 하에서, 에틸 아세토아세토아세테이트(ethyl acetoacetate, 860 mg, 6.64 mmol)와 스티레닐 N-벤조일-2-피롤릴 케톤 (styrenyl N-benzoyl-2-pyrrolyl ketone, 2.00 g, 6.64 mmol)을 아세토니트릴(30 mL)에 녹인 용액에 CeCl3.7H2O(0.25 g, 0.66 mmol) 및 NaI(0.10 g, 0.66 mmol)를 첨가하였다. 상기 혼합물을 50 ℃ 하루 동안 교반한 뒤, 실온으로 식히고 CH2Cl2로 묽힌 다음, 고체를 거름종이로 거르고, 여과액을 감압 하에서 농축하여 정제되지 않은 생성물(crude product)을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 1.2:1 입체이성질체의 혼합물로 이루어진 황갈색 고체의 화학식 1-3으로 표시되는 화합물(0.80 g, 1.85 mmol)을 얻었다(수율 28%).Under an argon atmosphere, ethyl acetoacetate acetoacetate (ethyl acetoacetate, 860 mg, 6.64 mmol) and stickies alkylenyl N - benzoyl-2-pyrrolyl ketone (styrenyl N -benzoyl-2-pyrrolyl ketone, 2.00 g, 6.64 mmol) in acetonitrile To a solution dissolved in (30 mL) were added CeCl 3 .7H 2 O (0.25 g, 0.66 mmol) and NaI (0.10 g, 0.66 mmol). The mixture was stirred at 50 ° C. for one day, cooled to room temperature and diluted with CH 2 Cl 2 , then the solid was filtered through a filter paper and the filtrate was concentrated under reduced pressure to give a crude product. This was purified by silica gel flash column chromatography to obtain the compound (0.80 g, 1.85 mmol) represented by Chemical Formula 1-3 of a tan solid consisting of a mixture of 1.2: 1 stereoisomers (yield 28%).
화학식 1-3으로 표시되는 화합물의 데이터: Rf = 0.09 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 0.94 (t, J = 7.2 Hz, 3H), 2.17 (s, 3H), 3.03-3.15 (m, 2H), 3.87 (q, J = 7.2 Hz, 2H), 3.92-4.03 (m, 2H), 6.24-6.27 (m, 1H), 6.95-6.98 (m, 1H), 7.10-7.24 (m, 6H), 7.26-7.36 (m, 2H), 7.44-7.57 (m, 3H) ppm; (minor) δ 1.21 (t, J = 7.2 Hz, 3H), 1.93 (s, 3H), 3.15 (d of A of ABq, J AB = 16.0, J d = 5.2 Hz, 1H), 3.21 (d of B of ABq, J AB = 16.0, J d = 8.4 Hz, 1H), 3.92-4.03 (m, 2H), 4.14 (q, J = 7.2 Hz, 2H), 6.26-6.29 (m, 1H), 7.04-7.07 (m, 1H), 7.10-7.24 (m, 6H), 7.26-7.36 (m, 2H), 7.44-7.57 (m, 3H) ppm; 13C-NMR (major) δ 13.7, 29.3, 40.6, 42.4, 61.2, 64.6, 110.6, 121.1, 127.0, 128.1, 128.3, 128.5, 129.0, 129.5, 133.4, 133.4, 134.6, 140.3, 167.9, 169.2, 187.0, 202.5 ppm; (minor) δ 14.0, 29.9, 41.0, 42.5, 61.6, 64.9, 110.6, 120.9, 127.1, 128.1, 128.5, 128.6, 129.0, 129.5, 133.3, 133.3, 134.5, 140.0, 168.3, 169.2, 187.3, 202.1 ppm.Data of the compound represented by Formula 1-3: R f = 0.09 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 0.94 (t, J = 7.2 Hz, 3H), 2.17 (s, 3H), 3.03-3.15 (m, 2H), 3.87 (q, J = 7.2 Hz, 2H), 3.92- 4.03 (m, 2H), 6.24-6.27 (m, 1H), 6.95-6.98 (m, 1H), 7.10-7.24 (m, 6H), 7.26-7.36 (m, 2H), 7.44-7.57 (m, 3H ) ppm; (minor) δ 1.21 (t, J = 7.2 Hz, 3H), 1.93 (s, 3H), 3.15 (d of A of ABq, J AB = 16.0, J d = 5.2 Hz, 1H), 3.21 (d of B of ABq, J AB = 16.0, J d = 8.4 Hz, 1H), 3.92-4.03 (m, 2H), 4.14 (q, J = 7.2 Hz, 2H), 6.26-6.29 (m, 1H), 7.04-7.07 (m, 1 H), 7.10-7.24 (m, 6H), 7.26-7.36 (m, 2H), 7.44-7.57 (m, 3H) ppm; 13 C-NMR (major) δ 13.7, 29.3, 40.6, 42.4, 61.2, 64.6, 110.6, 121.1, 127.0, 128.1, 128.3, 128.5, 129.0, 129.5, 133.4, 133.4, 134.6, 140.3, 167.9, 169.2, 187.0, 202.5 ppm; (minor) δ 14.0, 29.9, 41.0, 42.5, 61.6, 64.9, 110.6, 120.9, 127.1, 128.1, 128.5, 128.6, 129.0, 129.5, 133.3, 133.3, 134.5, 140.0, 168.3, 169.2, 187.3, 202.1 ppm.
실시예 12: 하기 화학식 2-3으로 표시되는 화합물(Ethyl 5-(1-benzoyl-1Example 12: Compound represented by Chemical Formula 2-3 (Ethyl 5- (1-benzoyl-1) HH -pyrrol-2-yl)-2,5-dioxo-3-phenylpentanoate)의 제조-pyrrol-2-yl) -2,5-dioxo-3-phenylpentanoate)
[화학식 2-3][Formula 2-3]
화학식 1-3으로 표시되는 화합물(2.00 g, 4.64 mmol)을 아세트산(20 mL)에 녹이고 Mn(OAc)3·2H2O(0.12 g, 0.46 mmol) 및 CoCl2(60 mg, 0.46 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 50 ℃에서 12시간 동안 격렬하게 교반하고 감압 하에서 용매를 제거하여 정제되지 않은 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 오일 타입의 화학식 2-3으로 표시되는 화합물(0.30 g, 0.74 mmol)을 얻었다(수율 16%).The compound represented by Formula 1-3 (2.00 g, 4.64 mmol) was dissolved in acetic acid (20 mL), and Mn (OAc) 3 .2H 2 O (0.12 g, 0.46 mmol) and CoCl 2 (60 mg, 0.46 mmol) were added thereto. Added. The mixture was stirred vigorously at 50 ° C. under air for 12 hours and the solvent was removed under reduced pressure to give the crude product. This was purified by silica gel flash column chromatography to obtain a compound (0.30 g, 0.74 mmol) represented by the general formula 2-3 of the brown oil type (yield 16%).
화학식 2-3으로 표시되는 화합물의 데이터: Rf = 0.18 (hexane:EtOAc = 4:1); 1H-NMR δ 1.20 (t, J = 7.2 Hz, 3H), 3.15 (dd, J = 15.6, 4.8 Hz, 1H), 3.77 (dd, J = 15.6, 10.0 Hz, 1H), 4.08-4.22 (m, 2H), 4.94 (dd, J = 10.0, 4.8 Hz, 1H), 6.33 (dd, J = 4.0, 2.8 Hz, 1H), 7.13 (dd, J = 4.0, 1.6 Hz, 1H), 7.21-7.34 (m, 6H), 7.40-7.46 (m, 2H), 7.56-7.61 (m, 1H), 7.65-7.69 (m, 2H) ppm; 13C-NMR δ 13.8,42.1,48.6, 62.3, 110.7, 117.9, 121.5, 127.9, 128.6, 128.8, 129.1, 129.3, 129.8, 133.1, 133.6, 135.3, 160.0, 168.9, 186.6, 191.8 ppm.Data of compounds represented by formula 2-3: R f = 0.18 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.20 (t, J = 7.2 Hz, 3H), 3.15 (dd, J = 15.6, 4.8 Hz, 1H), 3.77 (dd, J = 15.6, 10.0 Hz, 1H), 4.08-4.22 (m , 2H), 4.94 (dd, J = 10.0, 4.8 Hz, 1H), 6.33 (dd, J = 4.0, 2.8 Hz, 1H), 7.13 (dd, J = 4.0, 1.6 Hz, 1H), 7.21-7.34 ( m, 6H), 7.40-7.46 (m, 2H), 7.56-7.61 (m, 1H), 7.65-7.69 (m, 2H) ppm; 13 C-NMR δ 13.8,42.1,48.6, 62.3, 110.7, 117.9, 121.5, 127.9, 128.6, 128.8, 129.1, 129.3, 129.8, 133.1, 133.6, 135.3, 160.0, 168.9, 186.6, 191.8 ppm.
실시예 13: 하기 화학식 3-7로 표시되는 화합물(Ethyl 5-(1-benzoyl-1Example 13: A compound represented by Chemical Formula 3-7 (Ethyl 5- (1-benzoyl-1) HH -pyrrol-2-yl)-3-phenylfuran-2-carboxylate)의 제조 -pyrrol-2-yl) -3-phenylfuran-2-carboxylate)
[화학식 3-7][Formula 3-7]
화학식 2-3으로 표시되는 화합물(0.16 g, 0.40 mmol)을 아세트산 무수물(10 mL)에 녹인 용액에 진한 염산(0.7 mL)을 첨가하였다. 이 혼합물을 60 ℃에서 6 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 NaHCO3(saturated NaHCO3)로 중화 후, CH2Cl2로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-7로 표시되는 화합물(15 mg, 0.039 mmol)을 얻었다(수율 10%).Concentrated hydrochloric acid (0.7 mL) was added to a solution of the compound represented by Formula 2-3 (0.16 g, 0.40 mmol) in acetic anhydride (10 mL). The mixture was heated at 60 ° C. for 6 hours and cooled to room temperature. The mixture was extracted after neutralization with saturated NaHCO 3 (saturated NaHCO 3) was poured into ice water, CH 2 Cl 2. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound represented by the formula (3-7) (15 mg, 0.039 mmol) (yield 10%).
화학식 3-7로 표시되는 화합물의 데이터: Rf = 0.40 (hexane/EtOAc = 4:1); 1H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.36 (dd, J = 3.6, 3.2 Hz, 1H), 6.68 (s, 1H), 6.88 (dd, J = 3.6, 1.6 Hz, 1H), 7.16 (dd, J = 3.2, 1.6 Hz, 1H), 7.33-7.40 (m, 3H), 7.43-7.48 (m, 2H), 7.52-7.62 (m, 3H), 7.77-7.81 (m, 2H) ppm; 13C-NMR δ 14.2, 60.6, 111.5, 112.4, 117.1, 125.0, 125.9, 127.8, 128.1, 128.4, 129.3, 130.2, 132.0, 133.1, 135.9, 137.6, 148.4, 158.9, 168.3 ppm; IR 3061, 2981, 1707, 1601, 1561, 1521, 1488, 1446, 1379, 1327, 1290, 1170, 1111, 1021, 880, 760, 693 cm-1; HRMS (ESI) calcd for C24H19NO4Na 408.1206, found 408.1209.Data for compounds represented by formula 3-7: R f = 0.40 (hexane / EtOAc = 4: 1); 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.36 (dd, J = 3.6, 3.2 Hz, 1H), 6.68 (s, 1H), 6.88 (dd, J = 3.6, 1.6 Hz, 1H), 7.16 (dd, J = 3.2, 1.6 Hz, 1H), 7.33-7.40 (m, 3H), 7.43-7.48 (m, 2H), 7.52-7.62 ( m, 3H), 7.77-7.81 (m, 2H) ppm; 13 C-NMR δ 14.2, 60.6, 111.5, 112.4, 117.1, 125.0, 125.9, 127.8, 128.1, 128.4, 129.3, 130.2, 132.0, 133.1, 135.9, 137.6, 148.4, 158.9, 168.3 ppm; IR 3061, 2981, 1707, 1601, 1561, 1521, 1488, 1446, 1379, 1327, 1290, 1170, 1111, 1021, 880, 760, 693 cm −1 ; HRMS (ESI) calcd for C 24 H 19 NO 4 Na 408.1206, found 408.1209.
실시예 14: 하기 화학식 3-8로 표시되는 화합물(Ethyl 1'-benzoyl-4-phenyl-1Example 14 Compound represented by Chemical Formula 3-8 (Ethyl 1′-benzoyl-4-phenyl-1 HH ,1',One' HH -[2,2'-bipyrrole]-5-carboxylate)의 제조-[2,2'-bipyrrole] -5-carboxylate)
[화학식 3-8] [Formula 3-8]
화학식 2-3으로 표시되는 화합물(0.30 g, 0.74 mmol)을 아세트산(10 mL)에 녹이고 NH4OAc(0.12 g, 1.48 mmol)와 sulfamic acid(7 mg, 0.07 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 3시간 동안 가열하고 실온으로 식힌 다음, 용매를 감압 하에서 제거하였다. 이를 CH2Cl2로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 정제되지 않은 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 고체 타입의 화학식 3-8로 표시되는 화합물(78 mg, 0.20 mmol)을 얻었다(수율 27%). The compound represented by Formula 2-3 (0.30 g, 0.74 mmol) was dissolved in acetic acid (10 mL), and NH 4 OAc (0.12 g, 1.48 mmol) and sulfamic acid (7 mg, 0.07 mmol) were added thereto. The mixture was heated at 60 ° C. for 3 hours and cooled to room temperature, then the solvent was removed under reduced pressure. It was diluted with CH 2 Cl 2 , washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give a crude product. This was purified by silica gel flash column chromatography to obtain a compound (78 mg, 0.20 mmol) represented by the formula (3-8) as a yellow solid type (yield 27%).
화학식 3-8로 표시되는 화합물의 데이터: Rf = 0.42 (hexane:EtOAc = 4:1); 1H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 4.28 (q, J = 7.2 Hz, 2H), 6.31 (t, J = 3.2 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.76 (dd, J = 3.6, 1.6 Hz, 1H), 6.96 (dd, J = 3.2, 1.6 Hz, 1H), 7.26-7.40 (m, 3H), 7.45-7.55 (m, 2H), 7.57-7.66 (m, 3H), 7.79-7.84 (m, 2H), 10.91 (br s, 1H) ppm; 13C-NMR δ 14.3, 60.2, 111.7, 112.7, 115.9, 117.5, 125.6, 126.9, 127.6, 128.5, 128.5, 129.5, 130.2, 130.3, 132.7, 133.2, 133.6, 135.0, 160.8, 170.0 ppm.Data for the compound represented by Formula 3-8: R f = 0.42 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 4.28 (q, J = 7.2 Hz, 2H), 6.31 (t, J = 3.2 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.76 (dd, J = 3.6, 1.6 Hz, 1H), 6.96 (dd, J = 3.2, 1.6 Hz, 1H), 7.26-7.40 (m, 3H), 7.45-7.55 (m, 2H), 7.57 -7.66 (m, 3H), 7.79-7.84 (m, 2H), 10.91 (br s, 1H) ppm; 13 C-NMR δ 14.3, 60.2, 111.7, 112.7, 115.9, 117.5, 125.6, 126.9, 127.6, 128.5, 128.5, 129.5, 130.2, 130.3, 132.7, 133.2, 133.6, 135.0, 160.8, 170.0 ppm.
실시예 15: 하기 화학식 3-9로 표시되는 화합물(Ethyl 5-(1-benzoyl-1Example 15: A compound represented by the following Chemical Formula 3-9 (Ethyl 5- (1-benzoyl-1) HH -pyrrol-2-yl)-3-phenylthiophene-2-carboxylate)의 제조 -pyrrol-2-yl) -3-phenylthiophene-2-carboxylate)
[화학식 3-9][Formula 3-9]
화학식 2-3으로 표시되는 화합물(0.12 g, 0.30 mmol)을 벤젠(12 mL)에 녹인 다음 Lawesson’s Reagent(0.14 g, 0.36 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 4 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3(saturated NaHCO3)로 퀀치하고, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 오일 타입의 화학식 3-9로 표시되는 화합물(0.010 g, 0.025mmol)을 얻었다(수율 8%).The compound represented by Chemical Formula 2-3 (0.12 g, 0.30 mmol) was dissolved in benzene (12 mL), and Lawesson's Reagent (0.14 g, 0.36 mmol) was added thereto. The mixture was heated at 60 ° C. for 4 hours and cooled to room temperature. Quench the mixture with saturated NaHCO 3 (saturated NaHCO 3) and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain a compound (0.010 g, 0.025 mmol) represented by the formula (3-9) of the brown oil type (yield 8%).
화학식 3-9로 표시되는 화합물의 데이터: Rf = 0.48 (hexane:EtOAc = 4:1); 1H-NMR δ 1.22 (t,J = 7.2 Hz, 3H), 4.20 (q, J = 7.2 Hz, 2H), 6.32 (t, J = 3.2 Hz, 1H), 6.65 (dd, J = 3.6, 1.6 Hz, 1H), 6.90 (s, 1H), 7.11 (dd, J = 3.2, 1.6 Hz, 1H), 7.31-7.39 (m, 5H), 7.44-7.50 (m, 2H), 7.58-7.64 (m, 1H), 7.78-7.82 (m, 2H) ppm; 13C-NMR δ 14.1, 60.8, 111.5, 117.3, 126.0, 126.0, 127.6, 127.8, 128.0, 128.6, 129.2, 130.4, 130.5, 133.0, 133.3, 135.7, 138.5, 148.3, 161.9, 168.4 ppm.Data of compounds represented by formula 3-9: R f = 0.48 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.22 (t, J = 7.2 Hz, 3H), 4.20 (q, J = 7.2 Hz, 2H), 6.32 (t, J = 3.2 Hz, 1H), 6.65 (dd, J = 3.6, 1.6 Hz, 1H), 6.90 (s, 1H), 7.11 (dd, J = 3.2, 1.6 Hz, 1H), 7.31-7.39 (m, 5H), 7.44-7.50 (m, 2H), 7.58-7.64 (m, 1H), 7.78-7.82 (m, 2H) ppm; 13 C-NMR δ 14.1, 60.8, 111.5, 117.3, 126.0, 126.0, 127.6, 127.8, 128.0, 128.6, 129.2, 130.4, 130.5, 133.0, 133.3, 135.7, 138.5, 148.3, 161.9, 168.4 ppm.
실시예 16: 하기 화학식 1-4로 표시되는 화합물(Ethyl 2-acetyl-5-(furan-2-yl)-3-(4-nitrophenyl)-5-oxopentanoate)의 제조Example 16: Preparation of the compound represented by Chemical Formula 1-4 (Ethyl 2-acetyl-5- (furan-2-yl) -3- (4-nitrophenyl) -5-oxopentanoate)
[화학식 1-4][Formula 1-4]
아르곤 분위기 하에서, 에틸 아세토아세테이트(10 mL, 78 mmol)와 (E)-1-(퓨란-2-일)-3-(4-니트로페닐)-2-프로펜-1-온(2.00 g, 8.13 mmol)의 혼합물에 CeCl3.7H2O(0.30 g, 0.80 mmol) 및 NaI(0.12 g, 0.80 mmol)를 첨가하였다. 상기 혼합물을 실온에서 12시간 동안 교반한 뒤, EtOAc로 묽힌 다음, 고체를 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물(crude product)을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하고, EtOH로 재결정하여 흰색 고체의 화학식 1-4로 표시되는 화합물(1.02 g, 2.72 mmol)을 얻었다(수율 33%).Under argon atmosphere, ethyl acetoacetate (10 mL, 78 mmol) and ( E ) -1- (furan-2-yl) -3- (4-nitrophenyl) -2-propen-1-one (2.00 g, 8.13 mmol) was added CeCl 3 .7H 2 O (0.30 g, 0.80 mmol) and NaI (0.12 g, 0.80 mmol). The mixture was stirred at rt for 12 h, then diluted with EtOAc, the solids were filtered off with filter paper and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography and recrystallized with EtOH to give the compound represented by the formula (1-4) as a white solid (1.02 g, 2.72 mmol) (yield 33%).
화학식 1-4로 표시되는 화합물의 데이터: Rf = 0.45 (hexane:EtOAc = 2:1); 1H-NMR δ 1.03 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 3.25 (d, J = 6.8 Hz, 2H), 3.95 (dq, J d = 0.8, J q = 7.2 Hz, 2H), 4.10 (d, J = 10.8 Hz, 1H), 4.26 (dt, J d = 10.8, J t = 6.8 Hz, 1H), 6.50 (dd, J = 3.6, 2.0 Hz, 1H), 7.13 (dd, J = 3.6, 0.8 Hz, 1H), 7.44-7.49 (m, 2H), 7.53 (dd, J = 2.0, 0.8 Hz, 1H), 8.09-8.14 (m, 2H) ppm; 13C-NMR δ 13.6, 29.6, 39.6, 41.7, 61.6, 64.1, 112.3, 117.5, 123.4, 129.2, 146.6, 146.7, 148.3, 152.1, 167.2, 185.9, 201.1 ppm; IR 1715, 1670, 1521, 1469, 1342, 1275, 1215, 1148, 1014, 857, 745, 701, 663, 544 cm-1.Data for the compound represented by Formula 1-4: R f = 0.45 (hexane: EtOAc = 2: 1); 1 H-NMR δ 1.03 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 3.25 (d, J = 6.8 Hz, 2H), 3.95 (dq, J d = 0.8, J q = 7.2 Hz , 2H), 4.10 (d, J = 10.8 Hz, 1H), 4.26 (dt, J d = 10.8, J t = 6.8 Hz, 1H), 6.50 (dd, J = 3.6, 2.0 Hz, 1H), 7.13 ( dd, J = 3.6, 0.8 Hz, 1H), 7.44-7.49 (m, 2H), 7.53 (dd, J = 2.0, 0.8 Hz, 1H), 8.09-8.14 (m, 2H) ppm; 13 C-NMR δ 13.6, 29.6, 39.6, 41.7, 61.6, 64.1, 112.3, 117.5, 123.4, 129.2, 146.6, 146.7, 148.3, 152.1, 167.2, 185.9, 201.1 ppm; IR 1715, 1670, 1521, 1469, 1342, 1275, 1215, 1148, 1014, 857, 745, 701, 663, 544 cm -1 .
실시예 17: 하기 화학식 2-4로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(4-nitrophenyl)-2,5-dioxopentanoate)의 제조Example 17 Preparation of a Compound Represented by Chemical Formula 2-4 (Ethyl 5- (furan-2-yl) -3- (4-nitrophenyl) -2,5-dioxopentanoate)
[화학식 2-4][Formula 2-4]
화학식 1-4로 표시되는 화합물(770 mg, 2.05 mmol)을 아세트산(10 mL)에 녹이고 Mn(OAc)3·2H2O(55 mg, 0.21 mmol) 및 CoCl2(27 mg, 0.21 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 실온에서 72시간 동안 교반하고 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 엷은 노란색 오일 타입의 화학식 2-4로 표시되는 화합물(147 mg, 0.42 mmol)을 얻었다(수율 21%).Compound (770 mg, 2.05 mmol) represented by Formula 1-4 was dissolved in acetic acid (10 mL), and Mn (OAc) 3 .2H 2 O (55 mg, 0.21 mmol) and CoCl 2 (27 mg, 0.21 mmol) were added thereto. Added. The mixture was stirred for 72 h at room temperature under air and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound (147 mg, 0.42 mmol) represented by the formula 2-4 as a pale yellow oil type (yield 21%).
화학식 2-4로 표시되는 화합물의 데이터: Rf = 0.51 (hexane:EtOAc = 4:1); 1H-NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.38 (dd, J = 18.0, 4.4 Hz, 1H), 3.89 (dd, J = 18.0, 10.0 Hz, 1H), 4.23-4.37 (m, 2H), 5.23 (dd, J = 10.0, 4.4 Hz, 1H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H), 7.23 (dd, J = 3.6, 0.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.59 (dd, J = 1.6, 0.8 Hz, 1H), 8.18-8.24 (m, 2H) ppm; 13C NMR δ = 15.6, 44.1, 49.4, 64.7, 114.3, 119.5, 125.9, 131.5, 144.5, 148.6, 149.3, 153.4, 161.7, 187.3, 192.8 ppm; IR 1729, 1670, 1521, 1469, 1342, 1260, 1230, 1081, 1036, 857, 753, 693 cm-1.Data for the compound represented by Formula 2-4: R f = 0.51 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.38 (dd, J = 18.0, 4.4 Hz, 1H), 3.89 (dd, J = 18.0, 10.0 Hz, 1H), 4.23-4.37 (m , 2H), 5.23 (dd, J = 10.0, 4.4 Hz, 1H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H), 7.23 (dd, J = 3.6, 0.8 Hz, 1H), 7.52-7.57 ( m, 2H), 7.59 (dd, J = 1.6, 0.8 Hz, 1H), 8.18-8.24 (m, 2H) ppm; 13 C NMR δ = 15.6, 44.1, 49.4, 64.7, 114.3, 119.5, 125.9, 131.5, 144.5, 148.6, 149.3, 153.4, 161.7, 187.3, 192.8 ppm; IR 1729, 1670, 1521, 1469, 1342, 1260, 1230, 1081, 1036, 857, 753, 693 cm -1 .
실시예 18: 하기 화학식 3-10으로 표시되는 화합물(Ethyl 4-(4-nitrophenyl)-[2,2'-bifuran]-5-carboxylate)의 제조Example 18 Preparation of a Compound (Ethyl 4- (4-nitrophenyl)-[2,2'-bifuran] -5-carboxylate) represented by Chemical Formula 3-10
[화학식 3-10][Formula 3-10]
화학식 2-4로 표시되는 화합물(97 mg, 0.28 mmol)을 아세트산(10 mL)에 녹인 용액에 진한 염산(1.0 mL)을 첨가하였다. 이 혼합물을 55 ℃에서 7 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 Na2CO3 수용액으로 중화 후, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-10으로 표시되는 화합물(53 mg, 0.16 mmol)을 얻었다(수율 68%).To the solution of the compound represented by the formula (2-4) (97 mg, 0.28 mmol) in acetic acid (10 mL) was added concentrated hydrochloric acid (1.0 mL). The mixture was heated at 55 ° C. for 7 hours and cooled to room temperature. The mixture was poured into ice water, neutralized with saturated aqueous Na 2 CO 3 , and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound represented by Formula 3-10 (53 mg, 0.16 mmol) (yield 68%).
화학식 3-10으로 표시되는 화합물의 데이터: Rf = 0.56 (hexane:EtOAc = 4:1); 1H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 7.2 Hz, 2H), 6.54 (dd, J = 3.6, 2.0 Hz, 1H), 6.77 (s, 1H), 6.90 (dd, J = 3.6, 1.2 Hz, 1H), 7.52 (dd, J = 2.0, 1.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 8.28 (d, J = 8.4 Hz, 2H) ppm; 13C-NMR δ14.2, 61.2, 108.5, 109.0, 111.9, 123.2, 130.4, 133.8, 138.3, 138.6, 143.6, 144.7, 147.6, 148.7, 158.6ppm; IR 1707, 1521, 1342, 1297, 1178, 1111, 1014, 857, 753 cm-1.Data for the compound represented by Formula 3-10: R f = 0.56 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 7.2 Hz, 2H), 6.54 (dd, J = 3.6, 2.0 Hz, 1H), 6.77 (s, 1H), 6.90 (dd, J = 3.6, 1.2 Hz, 1H), 7.52 (dd, J = 2.0, 1.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 8.28 (d, J = 8.4 Hz, 2H ) ppm; 13 C-NMR δ 14.2, 61.2, 108.5, 109.0, 111.9, 123.2, 130.4, 133.8, 138.3, 138.6, 143.6, 144.7, 147.6, 148.7, 158.6 ppm; IR 1707, 1521, 1342, 1297, 1178, 1111, 1014, 857, 753 cm -1 .
실시예 19: 하기 화학식 3-11로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(4-nitrophenyl)-1Example 19: Compound represented by Chemical Formula 3-11 (Ethyl 5- (furan-2-yl) -3- (4-nitrophenyl) -1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-11][Formula 3-11]
화학식 2-4로 표시되는 화합물(35 mg, 0.10 mmol)을 아세트산(3.0 mL)에 녹이고 NH4OAc(32 mg, 0.42 mmol)와 sulfamic acid(2 mg, 0.02 mmol)를 첨가하였다. 이 혼합물을 50 ℃에서 8시간 동안 가열하고 실온으로 식힌 다음, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체 타입의 화학식 3-11로 표시되는 화합물(10 mg, 0.031 mmol)을 얻었다(수율 30%). The compound represented by Formula 2-4 (35 mg, 0.10 mmol) was dissolved in acetic acid (3.0 mL), and NH 4 OAc (32 mg, 0.42 mmol) and sulfamic acid (2 mg, 0.02 mmol) were added. The mixture was heated at 50 ° C. for 8 hours, cooled to room temperature, and the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain a compound (10 mg, 0.031 mmol) represented by Chemical Formula 3-11 of a white solid type (yield 30%).
화학식 3-11로 표시되는 화합물의 데이터: Rf = 0.44 (hexane:EtOAc = 4:1); 1H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 6.51 (dd, J = 3.6, 1.6 Hz, 1H), 6.57 (d, J = 3.2 Hz. 1H), 6.61 (dd, J = 3.6, 0.8 Hz, 1H), 7.47 (dd, J = 1.6, 0.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.4 Hz, 2H), 9.42 (br s, 1H) ppm; IR 3295, 3265, 1670, 1595, 1513, 1439, 1342, 1275 cm-1.Data for the compound represented by Formula 3-11: R f = 0.44 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 6.51 (dd, J = 3.6, 1.6 Hz, 1H), 6.57 (d, J = 3.2 Hz. 1H), 6.61 (dd, J = 3.6, 0.8 Hz, 1H), 7.47 (dd, J = 1.6, 0.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 8.24 (d, J = 8.4 Hz, 2H), 9.42 (br s, 1H) ppm; IR 3295, 3265, 1670, 1595, 1513, 1439, 1342, 1275 cm -1 .
실시예 20: 하기 화학식 3-12로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(4-nitrophenyl)thiophene-2-carboxylate)의 제조Example 20 Preparation of Compound (Ethyl 5- (furan-2-yl) -3- (4-nitrophenyl) thiophene-2-carboxylate) represented by Chemical Formula 3-12
[화학식 3-12][Formula 3-12]
화학식 2-4로 표시되는 화합물(53 mg, 0.15 mmol)을 톨루엔(5 mL)에 녹인 다음 Lawesson’s Reagent(0.15 g, 0.38 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 9 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 타입의 화학식 3-12로 표시되는 화합물(50 mg, 0.15 mmol)을 얻었다(수율 95%).The compound represented by Formula 2-4 (53 mg, 0.15 mmol) was dissolved in toluene (5 mL), and Lawesson's Reagent (0.15 g, 0.38 mmol) was added thereto. The mixture was heated at 60 ° C. for 9 hours and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain the compound (50 mg, 0.15 mmol) represented by the formula 3-12 as a brown solid type (yield 95%).
화학식 3-12로 표시되는 화합물의 데이터: Rf = 0.58 (hexane:EtOAc = 4:1); 1H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 6.51 (dd, J = 3.2, 2.0 Hz, 1H), 6.70 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 7.48 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 8.4 Hz, 2H) ppm; 13C-NMRδ14.1, 61.3, 107.9, 112.2, 123.0, 125.3, 126.2, 130.2, 138.2, 142.2, 143.2, 146.3, 147.4, 147.9, 161.5 ppm.Data for the compound represented by Formula 3-12: R f = 0.58 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 6.51 (dd, J = 3.2, 2.0 Hz, 1H), 6.70 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 7.48 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 8.4 Hz, 2H) ppm; 13 C-NMRδ 14.1, 61.3, 107.9, 112.2, 123.0, 125.3, 126.2, 130.2, 138.2, 142.2, 143.2, 146.3, 147.4, 147.9, 161.5 ppm.
실시예 21: 하기 화학식 1-5로 표시되는 화합물(Ethyl 2-acetyl-5-(furan-2-yl)-3-(4-methoxyphenyl)-5-oxopentanoate)의 제조Example 21 Preparation of a Compound Represented by Chemical Formula 1-5 (Ethyl 2-acetyl-5- (furan-2-yl) -3- (4-methoxyphenyl) -5-oxopentanoate)
[화학식 1-5][Formula 1-5]
아르곤 분위기 하에서, 에틸 아세토아세테이트(5.14 g, 39.46 mmol)와 (E)-1-(퓨란-2-일)-3-(4-메톡시페닐)-2-프로펜-1-온(3.00 g, 13.15 mmol)의 혼합물에 CeCl3.7H2O(0.49 g, 1.32 mmol)과 NaI(0.20 g, 1.32 mmol)를 첨가하였다. 상기 혼합물을 60 ℃에서 하루 동안 교반한 뒤, 실온으로 식히고, CH2Cl2로 묽힌 다음, 고체를 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체의 화학식 1-5로 표시되는 화합물(4.29 g, 11.98 mmol, 1.3:1 입체이성질체 혼합물)을 얻었다(수율 91%).Under argon atmosphere, ethyl acetoacetate (5.14 g, 39.46 mmol) and ( E ) -1- (furan-2-yl) -3- (4-methoxyphenyl) -2-propen-1-one (3.00 g , 13.15 mmol) was added CeCl 3 .7H 2 O (0.49 g, 1.32 mmol) and NaI (0.20 g, 1.32 mmol). The mixture was stirred at 60 ° C. for 1 day, then cooled to room temperature, diluted with CH 2 Cl 2 , the solids were filtered off with filter paper, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound (4.29 g, 11.98 mmol, 1.3: 1 stereoisomer mixture) of the white solid (yield 91%).
화학식 1-5로 표시되는 화합물의 데이터: Rf= 0.13 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 1.00 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 3.13 (d of A of ABq, J AB = 16.0, J d = 5.2 Hz, 1H), 3.17 (d of B of ABq, J AB = 16.0, J d = 8.0 Hz, 1H), 3.73 (s, 3H), 3.92 (q, J = 7.2 Hz, 2H), 4.00 (d, J = 10.4 Hz, 1H), 4.05-4.14 (m, 1H), 6.45-6.48 (m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 7.10-7.13 (m, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.50-7.53 (m, 1H) ppm; (minor) δ 1.26 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.22 (d of A of ABq, J AB = 15.2, J d = 5.2 Hz, 1H), 3.26 (d of B of ABq, J AB = 15.2, J d = 8.4 Hz, 1H), 3.73 (s, 3H), 3.96 (d, J = 10.8 Hz, 1H), 4.05-4.14 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 6.45-6.48 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 7.10-7.13 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.50-7.53 (m, 1H) ppm; 13C-NMR (major) δ 13.7, 29.5, 39.8, 42.6, 55.1, 61.3, 65.5, 112.2, 113.7, 117.3, 129.2, 132.3, 146.3, 152.6, 158.5, 168.4, 186.9, 202.4 ppm; (minor) δ 14.0, 29.9, 40.1, 42.8, 55.1, 61.6, 65.0, 112.2, 114.0, 117.2, 129.1, 131.9, 146.2, 152.6, 158.5, 167.9, 186.7, 202.1 ppm; IR 1737, 1715, 1670, 1513, 1469, 1357, 1245, 1178, 1148, 1111, 1088, 1029, 827, 760, 552 cm-1; HRMS (ESI) calcd for C20H22O6Na [M+Na]+ 381.1309, found 381.1312.Data for the compound represented by Formula 1-5: R f = 0.13 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 1.00 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 3.13 (d of A of ABq, J AB = 16.0, J d = 5.2 Hz, 1H), 3.17 (d of B of ABq, J AB = 16.0, J d = 8.0 Hz, 1H), 3.73 (s, 3H), 3.92 (q, J = 7.2 Hz, 2H), 4.00 (d, J = 10.4 Hz, 1H ), 4.05-4.14 (m, 1H), 6.45-6.48 (m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 7.10-7.13 (m, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.50-7.53 (m, 1H) ppm; (minor) δ 1.26 (t, J = 7.2 Hz, 3H), 2.00 (s, 3H), 3.22 (d of A of ABq, J AB = 15.2, J d = 5.2 Hz, 1H), 3.26 (d of B of ABq, J AB = 15.2, J d = 8.4 Hz, 1H), 3.73 (s, 3H), 3.96 (d, J = 10.8 Hz, 1H), 4.05-4.14 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 6.45-6.48 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 7.10-7.13 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.50 -7.53 (m, 1 H) ppm; 13 C-NMR (major) δ 13.7, 29.5, 39.8, 42.6, 55.1, 61.3, 65.5, 112.2, 113.7, 117.3, 129.2, 132.3, 146.3, 152.6, 158.5, 168.4, 186.9, 202.4 ppm; (minor) δ 14.0, 29.9, 40.1, 42.8, 55.1, 61.6, 65.0, 112.2, 114.0, 117.2, 129.1, 131.9, 146.2, 152.6, 158.5, 167.9, 186.7, 202.1 ppm; IR 1737, 1715, 1670, 1513, 1469, 1357, 1245, 1178, 1148, 1111, 1088, 1029, 827, 760, 552 cm -1 ; HRMS (ESI) calcd for C 20 H 22 O 6 Na [M + Na] + 381.1309, found 381.1312.
실시예 22: 하기 화학식 2-5로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(4-methoxyphenyl)-2,5-dioxopentanoate)의 제조Example 22 Preparation of a Compound Represented by Chemical Formula 2-5 (Ethyl 5- (furan-2-yl) -3- (4-methoxyphenyl) -2,5-dioxopentanoate)
[화학식 2-5][Formula 2-5]
화학식 1-5로 표시되는 화합물(1.60 g, 4.47 mmol)을 아세트산(30 mL)에 녹이고 Mn(OAc)3·2H2O(0.12 g, 0.45 mmol) 및 CoCl2(0.060 g, 0.45 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 실온에서 23시간 동안 교반하고 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 엷은 흰색 고체의 화학식 2-5로 표시되는 화합물(0.31 g, 0.94 mmol)을 얻었다(수율 23%).The compound represented by Formula 1-5 (1.60 g, 4.47 mmol) was dissolved in acetic acid (30 mL), and Mn (OAc) 3 .2H 2 O (0.12 g, 0.45 mmol) and CoCl 2 (0.060 g, 0.45 mmol) were added. Added. The mixture was stirred for 23 h at room temperature under air and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound represented by the formula (2-5) as a pale white solid (0.31 g, 0.94 mmol) (yield 23%).
화학식 2-5로 표시되는 화합물의 데이터: Rf = 0.23 (hexane:EtOAc = 4:1); 1H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 3.26 (dd, J = 18.0, 4.0 Hz, 1H), 3.79 (s, 3H), 3.83 (dd, J = 18.0, 10.0 Hz, 1H), 4.19-4.32 (m, 2H), 5.06 (dd, J = 10.0, 4.0 Hz, 1H), 6.53 (dd, J = 3.6, 1.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 7.20 (dd, J = 3.6, 0.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 2.0, 0.8 Hz, 1H) ppm; 13C-NMR δ 13.9, 42.0, 47.3, 55.3, 62.4, 112.4, 114.6, 117.4, 126.8, 130.1, 146.5, 152.1, 159.3, 160.4, 186.5, 192.0 ppm; IR 1722, 1670, 1513, 1469, 1394, 1252, 1178, 1081, 1036, 969, 909, 835, 753, 552 cm-1; HRMS (ESI) calcd for C18H18O6Na [M+Na]+ 353.0996, found 353.0997.Data for the compound represented by Formula 2-5: R f = 0.23 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 3.26 (dd, J = 18.0, 4.0 Hz, 1H), 3.79 (s, 3H), 3.83 (dd, J = 18.0, 10.0 Hz, 1H ), 4.19-4.32 (m, 2H), 5.06 (dd, J = 10.0, 4.0 Hz, 1H), 6.53 (dd, J = 3.6, 1.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H) , 7.20 (dd, J = 3.6, 0.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 2.0, 0.8 Hz, 1H) ppm; 13 C-NMR δ 13.9, 42.0, 47.3, 55.3, 62.4, 112.4, 114.6, 117.4, 126.8, 130.1, 146.5, 152.1, 159.3, 160.4, 186.5, 192.0 ppm; IR 1722, 1670, 1513, 1469, 1394, 1252, 1178, 1081, 1036, 969, 909, 835, 753, 552 cm −1 ; HRMS (ESI) calcd for C 18 H 18 O 6 Na [M + Na] + 353.0996, found 353.0997.
실시예 23: 하기 화학식 3-13으로 표시되는 화합물(Ethyl 4-(4-methoxyphenyl)-[2,2'-bifuran]-5-carboxylate)의 제조Example 23 Preparation of Compound (Ethyl 4- (4-methoxyphenyl)-[2,2'-bifuran] -5-carboxylate) represented by Chemical Formula 3-13
[화학식 3-13][Formula 3-13]
화학식 2-5로 표시되는 화합물(250 mg, 0.76 mmol)을 아세트산 무수물(15 mL)에 녹인 용액에 진한 염산(2.0 mL)을 첨가하였다. 이 혼합물을 55 ℃에서 1 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 Na2CO3 수용액으로 중화 후, EtOAc로 추출하였다. 유기 상(organic phase)을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-13으로 표시되는 노란색 오일 타입의 화합물(112 mg, 0.39 mmol)을 얻었다(수율 49%).Concentrated hydrochloric acid (2.0 mL) was added to a solution of the compound represented by Formula 2-5 (250 mg, 0.76 mmol) in acetic anhydride (15 mL). The mixture was heated at 55 ° C. for 1 hour and cooled to room temperature. The mixture was poured into ice water, neutralized with saturated aqueous Na 2 CO 3 , and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to give a compound (112 mg, 0.39 mmol) of the yellow oil type represented by Chemical Formula 3-13 (yield 49%).
화학식 3-13으로 표시되는 화합물의 데이터: Rf = 0.52 (hexane:EtOAc = 4:1); 1H-NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 6.52 (dd, J = 3.6, 2.0 Hz, 1H), 6.73 (s, 1H), 6.85 (d, J = 3.6 Hz, 1H), 6.93-6.97 (m, 2H), 7.49 (dd, J = 2.0, 0.8 Hz, 1H), 7.56-7.61 (m, 2H) ppm; 13C-NMR δ 14.3, 55.3, 60.8, 108.3, 109.8, 111.8, 113.4, 124.0, 130.7, 136.1, 137.3, 143.2, 145.3, 148.0, 159.2, 159.8 ppm; IR 1707, 1610, 1506, 1297, 1252, 1178, 1103, 1029, 835 cm-1;HRMS (ESI) calcd for C18H16O5Na [M+Na]+ 335.0890, found 335.0894.Data of compounds represented by formula 3-13: R f = 0.52 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 6.52 (dd, J = 3.6, 2.0 Hz, 1H), 6.73 (s, 1H), 6.85 (d, J = 3.6 Hz, 1H), 6.93-6.97 (m, 2H), 7.49 (dd, J = 2.0, 0.8 Hz, 1H), 7.56-7.61 (m, 2H) ppm; 13 C-NMR δ 14.3, 55.3, 60.8, 108.3, 109.8, 111.8, 113.4, 124.0, 130.7, 136.1, 137.3, 143.2, 145.3, 148.0, 159.2, 159.8 ppm; IR 1707, 1610, 1506, 1297, 1252, 1178, 1103, 1029, 835 cm −1 ; HRMS (ESI) calcd for C 18 H 16 O 5 Na [M + Na] + 335.0890, found 335.0894.
실시예 24: 하기 화학식 3-14로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate)의 제조Example 24 Preparation of a Compound Represented by Chemical Formula 3-14 (Ethyl 5- (furan-2-yl) -3- (4-methoxyphenyl) -1H-pyrrole-2-carboxylate)
[화학식 3-14][Formula 3-14]
화학식 2-5로 표시되는 화합물(0.10 g, 0.30 mmol)을 아세트산(8 mL)에 녹이고 NH4OAc(50 mg, 0.60 mmol)와 sulfamic acid(3 mg, 0.03 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 6시간 동안 가열하고 실온으로 식힌 다음, 용매를 감압 하에서 제거하였다. 이를 CH2Cl2로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체 타입의 화학식 3-14로 표시되는 화합물(80 mg, 0.26 mmol)을 얻었다(수율 86%). The compound represented by Formula 2-5 (0.10 g, 0.30 mmol) was dissolved in acetic acid (8 mL), and NH 4 OAc (50 mg, 0.60 mmol) and sulfamic acid (3 mg, 0.03 mmol) were added. The mixture was heated at 60 ° C. for 6 hours and cooled to room temperature, then the solvent was removed under reduced pressure. It was diluted with CH 2 Cl 2 , washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain a compound (80 mg, 0.26 mmol) represented by the formula 3-14 of a white solid type (yield 86%).
화학식 3-14로 표시되는 화합물의 데이터: 1H-NMR δ 1.28 (t, J = 7.2 Hz, 3H), 3.84 (s, 3H), 4.28 (q, J = 7.2 Hz, 2H), 6.47 (dd, J = 3.6, 2.0 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 6.56 (dd, J = 3.6, 0.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 2.0, 0.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 9.34 (br s, 1H) ppm; 13C-NMR δ 14.3, 55.3, 60.3, 105.5, 108.6, 111.7, 113.1, 117.5, 126.8, 127.1, 130.6, 133.1, 141.8, 146.6, 158.9, 160.9 ppm; IR 3268, 2966, 2931, 2902, 2832, 1655, 1610, 1521, 1498, 1439, 1409, 1372, 1275, 1245, 1178, 1133, 1111, 1081, 1014, 984, 962, 880, 805, 731, 626, 596, 529 cm-1; HRMS (ESI) calcd for C18H17NO4Na [M+Na]+ 334.1050, found 334.1053.Data for compounds represented by Formulas 3-14: 1 H-NMR δ 1.28 (t, J = 7.2 Hz, 3H), 3.84 (s, 3H), 4.28 (q, J = 7.2 Hz, 2H), 6.47 (dd , J = 3.6, 2.0 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 6.56 (dd, J = 3.6, 0.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 2.0, 0.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 9.34 (br s, 1H) ppm; 13 C-NMR δ 14.3, 55.3, 60.3, 105.5, 108.6, 111.7, 113.1, 117.5, 126.8, 127.1, 130.6, 133.1, 141.8, 146.6, 158.9, 160.9 ppm; IR 3268, 2966, 2931, 2902, 2832, 1655, 1610, 1521, 1498, 1439, 1409, 1372, 1275, 1245, 1178, 1133, 1111, 1081, 1014, 984, 962, 880, 805, 731, 626 , 596, 529 cm −1 ; HRMS (ESI) calcd for C 18 H 17 NO 4 Na [M + Na] + 334.1050, found 334.1053.
실시예 25: 하기 화학식 3-15로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(4-methoxyphenyl)thiophene-2-carboxylate)의 제조Example 25 Preparation of Compound (Ethyl 5- (furan-2-yl) -3- (4-methoxyphenyl) thiophene-2-carboxylate) represented by Chemical Formula 3-15
[화학식 3-15][Formula 3-15]
화학식 2-5로 표시되는 화합물(180 mg, 0.154 mmol)을 벤젠(10 mL)에 녹인 다음 Lawesson’s Reagent(220 mg, 0.54 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 9 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 타입의 화학식 3-15로 표시되는 화합물(84 mg, 0.28 mmol)을 얻었다(수율 52%).The compound represented by Formula 2-5 (180 mg, 0.154 mmol) was dissolved in benzene (10 mL), and Lawesson's Reagent (220 mg, 0.54 mmol) was added thereto. The mixture was heated at 60 ° C. for 9 hours and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain the compound represented by the formula (3-15) as a brown solid type (84 mg, 0.28 mmol) (yield 52%).
화학식 3-15로 표시되는 화합물의 데이터: Rf = 0.51 (hexane:EtOAc = 4:1); 1H-NMR δ 1.28(t,J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 6.48 (dd, J = 3.2, 1.6 Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 6.92-6.96 (m, 2H), 7.20 (s, 1H), 7.42-7.46 (m, 3H) ppm; 13C-NMR δ 14.2, 55.3, 60.9, 107.3, 112.0, 113.2, 124.2, 126.3, 127.8, 130.5, 137.1, 142.8, 148.5, 148.9, 159.5, 162.1 ppm; IR 1707, 1610, 1506, 1431, 1245, 1223, 1178, 1111, 1073, 1029, 827, 753 cm-1; HRMS (ESI) calcd for C18H16O4SNa [M+Na]+ 351.0662, found 351.0664.Data for compounds represented by formula 3-15: R f = 0.51 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.28 (t, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 6.48 (dd, J = 3.2, 1.6 Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 6.92-6.96 (m, 2H), 7.20 (s, 1H), 7.42-7.46 (m, 3H) ppm; 13 C-NMR δ 14.2, 55.3, 60.9, 107.3, 112.0, 113.2, 124.2, 126.3, 127.8, 130.5, 137.1, 142.8, 148.5, 148.9, 159.5, 162.1 ppm; IR 1707, 1610, 1506, 1431, 1245, 1223, 1178, 1111, 1073, 1029, 827, 753 cm −1 ; HRMS (ESI) calcd for C 18 H 16 O 4 SNa [M + Na] + 351.0662, found 351.0664.
실시예 26: 하기 화학식 1-6으로 표시되는 화합물(Ethyl 2-acetyl-3-(4-bromophenyl)-5-(furan-2-yl)-5-oxopentanoate)의 제조Example 26 Preparation of a Compound (Ethyl 2-acetyl-3- (4-bromophenyl) -5- (furan-2-yl) -5-oxopentanoate) Represented by Chemical Formula 1-6
[화학식 1-6][Formula 1-6]
아르곤 분위기 하에서, 에틸 아세토아세테이트(10 mL, 78 mmol)와 (E)-3-(4-브로모페닐)-1-(퓨란-2-일)-2-프로펜-1-온(1.00 g, 3.61 mmol)의 혼합물에 CeCl3.7H2O(150 mg, 0.36 mmol) 및 NaI(60 mg, 0.36 mmol)를 첨가하였다. 상기 혼합물을 50 ℃에서 10시간 동안 교반한 뒤, 실온으로 식히고, EtOAc로 묽힌 다음, 물로 씻고, 무수 Na2SO4로 수분을 제거한 다음, 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체의 화학식 1-6으로 표시되는 화합물(1.10 g, 2.70 mmol, 1.3:1 입체이성질체 혼합물)을 얻었다(수율 75%).Under argon atmosphere, ethyl acetoacetate (10 mL, 78 mmol) and ( E ) -3- (4-bromophenyl) -1- (furan-2-yl) -2-propen-1-one (1.00 g , 3.61 mmol) was added CeCl 3 .7H 2 O (150 mg, 0.36 mmol) and NaI (60 mg, 0.36 mmol). The mixture was stirred at 50 ° C. for 10 hours, then cooled to room temperature, diluted with EtOAc, washed with water, dried with anhydrous Na 2 SO 4 , filtered over filter paper, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a compound (1.10 g, 2.70 mmol, 1.3: 1 stereoisomer mixture) of white solid (yield 75%).
화학식 1-6으로 표시되는 화합물의 데이터: Rf = 0.16 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 1.02 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.16 (d, J = 6.8 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H), 4.01 (d, J = 10.8 Hz, 1H), 4.07-4.16 (m, 1H), 6.48 (dd, J = 3.6, 1.6 Hz, 1H), 7.11-7.16 (m, 3H), 7.34-7.38 (m, 2H), 7.52 (dd, J = 1.6, 0.8 Hz, 1H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H), 3.20-3.32 (m, 2H), 3.97 (d, J = 10.4 Hz, 1H), 4.07-4.16 (m, 1H), 4.20 (dq, J d = 1.2, J q = 7.2 Hz, 2H), 6.47-6.50 (m, 1H), 7.11-7.16 (m, 3H), 7.34-7.38 (m, 2H), 7.52-7.54 (m, 1H) ppm; 13C-NMR (major) δ 13.8, 29.6, 39.7, 42.1, 61.6, 64.8, 112.2, 117.5, 121.0, 129.9, 131.5, 139.5, 146.5, 152.4, 167.7, 186.6, 201.9 ppm; (major) δ 14.0, 30.0, 39.9, 42.2, 61.8, 64.5, 112.3, 117.3, 121.2, 130.0, 131.8, 139.3, 146.4, 152.4, 168.1, 186.3, 201.5 ppm; IR 1737, 1715, 1677, 1469, 1275, 1230, 1014 cm-1.Data for the compound represented by Formula 1-6: R f = 0.16 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 1.02 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.16 (d, J = 6.8 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H) , 4.01 (d, J = 10.8 Hz, 1H), 4.07-4.16 (m, 1H), 6.48 (dd, J = 3.6, 1.6 Hz, 1H), 7.11-7.16 (m, 3H), 7.34-7.38 (m , 2H), 7.52 (dd, J = 1.6, 0.8 Hz, 1H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.04 (s, 3H), 3.20-3.32 (m, 2H), 3.97 (d, J = 10.4 Hz, 1H), 4.07-4.16 (m, 1H), 4.20 (dq, J d = 1.2, J q = 7.2 Hz, 2H), 6.47-6.50 (m, 1H), 7.11-7.16 (m, 3H), 7.34-7.38 (m, 2H), 7.52- 7.54 (m, 1 H) ppm; 13 C-NMR (major) δ 13.8, 29.6, 39.7, 42.1, 61.6, 64.8, 112.2, 117.5, 121.0, 129.9, 131.5, 139.5, 146.5, 152.4, 167.7, 186.6, 201.9 ppm; (major) δ 14.0, 30.0, 39.9, 42.2, 61.8, 64.5, 112.3, 117.3, 121.2, 130.0, 131.8, 139.3, 146.4, 152.4, 168.1, 186.3, 201.5 ppm; IR 1737, 1715, 1677, 1469, 1275, 1230, 1014 cm -1 .
실시예 27: 하기 화학식 2-6으로 표시되는 화합물(Ethyl 3-(4-bromophenyl)-5-(furan-2-yl)-2,5-dioxopentanoate)의 제조Example 27 Preparation of Compound (Ethyl 3- (4-bromophenyl) -5- (furan-2-yl) -2,5-dioxopentanoate) Represented by Chemical Formula 2-6
[화학식 2-6][Formula 2-6]
화학식 1-6으로 표시되는 화합물(200 mg, 0.49 mmol)을 아세트산(8.0 mL)에 녹이고 Mn(OAc)3·2H2O(13 mg, 0.05 mmol) 및 CoCl2(10 mg, 0.05 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 60 ℃에서 14시간 동안 교반하고, 실온으로 식힌 뒤, 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 엷은 흰색 결정의 화학식 2-6으로 표시되는 화합물(28 mg, 0.074 mmol)을 얻었다(수율 19%).The compound represented by Formula 1-6 (200 mg, 0.49 mmol) was dissolved in acetic acid (8.0 mL), and Mn (OAc) 3 .2H 2 O (13 mg, 0.05 mmol) and CoCl 2 (10 mg, 0.05 mmol) were added. Added. The mixture was stirred for 14 h at 60 ° C. under air, cooled to room temperature and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound represented by the formula (2-6) as pale white crystals (28 mg, 0.074 mmol) (yield 19%).
화학식 2-6으로 표시되는 화합물의 데이터: Rf = 0.45 (hexane:EtOAc = 4:1); 1H-NMR δ 1.31(t,J = 7.2 Hz, 3H), 3.30 (dd, J = 18.0, 4.4 Hz, 1H), 3.84 (dd, J = 18.0, 10.0 Hz, 1H), 4.21-4.35 (m, 2H), 5.08 (dd, J = 10.0, 4.4 Hz, 1H), 6.55 (dd, J = 3.6, 1.6 Hz, 1H), 7.20-7.24 (m, 3H), 7.40-7.50 (m, 2H) 7.59 (dd, J = 1.6, 0.8 Hz, 1H) ppm; 13C-NMR δ 13.9, 42.1, 47.4, 62.7, 112.5, 117.6, 122.2, 130.5, 132.2, 134.2, 146.7, 151.9, 160.1, 186.1, 191.6 ppm; IR 1729, 1670, 1469, 1267, 1044, 1014 cm-1.Data of the compound represented by Formula 2-6: R f = 0.45 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.31 (t, J = 7.2 Hz, 3H), 3.30 (dd, J = 18.0, 4.4 Hz, 1H), 3.84 (dd, J = 18.0, 10.0 Hz, 1H), 4.21-4.35 (m , 2H), 5.08 (dd, J = 10.0, 4.4 Hz, 1H), 6.55 (dd, J = 3.6, 1.6 Hz, 1H), 7.20-7.24 (m, 3H), 7.40-7.50 (m, 2H) 7.59 (dd, J = 1.6, 0.8 Hz, 1H) ppm; 13 C-NMR δ 13.9, 42.1, 47.4, 62.7, 112.5, 117.6, 122.2, 130.5, 132.2, 134.2, 146.7, 151.9, 160.1, 186.1, 191.6 ppm; IR 1729, 1670, 1469, 1267, 1044, 1014 cm -1 .
실시예 28: 하기 화학식 3-16으로 표시되는 화합물(Ethyl 4-(4-bromophenyl)-[2,2'-bifuran]-5-carboxylate)의 제조Example 28 Preparation of Compound (Ethyl 4- (4-bromophenyl)-[2,2'-bifuran] -5-carboxylate) represented by Chemical Formula 3-16
[화학식 3-16][Formula 3-16]
화학식 2-6으로 표시되는 화합물(87 mg, 0.23 mmol)을 아세트산(5.0 mL)에 녹인 용액에 진한 염산(1.0 mL)을 첨가하였다. 이 혼합물을 50 ℃에서 7 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 Na2CO3 수용액으로 중화 후, EtOAc로 추출하고, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-16으로 표시되는 노란색 오일 타입의 화합물(24 mg, 0.065 mmol)을 얻었다(수율 29%).To the solution of the compound represented by the formula (2-6) (87 mg, 0.23 mmol) in acetic acid (5.0 mL) was added concentrated hydrochloric acid (1.0 mL). The mixture was heated at 50 ° C. for 7 hours and cooled to room temperature. The mixture was poured into ice water, neutralized with saturated Na 2 CO 3 aqueous solution, extracted with EtOAc, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a compound of the yellow oil type (24 mg, 0.065 mmol) represented by Formula 3-16 (yield 29%).
화학식 3-16으로 표시되는 화합물의 데이터: Rf = 0.63 (hexane:EtOAc = 4:1); 1H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.30 (q, J = 7.2 Hz, 2H), 6.52 (d, J = 1.2 Hz, 1H), 6.72 (s, 1H), 6.87 (d, J = 3.2 Hz, 1H), 7.46-7.62 (m, 5H) ppm; 13C-NMR δ 14.2, 61.0, 108.6, 108.8, 111.8, 122.6, 130.7, 131.0, 131.2, 135.1, 137.7, 143.4, 145.0, 148.3, 158.9 ppm; IR 1715, 1282, 1178, 1111, 1073, 1014, 813 cm-1.Data for the compound represented by Formula 3-16: R f = 0.63 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.30 (q, J = 7.2 Hz, 2H), 6.52 (d, J = 1.2 Hz, 1H), 6.72 (s, 1H), 6.87 ( d, J = 3.2 Hz, 1H), 7.46-7.62 (m, 5H) ppm; 13 C-NMR δ 14.2, 61.0, 108.6, 108.8, 111.8, 122.6, 130.7, 131.0, 131.2, 135.1, 137.7, 143.4, 145.0, 148.3, 158.9 ppm; IR 1715, 1282, 1178, 1111, 1073, 1014, 813 cm -1 .
실시예 29: 하기 화학식 3-17로 표시되는 화합물(Ethyl 3-(4-bromophenyl)-5-(furan-2-yl)-1Example 29: Compound represented by Chemical Formula 3-17 (Ethyl 3- (4-bromophenyl) -5- (furan-2-yl) -1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-17][Formula 3-17]
화학식 2-6으로 표시되는 화합물(60 mg, 0.16 mmol)을 아세트산(2.0 mL)에 녹이고 NH4OAc(24 mg, 0.32 mmol)와 sulfamic acid(1.5 mg, 0.01 mmol)를 첨가하였다. 이 혼합물을 실온에서 9시간 동안 교반하고, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체 타입의 화학식 3-17로 표시되는 화합물(29 mg, 0.081 mmol)을 얻었다(수율 25%).The compound represented by Formula 2-6 (60 mg, 0.16 mmol) was dissolved in acetic acid (2.0 mL), and NH 4 OAc (24 mg, 0.32 mmol) and sulfamic acid (1.5 mg, 0.01 mmol) were added thereto. The mixture was stirred at rt for 9 h and the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain a compound (29 mg, 0.081 mmol) represented by the formula 3-17 as a white solid type (yield 25%).
화학식 3-17로 표시되는 화합물의 데이터: Rf = 0.56 (hexane:EtOAc = 4:1); 1H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 4.29 (q, J = 7.2 Hz, 2H), 6.49-6.50 (m, 2H), 6.57 (d, J = 3.2 Hz, 1H), 7.44-7.53 (m, 5H), 9.32 (br s, 1H) ppm; 13C-NMR δ 14.3, 60.5, 105.7, 108.5, 111.8, 117.8, 121.3, 126.9, 130.8, 131.1, 132.0, 133.7, 142.0, 146.3, 160.6 ppm; IR 3295, 1670, 1483, 1446, 1275, 1200, 1133, 1073, 1014, 805, 738 cm-1.Data of compounds represented by formula 3-17: R f = 0.56 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.29 (t, J = 7.2 Hz, 3H), 4.29 (q, J = 7.2 Hz, 2H), 6.49-6.50 (m, 2H), 6.57 (d, J = 3.2 Hz, 1H), 7.44-7.53 (m, 5H), 9.32 (br s, 1H) ppm; 13 C-NMR δ 14.3, 60.5, 105.7, 108.5, 111.8, 117.8, 121.3, 126.9, 130.8, 131.1, 132.0, 133.7, 142.0, 146.3, 160.6 ppm; IR 3295, 1670, 1483, 1446, 1275, 1200, 1133, 1073, 1014, 805, 738 cm -1 .
실시예 30: 하기 화학식 3-18로 표시되는 화합물(Ethyl 3-(4-bromophenyl)-5-(furan-2-yl)thiophene-2-carboxylate)의 제조Example 30 Preparation of Compound (Ethyl 3- (4-bromophenyl) -5- (furan-2-yl) thiophene-2-carboxylate) represented by Chemical Formula 3-18
[화학식 3-18][Formula 3-18]
화학식 2-6으로 표시되는 화합물(120 mg, 0.31 mmol)을 톨루엔(8.0 mL)에 녹인 다음 Lawesson’s Reagent(154 mg, 0.37 mmol)를 첨가하였다. 이 혼합물을 50 ℃에서 8 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 타입의 화학식 3-18로 표시되는 화합물(70 mg, 0.19 mmol)을 얻었다(수율 61%).The compound represented by Formula 2-6 (120 mg, 0.31 mmol) was dissolved in toluene (8.0 mL), and Lawesson's Reagent (154 mg, 0.37 mmol) was added thereto. The mixture was heated at 50 ° C. for 8 hours and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain the compound represented by the formula (3-18) of the brown solid type (70 mg, 0.19 mmol) (yield 61%).
화학식 3-18로 표시되는 화합물의 데이터: 1H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.49 (dd, J = 3.6, 1.6 Hz, 1H), 6.66 (dd, J = 3.6, 0.8 Hz, 1H), 7.17 (s, 1H), 7.33-7.37 (m, 2H), 7.46 (dd, J = 1.6, 0.8 Hz, 1H), 7.50-7.55 (m, 2H) ppm; 13C-NMR δ 14.1, 61.1, 107.6, 112.1, 122.3, 125.1, 125.8, 130.8, 130.9, 134.4, 137.6, 143.0, 147.7, 148.2, 161.8 ppm; IR 1707, 1476, 1431, 1401, 1372, 1252, 1223, 1200, 1118, 1073, 1014, 984, 820, 760 cm-1.Data for compounds represented by Formulas 3-18: 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.49 (dd, J = 3.6, 1.6 Hz , 1H), 6.66 (dd, J = 3.6, 0.8 Hz, 1H), 7.17 (s, 1H), 7.33-7.37 (m, 2H), 7.46 (dd, J = 1.6, 0.8 Hz, 1H), 7.50- 7.55 (m, 2 H) ppm; 13 C-NMR δ 14.1, 61.1, 107.6, 112.1, 122.3, 125.1, 125.8, 130.8, 130.9, 134.4, 137.6, 143.0, 147.7, 148.2, 161.8 ppm; IR 1707, 1476, 1431, 1401, 1372, 1252, 1223, 1200, 1118, 1073, 1014, 984, 820, 760 cm -1 .
실시예 31: 하기 화학식 1-7로 표시되는 화합물(Ethyl 2-acetyl-3-(4-fluorophenyl)-5-(furan-2-yl)-5-oxopentanoate)의 제조Example 31 Preparation of a Compound Represented by Chemical Formula 1-7 (Ethyl 2-acetyl-3- (4-fluorophenyl) -5- (furan-2-yl) -5-oxopentanoate)
[화학식 1-7][Formula 1-7]
아르곤 분위기 하에서, 에틸 아세토아세테이트(2 mL, 15.6 mmol)와 (E)-3-(4-플루오로페닐)-1-(퓨란-2-일)-2-프로펜-1-온(0.97 g, 4.48 mmol)을 아세토니트릴(20 mL)에 녹인 용액에 CeCl3.7H2O(0.17 g, 0.42 mmol) 및 NaI(70 mg, 0.42 mmol)를 첨가하였다. 상기 혼합물을 50 ℃에서 12시간 동안 교반한 뒤, 실온으로 식히고, EtOAc로 묽힌 다음, 물로 씻고, 무수 Na2SO4로 수분을 제거한 다음, 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체의 화학식 1-7로 표시되는 화합물(1.40 g, 4.04 mmol, 1.3:1 입체이성질체 혼합물)을 얻었다(수율 90%).Under argon atmosphere, ethyl acetoacetate (2 mL, 15.6 mmol) and ( E ) -3- (4-fluorophenyl) -1- (furan-2-yl) -2-propen-1-one (0.97 g , 4.48 mmol) in acetonitrile (20 mL) was added CeCl 3 .7H 2 O (0.17 g, 0.42 mmol) and NaI (70 mg, 0.42 mmol). The mixture was stirred at 50 ° C. for 12 h, then cooled to rt, diluted with EtOAc, washed with water, dried with anhydrous Na 2 SO 4 , filtered over filter paper, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound (1.40 g, 4.04 mmol, 1.3: 1 stereoisomer mixture) of the white solid (yield 90%).
화학식 1-7로 표시되는 화합물의 데이터: Rf = 0.08(hexane:EtOAc = 4:1);1H-NMR (major) δ 1.00 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.16 (d, J = 7.2 Hz, 2H), 3.93 (q, J = 7.2 Hz, 2H), 4.01 (d, J = 10.8 Hz, 1H), 4.09-4.16 (m, 1H), 6.47-6.50 (m, 1H), 6.90-6.96 (m, 2H), 7.12 (dd, J = 3.6, 0.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.52-7.54 (m, 1H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.02 (s, 3H), 3.22-3.32 (m, 2H), 3.97 (d, J = 10.4 Hz, 1H), 4.09-4.16 (m, 1H), 4.21 (dq, J d = 0.8, J q = 7.2 Hz, 2H), 6.47-6.50 (m, 1H), 6.90-6.96 (m, 2H), 7.15 (dd, J = 3.6, 0.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.52-7.54 (m, 1H) ppm; 13C-NMR (major) δ 13.7, 29.5, 39.6, 42.4, 61.5, 65.2, 112.3, 115.3 (d, J = 21.2 Hz), 117.4, 129.8 (d, J = 5.3 Hz), 136.1, 146.5, 152.5, 162.8 (d, J = 245.7 Hz), 167.8, 186.7, 202.0 ppm; (minor) δ 14.0, 30.0, 39.9, 42.5, 61.8, 64.7, 112.3, 115.5 (d, J = 21.2 Hz), 117.3, 129.7 (d, J = 5.3 Hz), 135.8, 146.4, 152.5, 162.8 (d, J = 245.7 Hz), 168.2, 186.5, 202.7 ppm; IR 1737, 1715, 1670, 1565, 1513, 1469, 1394, 1364, 1275, 1223, 1155, 1088, 1014, 835, 768, 552 cm-1; HRMS (ESI) calcd for C19H19FO5Na [M+Na]+ 369.1109, found 369.1112.Data of the compound represented by Formula 1-7: R f = 0.08 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 1.00 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.16 (d, J = 7.2 Hz, 2H), 3.93 (q, J = 7.2 Hz, 2H) , 4.01 (d, J = 10.8 Hz, 1H), 4.09-4.16 (m, 1H), 6.47-6.50 (m, 1H), 6.90-6.96 (m, 2H), 7.12 (dd, J = 3.6, 0.8 Hz , 1H), 7.19-7.25 (m, 2H), 7.52-7.54 (m, 1H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.02 (s, 3H), 3.22-3.32 (m, 2H), 3.97 (d, J = 10.4 Hz, 1H), 4.09-4.16 (m, 1H), 4.21 (dq, J d = 0.8, J q = 7.2 Hz, 2H), 6.47-6.50 (m, 1H), 6.90-6.96 (m, 2H), 7.15 (dd, J = 3.6, 0.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.52-7.54 (m, 1H) ppm; 13 C-NMR (major) δ 13.7, 29.5, 39.6, 42.4, 61.5, 65.2, 112.3, 115.3 (d, J = 21.2 Hz), 117.4, 129.8 (d, J = 5.3 Hz), 136.1, 146.5, 152.5, 162.8 (d, J = 245.7 Hz), 167.8, 186.7, 202.0 ppm; (minor) δ 14.0, 30.0, 39.9, 42.5, 61.8, 64.7, 112.3, 115.5 (d, J = 21.2 Hz), 117.3, 129.7 (d, J = 5.3 Hz), 135.8, 146.4, 152.5, 162.8 (d, J = 245.7 Hz), 168.2, 186.5, 202.7 ppm; IR 1737, 1715, 1670, 1565, 1513, 1469, 1394, 1364, 1275, 1223, 1155, 1088, 1014, 835, 768, 552 cm -1 ; HRMS (ESI) calcd for C 19 H 19 FO 5 Na [M + Na] + 369.1109, found 369.1112.
실시예 32: 하기 화학식 2-7로 표시되는 화합물(Ethyl 3-(4-fluorophenyl)-5-(furan-2-yl)-2,5-dioxopentanoate)의 제조Example 32: Preparation of the compound represented by Chemical Formula 2-7 (Ethyl 3- (4-fluorophenyl) -5- (furan-2-yl) -2,5-dioxopentanoate)
[화학식 2-7][Formula 2-7]
화학식 1-7로 표시되는 화합물(0.98 g, 2.83 mmol)을 아세트산(20 mL)에 녹이고 Mn(OAc)3·2H2O(80 mg, 0.28 mmol) 및 CoCl2(40 mg, 0.28 mmol)를 첨가하였다. 이 혼합물을 공기(air) 하, 실온에서 24시간 동안 교반하고, 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 오일 타입의 화학식 2-7로 표시되는 화합물(0.39 g, 1.23 mmol)을 얻었다(수율 44%).The compound of Formula 1-7 (0.98 g, 2.83 mmol) was dissolved in acetic acid (20 mL), and Mn (OAc) 3 · 2H 2 O (80 mg, 0.28 mmol) and CoCl 2 (40 mg, 0.28 mmol) were added thereto. Added. The mixture was stirred for 24 hours at room temperature under air and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound represented by the formula (2-7) of the yellow oil type (0.39 g, 1.23 mmol) (yield 44%).
화학식 2-7로 표시되는 화합물의 데이터: Rf = 0.33(hexane:EtOAc = 4:1); 1H-NMR δ 1.30(t,J = 7.2 Hz, 3H), 3.29 (dd, J = 18.0, 4.4 Hz, 1H), 3.84 (dd, J = 18.0, 10.0 Hz, 1H), 4.20-4.34 (m, 2H), 5.10 (dd, J = 10.0, 4.4 Hz, 1H), 6.54 (dd, J = 3.6, 1.6 Hz, 1H), 7.00-7.06 (m, 2H), 7.21 (dd, J = 3.6, 0.8 Hz, 1H), 7.27-7.34 (m, 2H), 7.58 (dd, J = 1.6, 0.8 Hz, 1H) ppm; 13C-NMR δ 13.9, 42.2, 47.2, 62.6, 112.4, 116.1 (d, J = 21.2 Hz), 117.5, 130.5 (d, J = 7.6 Hz), 130.8 (d, J = 3.1 Hz), 146.6, 151.9, 160.7 (d, J = 95.6 Hz), 163.6, 186.2, 191.8 ppm; IR 1729, 1662, 1603, 1506, 1469, 1260, 1222, 1163, 1133, 1081, 1036, 842, 760 cm-1; HRMS (ESI) calcd for C17H15FO5Na [M+Na]+ 341.0796, found 341.0799.Data for the compound represented by Formula 2-7: R f = 0.33 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.30 (t, J = 7.2 Hz, 3H), 3.29 (dd, J = 18.0, 4.4 Hz, 1H), 3.84 (dd, J = 18.0, 10.0 Hz, 1H), 4.20-4.34 (m , 2H), 5.10 (dd, J = 10.0, 4.4 Hz, 1H), 6.54 (dd, J = 3.6, 1.6 Hz, 1H), 7.00-7.06 (m, 2H), 7.21 (dd, J = 3.6, 0.8 Hz, 1H), 7.27-7.34 (m, 2H), 7.58 (dd, J = 1.6, 0.8 Hz, 1H) ppm; 13 C-NMR δ 13.9, 42.2, 47.2, 62.6, 112.4, 116.1 (d, J = 21.2 Hz), 117.5, 130.5 (d, J = 7.6 Hz), 130.8 (d, J = 3.1 Hz), 146.6, 151.9 , 160.7 (d, J = 95.6 Hz), 163.6, 186.2, 191.8 ppm; IR 1729, 1662, 1603, 1506, 1469, 1260, 1222, 1163, 1133, 1081, 1036, 842, 760 cm −1 ; HRMS (ESI) calcd for C 17 H 15 FO 5 Na [M + Na] + 341.0796, found 341.0799.
실시예 33: 하기 화학식 3-19로 표시되는 화합물(Ethyl 4-(4-fluorophenyl)-[2,2'-bifuran]-5-carboxylate)의 제조Example 33 Preparation of Compound (Ethyl 4- (4-fluorophenyl)-[2,2'-bifuran] -5-carboxylate) represented by Chemical Formula 3-19
[화학식 3-19][Formula 3-19]
화학식 2-7로 표시되는 화합물(57 mg, 0.18 mmol)을 아세트산 무수물(4.0 mL)에 녹인 용액에 진한 염산(0.5 mL)을 첨가하였다. 이 혼합물을 50 ℃에서 1 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 아이스 워터에 붓고 포화 Na2CO3 수용액으로 중화 후, EtOAc로 추출하고, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-19로 표시되는 노란색 오일 타입의 화합물(25 mg, 0.083 mmol)을 얻었다(수율 47%).Concentrated hydrochloric acid (0.5 mL) was added to a solution of the compound represented by Formula 2-7 (57 mg, 0.18 mmol) in acetic anhydride (4.0 mL). The mixture was heated at 50 ° C. for 1 hour and cooled to room temperature. The mixture was poured into ice water, neutralized with saturated Na 2 CO 3 aqueous solution, extracted with EtOAc, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a yellow oil type compound represented by the formula (3-19) (25 mg, 0.083 mmol) (yield 47%).
화학식 3-19로 표시되는 화합물의 데이터: Rf = 0.38 (hexane:EtOAc = 4:1); 1H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.53 (dd, J = 3.2, 2.0 Hz, 1H), 6.72 (s, 1H), 6.87 (dd, J = 3.2, 0.8 Hz, 1H), 7.07-7.14 (m, 2H), 7.50 (dd, J = 2.0, 0.8 Hz, 1H), 7.57-7.62 (m, 2H) ppm; 13C-NMR δ 14.2, 60.9, 108.5, 109.0, 111.8, 114.9, 115.1, 127.8, 131.2 (d, J = 8.4 Hz), 135.3, 143.3, 145.1, 148.2, 159.0, 162.6 (d, J = 245.7 Hz) ppm; IR 2930, 2863, 1715, 1603, 1506, 1454, 1379, 1282, 1178, 1111, 1014, 887, 842, 745 cm-1; HRMS (ESI) calcd for C17H13FO4Na [M+Na]+ 323.0690, found 323.0693.Data of compounds represented by formula 3-19: R f = 0.38 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.53 (dd, J = 3.2, 2.0 Hz, 1H), 6.72 (s, 1H), 6.87 (dd, J = 3.2, 0.8 Hz, 1H), 7.07-7.14 (m, 2H), 7.50 (dd, J = 2.0, 0.8 Hz, 1H), 7.57-7.62 (m, 2H) ppm; 13 C-NMR δ 14.2, 60.9, 108.5, 109.0, 111.8, 114.9, 115.1, 127.8, 131.2 (d, J = 8.4 Hz), 135.3, 143.3, 145.1, 148.2, 159.0, 162.6 (d, J = 245.7 Hz) ppm; IR 2930, 2863, 1715, 1603, 1506, 1454, 1379, 1282, 1178, 1111, 1014, 887, 842, 745 cm −1 ; HRMS (ESI) calcd for C 17 H 13 FO 4 Na [M + Na] + 323.0690, found 323.0693.
실시예 34: 하기 화학식 3-20으로 표시되는 화합물(Ethyl 3-(4-fluorophenyl)-5-(furan-2-yl)-1Example 34: Compound represented by Chemical Formula 3-20 (Ethyl 3- (4-fluorophenyl) -5- (furan-2-yl) -1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-20][Formula 3-20]
화학식 2-7로 표시되는 화합물(57 mg, 0.17 mmol)을 아세트산(1.0 mL)에 녹이고 NH4OAc(28 mg, 0.34 mmol)와 sulfamic acid(1.7 mg, 0.02 mmol)를 첨가하였다. 이 혼합물을 실온에서 1시간 동안 교반하고, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체 타입의 화학식 3-20으로 표시되는 화합물(40 mg, 0.13 mmol)을 얻었다(수율 77%).The compound represented by Chemical Formula 2-7 (57 mg, 0.17 mmol) was dissolved in acetic acid (1.0 mL), and NH 4 OAc (28 mg, 0.34 mmol) and sulfamic acid (1.7 mg, 0.02 mmol) were added thereto. The mixture was stirred at rt for 1 h and the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain a compound (40 mg, 0.13 mmol) represented by the formula 3-20 as a white solid type (yield 77%).
화학식 3-20으로 표시되는 화합물의 데이터: Rf = 0.35 (hexane:EtOAc = 4:1); 1H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.49 (dd, J = 3.6, 1.6 Hz, 1H), 6.67 (dd, J = 3.6, 0.8 Hz, 1H), 7.06-7.13 (m, 2H), 7.19 (s, 1H), 7.43-7.49 (m, 3H) ppm; 13C-NMR δ 14.1, 61.0, 107.5, 112.1, 114.8 (d, J = 21.2 Hz), 125.0, 126.1, 131.0 (d, J = 8.3 Hz), 131.5 (d, J = 3.0 Hz), 137.5, 142.9, 148.0, 148.3, 161.6 (d, J = 53.8 Hz), 163.8 ppm; IR 3303, 1670, 1521, 1498, 1439, 1275, 1223, 1163, 1126, 1021, 842, 813, 760 cm-1; HRMS (ESI) calcd for C17H14FO3Na [M+Na]+ 322.0850, found 322.0853.Data for the compound represented by Formula 3-20: R f = 0.35 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.49 (dd, J = 3.6, 1.6 Hz, 1H), 6.67 (dd, J = 3.6 , 0.8 Hz, 1H), 7.06-7.13 (m, 2H), 7.19 (s, 1H), 7.43-7.49 (m, 3H) ppm; 13 C-NMR δ 14.1, 61.0, 107.5, 112.1, 114.8 (d, J = 21.2 Hz), 125.0, 126.1, 131.0 (d, J = 8.3 Hz), 131.5 (d, J = 3.0 Hz), 137.5, 142.9 , 148.0, 148.3, 161.6 (d, J = 53.8 Hz), 163.8 ppm; IR 3303, 1670, 1521, 1498, 1439, 1275, 1223, 1163, 1126, 1021, 842, 813, 760 cm −1 ; HRMS (ESI) calcd for C 17 H 14 FO 3 Na [M + Na] + 322.0850, found 322.0853.
실시예 35: 하기 화학식 3-21로 표시되는 화합물(Ethyl 3-(4-fluorophenyl)-5-(furan-2-yl)thiophene-2-carboxylate)의 제조Example 35 Preparation of Compound (Ethyl 3- (4-fluorophenyl) -5- (furan-2-yl) thiophene-2-carboxylate) represented by Chemical Formula 3-21
[화학식 3-21][Formula 3-21]
화학식 2-7로 표시되는 화합물(92 mg, 0.29 mmol)을 톨루엔(5.0 mL)에 녹인 다음 Lawesson’s Reagent(198 mg, 0.49 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 9.5 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 타입의 화학식 3-21로 표시되는 화합물(51 mg, 0.16 mmol)을 얻었다(수율 55%).The compound represented by Formula 2-7 (92 mg, 0.29 mmol) was dissolved in toluene (5.0 mL), and Lawesson's Reagent (198 mg, 0.49 mmol) was added thereto. This mixture was heated at 60 ° C. for 9.5 hours and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain the compound (51 mg, 0.16 mmol) represented by the formula (3-21) as a brown solid type (yield 55%).
화학식 3-21로 표시되는 화합물의 데이터: Rf = 0.62 (hexane:EtOAc = 4:1); 1H-NMR δ 1.26(t,J = 6.8 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.48 (dd, J = 3.2, 2 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 7.059-7.117 (m, 2H), 7.178 (s, 1H), 7.43-7.47 (m, 3H) ppm; 13C-NMR δ 14.1, 61.0, 107.5, 112.1, 114.7 (d, J = 21.2 Hz), 125.0, 126.1, 130.9 (d, J = 7.6 Hz), 131.5, 137.5, 142.9, 147.9, 148.3, 161.9, 162.6 (d, J = 245.7 Hz) ppm; IR 1715, 1506, 1431, 1379, 1252, 1223, 1155, 1118, 1073, 1014, 835, 805, 738 cm-1; HRMS (ESI) calcd for C17H13FO3SNa [M+Na]+ 339.0462, found 339.0466.Data of compounds represented by formula 3-21: R f = 0.62 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.26 (t, J = 6.8 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.48 (dd, J = 3.2, 2 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 7.059-7.117 (m, 2H), 7.178 (s, 1H), 7.43-7.47 (m, 3H) ppm; 13 C-NMR δ 14.1, 61.0, 107.5, 112.1, 114.7 (d, J = 21.2 Hz), 125.0, 126.1, 130.9 (d, J = 7.6 Hz), 131.5, 137.5, 142.9, 147.9, 148.3, 161.9, 162.6 (d, J = 245.7 Hz) ppm; IR 1715, 1506, 1431, 1379, 1252, 1223, 1155, 1118, 1073, 1014, 835, 805, 738 cm −1 ; HRMS (ESI) calcd for C 17 H 13 FO 3 SNa [M + Na] + 339.0462, found 339.0466.
실시예 36: 하기 화학식 1-8로 표시되는 화합물(Ethyl 2-acetyl-3-(4-cyanophenyl)-5-oxo-5-(thiophen-2-yl)pentanoate)의 제조Example 36 Preparation of Compound (Ethyl 2-acetyl-3- (4-cyanophenyl) -5-oxo-5- (thiophen-2-yl) pentanoate) represented by Formula 1-8
[화학식 1-8][Formula 1-8]
아르곤 분위기 하에서, 에틸 아세토아세테이트(4.00 g, 30.73 mmol)와 (E)-4-(3-옥소-3-(티오펜-2-일)-1-프로펜-1-일)벤조니트릴(2.00 g, 8.37 mmol)을 아세토니트릴(40 mL)에 녹인 용액에 CeCl3.7H2O(0.31 g, 0.84 mmol) 및 NaI(0.13 g, 0.84 mmol)를 첨가하였다. 상기 혼합물을 50 ℃에서 하루 동안 교반한 뒤, 실온으로 식히고, CH2Cl2로 묽힌 다음, 고체를 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체의 화학식 1-8로 표시되는 화합물(2.89 g, 7.83 mmol, 1.3:1 입체이성질체 혼합물)을 얻었다(수율 94%).Under argon atmosphere, ethyl acetoacetate (4.00 g, 30.73 mmol) and ( E ) -4- (3-oxo-3- (thiophen-2-yl) -1-propen-1-yl) benzonitrile (2.00 g, 8.37 mmol) was added CeCl 3 .7H 2 O (0.31 g, 0.84 mmol) and NaI (0.13 g, 0.84 mmol) in a solution of acetonitrile (40 mL). The mixture was stirred at 50 ° C. for 1 day, then cooled to room temperature, diluted with CH 2 Cl 2 , the solids were filtered off with filter paper, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a compound (2.89 g, 7.83 mmol, 1.3: 1 stereoisomer mixture) of white solid (yield 94%).
화학식 1-8로 표시되는 화합물의 데이터: Rf = 0.10 (hexane:EtOAc = 4:1);1H-NMR δ (major) = 1.01 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.20-3.46 (m, 3H), 3.94 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 10.4 Hz, 1H), 7.09 (dd, J = 5.2, 4.0 Hz, 1H), 7.38-7.42 (m, 2H), 7.52-7.57 (m, 2H), 7.62 (dd, J = 5.2, 1.2 Hz, 1H), 7.67 (dd, J = 4.0, 1.2 Hz, 1H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.08 (s, 3H), 3.32-3.39 (m, 2H), 4.04 (d, J = 9.6 Hz, 1H), 4.17-4.26 (m, 3H), 7.10 (dd, J = 5.2, 4.0 Hz, 1H), 7.38-7.42 (m, 2H), 7.52-7.57 (m, 2H), 7.62 (dd, J = 5.2, 1.2 Hz, 1H), 7.71 (dd, J = 4.0, 1.2 Hz, 1H) ppm; 13C-NMR (major) δ 13.7, 29.7, 40.4, 42.6, 61.7, 64.1, 111.0, 118.6, 128.2, 129.1, 132.2, 132.4, 134.3, 143.6, 146.1, 167.4, 189.8, 201.3 ppm; (minor) δ 14.0, 30.1, 40.5, 42.5, 62.0, 63.9, 111.1, 118.5, 128.2, 129.2, 132.2, 132.3, 134.2, 143.6, 146.0, 167.8, 190.0, 200.9 ppm; IR 3096, 2980, 2929, 2229, 1737, 1715, 1659, 1606, 1517, 1506, 1416, 1357, 1249, 1219, 1189, 1152, 1114, 1018, 936, 857, 835, 731, 567 cm-1; HRMS (ESI) calcd for C20H19NO4SNa [M+Na]+ 392.0927, found 392.0930.Data for the compound represented by Formula 1-8: R f = 0.10 (hexane: EtOAc = 4: 1); 1 H-NMR δ (major) = 1.01 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.20-3.46 (m, 3H), 3.94 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 10.4 Hz, 1H), 7.09 (dd, J = 5.2, 4.0 Hz, 1H), 7.38-7.42 (m, 2H), 7.52-7.57 (m, 2H), 7.62 (dd, J = 5.2 , 1.2 Hz, 1H), 7.67 (dd, J = 4.0, 1.2 Hz, 1H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.08 (s, 3H), 3.32-3.39 (m, 2H), 4.04 (d, J = 9.6 Hz, 1H), 4.17-4.26 (m, 3H), 7.10 (dd, J = 5.2, 4.0 Hz, 1H), 7.38-7.42 (m, 2H), 7.52-7.57 (m, 2H), 7.62 (dd, J = 5.2, 1.2 Hz, 1H), 7.71 (dd, J = 4.0, 1.2 Hz, 1H) ppm; 13 C-NMR (major) δ 13.7, 29.7, 40.4, 42.6, 61.7, 64.1, 111.0, 118.6, 128.2, 129.1, 132.2, 132.4, 134.3, 143.6, 146.1, 167.4, 189.8, 201.3 ppm; (minor) δ 14.0, 30.1, 40.5, 42.5, 62.0, 63.9, 111.1, 118.5, 128.2, 129.2, 132.2, 132.3, 134.2, 143.6, 146.0, 167.8, 190.0, 200.9 ppm; IR 3096, 2980, 2929, 2229, 1737, 1715, 1659, 1606, 1517, 1506, 1416, 1357, 1249, 1219, 1189, 1152, 1114, 1018, 936, 857, 835, 731, 567 cm- 1 ; HRMS (ESI) calcd for C 20 H 19 NO 4 SNa [M + Na] + 392.0927, found 392.0930.
실시예 37: 하기 화학식 2-8로 표시되는 화합물(Ethyl 3-(4-cyanophenyl)-2,5-dioxo-5-(thiophen-2-yl)pentanoate)의 제조Example 37: Preparation of the compound represented by Chemical Formula 2-8 (Ethyl 3- (4-cyanophenyl) -2,5-dioxo-5- (thiophen-2-yl) pentanoate)
[화학식 2-8][Formula 2-8]
화학식 1-8로 표시되는 화합물(2.80 g, 7.59 mmol)을 아세트산(35 mL)에 녹이고 Mn(OAc)3·2H2O(200 mg, 0.76 mmol) 및 CoCl2(98 mg, 0.76 mmol)를 첨가하였다. 이 혼합물을 공기 하, 실온에서 하루 동안 교반하고, 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 오일 타입의 화학식 2-8로 표시되는 화합물(1.97 g, 5.78 mmol)을 얻었다(수율 76%).The compound represented by the formula (1-8) (2.80 g, 7.59 mmol) was dissolved in acetic acid (35 mL), and Mn (OAc) 3 · 2H 2 O (200 mg, 0.76 mmol) and CoCl 2 (98 mg, 0.76 mmol) were added thereto. Added. The mixture was stirred for one day at room temperature under air and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound (1.97 g, 5.78 mmol) represented by the formula (2-8) as a yellow oil type (yield 76%).
화학식 2-8로 표시되는 화합물의 데이터: Rf = 0.24 (hexane:EtOAc = 4:1); 1H-NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.42 (dd, J = 17.6, 4.4 Hz, 1H), 3.96 (dd, J = 17.6, 10.0 Hz, 1H), 4.23-4.37 (m, 2H), 5.20 (dd, J = 10.0, 4.4 Hz, 1H), 7.14 (dd, J = 5.0, 4.0 Hz, 1H), 7.47-7.52 (m, 2H), 7.60-7.80 (m, 2H), 7.68 (dd, J = 5.0, 1.2 Hz, 1H), 7.75 (dd, J = 4.0, 1.2 Hz, 1H) ppm; 13C-NMR δ 13.9, 43.3, 48.2, 62.9, 112.0, 118.3, 128.3, 129.6, 132.6, 132.8, 134.5, 140.8, 142.3, 159.9, 189.4, 191.1 ppm; IR 3096, 2984, 2913, 2229, 1726, 1651, 1606, 1517, 1506, 1413, 1360, 1275, 1249, 1208, 1174, 1092, 1059, 1032, 936, 857, 842, 727, 563 cm-1; HRMS (ESI) calcd for C18H15NO4SNa [M+Na]+ 364.0614, found 364.0618.Data for the compound represented by Formula 2-8: R f = 0.24 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.33 (t, J = 7.2 Hz, 3H), 3.42 (dd, J = 17.6, 4.4 Hz, 1H), 3.96 (dd, J = 17.6, 10.0 Hz, 1H), 4.23-4.37 (m , 2H), 5.20 (dd, J = 10.0, 4.4 Hz, 1H), 7.14 (dd, J = 5.0, 4.0 Hz, 1H), 7.47-7.52 (m, 2H), 7.60-7.80 (m, 2H), 7.68 (dd, J = 5.0, 1.2 Hz, 1H), 7.75 (dd, J = 4.0, 1.2 Hz, 1H) ppm; 13 C-NMR δ 13.9, 43.3, 48.2, 62.9, 112.0, 118.3, 128.3, 129.6, 132.6, 132.8, 134.5, 140.8, 142.3, 159.9, 189.4, 191.1 ppm; IR 3096, 2984, 2913, 2229, 1726, 1651, 1606, 1517, 1506, 1413, 1360, 1275, 1249, 1208, 1174, 1092, 1059, 1032, 936, 857, 842, 727, 563 cm −1 ; HRMS (ESI) calcd for C 18 H 15 NO 4 SNa [M + Na] + 364.0614, found 364.0618.
실시예 38: 하기 화학식 3-22로 표시되는 화합물(Ethyl 3-(4-cyanophenyl)-5-(thiophen-2-yl)furan-2-carboxylate)의 제조Example 38 Preparation of Compound (Ethyl 3- (4-cyanophenyl) -5- (thiophen-2-yl) furan-2-carboxylate) represented by Chemical Formula 3-22
[화학식 3-22][Formula 3-22]
화학식 2-8로 표시되는 화합물(0.62 g, 1.82 mmol)을 톨루엔(15 mL)에 녹인 용액에 피리디늄 파라-톨루엔설포내이트(0.09 g, 0.36 mmol)을 첨가하였다. 이 혼합물을 90 ℃에서 9 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물에 물을 더한 뒤, EtOAc로 추출하고, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-22로 표시되는 흰색 고체의 화합물(0.12 g, 0.38 mmol)을 얻었다(수율 21%).Pyridinium para-toluenesulfonate (0.09 g, 0.36 mmol) was added to a solution of the compound represented by Formula 2-8 (0.62 g, 1.82 mmol) in toluene (15 mL). The mixture was heated at 90 ° C. for 9 hours and cooled to room temperature. Water was added to the mixture, followed by extraction with EtOAc, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a compound (0.12 g, 0.38 mmol) as a white solid represented by the formula (3-22) (yield 21%).
화학식 3-22로 표시되는 화합물의 데이터: Rf = 0.30 (hexane:EtOAc = 4:1); m.p.: 156-158 ℃; 1H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.69 (s, 1H), 7.12 (dd, J = 5.2, 4.0 Hz, 1H), 7.39 (dd, J = 5.2, 1.2 Hz, 1H), 7.51 (dd, J = 4.0, 1.2 Hz, 1H), 7.68-7.76 (m, 4H) ppm; 13C-NMR δ 14.2, 61.1, 108.5, 111.9, 118.7, 125.7, 126.9, 128.1, 130.1, 131.5, 131.7, 134.5, 136.7, 138.0, 151.8, 158.7 ppm; IR 3108, 2980, 2933, 2229, 1756, 1711, 1662, 1603, 1558, 1487, 1416, 1286, 1178, 1103, 1018, 980, 850, 809, 708 cm-1; HRMS (ESI) calcd for C18H13NO3SNa [M+Na]+ 346.0508, found 346.0513.Data of compounds represented by formula 3-22: R f = 0.30 (hexane: EtOAc = 4: 1); mp: 156-158 ° C .; 1 H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.69 (s, 1H), 7.12 (dd, J = 5.2, 4.0 Hz, 1H), 7.39 (dd, J = 5.2, 1.2 Hz, 1H), 7.51 (dd, J = 4.0, 1.2 Hz, 1H), 7.68-7.76 (m, 4H) ppm; 13 C-NMR δ 14.2, 61.1, 108.5, 111.9, 118.7, 125.7, 126.9, 128.1, 130.1, 131.5, 131.7, 134.5, 136.7, 138.0, 151.8, 158.7 ppm; IR 3108, 2980, 2933, 2229, 1756, 1711, 1662, 1603, 1558, 1487, 1416, 1286, 1178, 1103, 1018, 980, 850, 809, 708 cm −1 ; HRMS (ESI) calcd for C 18 H 13 NO 3 SNa [M + Na] + 346.0508, found 346.0513.
실시예 39: 하기 화학식 3-23로 표시되는 화합물(Ethyl 3-(4-cyanophenyl)-5-(thiophen-2-yl)-1Example 39: Compound represented by the following Chemical Formula 3-23 (Ethyl 3- (4-cyanophenyl) -5- (thiophen-2-yl) -1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-23][Formula 3-23]
화학식 2-8로 표시되는 화합물(0.35 g, 1.03 mmol)을 아세트산(10 mL)에 녹이고 NH4OAc(0.16 g, 2.05 mmol)와 sulfamic acid(10 mg, 0.10 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 4시간 동안 교반하고, 실온으로 식힌 뒤, 용매를 감압 하에서 제거하였다. 이를 CH2Cl2로 묽히고 물로 씻은 다음, 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 타입의 화학식 3-23으로 표시되는 화합물(0.18 g, 0.56 mmol)을 얻었다(수율 54%).The compound represented by Formula 2-8 (0.35 g, 1.03 mmol) was dissolved in acetic acid (10 mL), and NH 4 OAc (0.16 g, 2.05 mmol) and sulfamic acid (10 mg, 0.10 mmol) were added thereto. The mixture was stirred at 60 ° C. for 4 hours, cooled to room temperature and the solvent was removed under reduced pressure. It was diluted with CH 2 Cl 2 , washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain the compound represented by the formula (3-23) of brown solid type (0.18 g, 0.56 mmol) (yield 54%).
화학식 3-23으로 표시되는 화합물의 데이터: Rf = 0.42 (hexane:EtOAc = 4:1); m.p.: 169-171 ℃; 1H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.29 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 3.2 Hz, 1H), 7.09 (dd, J = 5.2, 4.0 Hz, 1H), 7.28 (dd, J = 4.0, 1.2 Hz, 1H), 7.31 (dd, J = 5.2, 1.2 Hz, 1H), 7.64-7.71 (m, 4H), 9.42 (br s, 1H) ppm; 13C-NMR δ 14.2, 60.8, 110.1, 110.6, 118.5, 119.1, 123.6, 125.2, 128.0, 130.2, 130.4, 131.2, 131.5, 133.5, 139.6, 160.5 ppm; IR 3295, 3099, 2977, 2225, 1662, 1606, 1502, 1476, 1446, 1409, 1364. 1323, 1268, 1200, 1107, 1025, 909, 846, 809, 731, 697, 548 cm-1; HRMS (ESI) calcd for C18H14N2O2SNa [M+Na]+ 345.0668, found 345.0671.Data of compounds represented by formula 3-23: R f = 0.42 (hexane: EtOAc = 4: 1); mp: 169-171 ° C .; 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.29 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 3.2 Hz, 1H), 7.09 (dd, J = 5.2, 4.0 Hz, 1H), 7.28 (dd, J = 4.0, 1.2 Hz, 1H), 7.31 (dd, J = 5.2, 1.2 Hz, 1H), 7.64-7.71 (m, 4H), 9.42 (br s, 1H) ppm ; 13 C-NMR δ 14.2, 60.8, 110.1, 110.6, 118.5, 119.1, 123.6, 125.2, 128.0, 130.2, 130.4, 131.2, 131.5, 133.5, 139.6, 160.5 ppm; IR 3295, 3099, 2977, 2225, 1662, 1606, 1502, 1476, 1446, 1409, 1364. 1323, 1268, 1200, 1107, 1025, 909, 846, 809, 731, 697, 548 cm −1 ; HRMS (ESI) calcd for C 18 H 14 N 2 O 2 SNa [M + Na] + 345.0668, found 345.0671.
실시예 40: 하기 화학식 3-24로 표시되는 화합물(Ethyl 4-(4-cyanophenyl)-[2,2'-bithiophene]-5-carboxylate)의 제조Example 40 Preparation of Compound (Ethyl 4- (4-cyanophenyl)-[2,2'-bithiophene] -5-carboxylate) represented by Chemical Formula 3-24
[화학식 3-24][Formula 3-24]
화학식 2-8로 표시되는 화합물(0.42 g, 1.23 mmol)을 벤젠(10 mL)에 녹인 다음 Lawesson’s Reagent(750 mg, 1.85 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 6 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체 의 화학식 3-24로 표시되는 화합물(200 mg, 0.60 mmol)을 얻었다(수율 49%).The compound represented by Formula 2-8 (0.42 g, 1.23 mmol) was dissolved in benzene (10 mL), and Lawesson's Reagent (750 mg, 1.85 mmol) was added thereto. The mixture was heated at 60 ° C. for 6 hours and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain a compound (200 mg, 0.60 mmol) represented by the formula 3-24 as a white solid (yield 49%).
화학식 3-24로 표시되는 화합물의 데이터: Rf = 0.48 (hexane:EtOAc = 4:1); m.p.: 136-137 ℃; 1H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 7.08 (dd, J = 5.2, 4.0 Hz, 1H), 7.11 (s, 1H), 7.31-7.36 (m, 2H), 7.57-7.62 (m, 2H), 7.68-7.73 (m, 2H) ppm; 13C-NMR δ 14.1, 61.3, 111.7, 118.8, 125.6, 126.1, 126.6, 126.7, 128.3, 130.0, 131.6, 135.6, 140.2, 142.3, 146.8, 161.4 ppm; IR 3103, 3068, 2977, 2929, 2229, 1711, 1604, 1498, 1446, 1416, 1375, 1278, 1255, 1230, 1118, 1077, 1015, 846, 827, 761, 701 cm-1; HRMS (ESI) calcd for C18H13NO2S2Na [M+Na]+ 362.0280, found 362.0281.Data of compounds represented by formula 3-24: R f = 0.48 (hexane: EtOAc = 4: 1); mp: 136-137 ° C .; 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 7.08 (dd, J = 5.2, 4.0 Hz, 1H), 7.11 (s, 1H), 7.31-7.36 (m, 2H), 7.57-7.62 (m, 2H), 7.68-7.73 (m, 2H) ppm; 13 C-NMR δ 14.1, 61.3, 111.7, 118.8, 125.6, 126.1, 126.6, 126.7, 128.3, 130.0, 131.6, 135.6, 140.2, 142.3, 146.8, 161.4 ppm; IR 3103, 3068, 2977, 2929, 2229, 1711, 1604, 1498, 1446, 1416, 1375, 1278, 1255, 1230, 1118, 1077, 1015, 846, 827, 761, 701 cm -1 ; HRMS (ESI) calcd for C 18 H 13 NO 2 S 2 Na [M + Na] + 362.0280, found 362.0281.
실시예 41: 하기 화학식 1-9로 표시되는 화합물(Ethyl 2-acetyl-3-(4-cyanophenyl)-5-(furan-2-yl)-5-oxopentanoate)의 제조Example 41: Preparation of the compound represented by Chemical Formula 1-9 (Ethyl 2-acetyl-3- (4-cyanophenyl) -5- (furan-2-yl) -5-oxopentanoate)
[화학식 1-9][Formula 1-9]
아르곤 분위기 하에서, 에틸 아세토아세테이트(2.45 g, 18.83 mmol)와 (E)-4-(3-(퓨란-2-일)-3-옥소-1-프로펜-1-일)벤조니트릴(1.40 g, 6.28 mmol)을 아세토니트릴(30 mL)에 녹인 용액에 CeCl3.7H2O(0.23 g, 0.63 mmol)와 NaI(90 mg, 0.63 mmol)를 첨가하였다. 상기 혼합물을 50 ℃에서 24시간 동안 교반한 뒤, 실온으로 식힌다. CH2Cl2로 묽힌 다음 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 고체의 화학식 1-9로 표시되는 화합물(1.56 g, 4.42 mmol, 1.3:1 입체이성질체 혼합물)을 얻었다(수율 70%).Under argon atmosphere, ethyl acetoacetate (2.45 g, 18.83 mmol) and ( E ) -4- (3- (furan-2-yl) -3-oxo-1-propen-1-yl) benzonitrile (1.40 g , 6.28 mmol) in acetonitrile (30 mL) was added CeCl 3 .7H 2 O (0.23 g, 0.63 mmol) and NaI (90 mg, 0.63 mmol). The mixture is stirred at 50 ° C. for 24 hours and then cooled to room temperature. Diluted with CH 2 Cl 2 and then filtered through a filter paper, the filtrate was concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound (1.56 g, 4.42 mmol, 1.3: 1 stereoisomer mixture) of yellow solid (yield 70%).
화학식 1-9로 표시되는 화합물의 데이터: Rf = 0.16 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 1.01 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.22 (d, J = 6.8 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H), 4.07 (d, J = 10.0 Hz, 1H), 4.16-4.26 (m, 1H), 6.50 (dd, J = 3.6, 2.0 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.37-7.43 (m, 2H), 7.52-7.58 (m, 3H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.07 (s, 3H), 3.25-3.38 (m, 2H), 4.03 (d, J = 10.0 Hz, 1H), 4.16-4.26 (m, 3H), 6.48-6.52 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.37-7.43 (m, 2H), 7.52-7.58 (m, 3H) ppm; 13C-NMR (major) δ 13.7, 29.6, 40.0, 41.8, 61.7, 64.2, 111.0, 112.4, 117.5, 118.6, 129.2, 132.1, 146.2, 146.6, 152.2, 167.4, 186.1, 201.3 ppm; (minor) δ 14.0, 30.0, 40.0, 41.6, 62.0, 64.0, 111.0, 112.4, 117.4, 118.5, 129.1, 132.3, 146.1, 146.5, 152.2, 167.8, 185.9, 200.9 ppm; IR 2223, 1715, 1670, 1469, 1364, 1267, 1230, 1148, 1014, 835, 750, 663, 596, 567 cm-1; HRMS (ESI) calcd for C20H19NO5Na [M+Na]+ 376.1155, found 376.1159.Data for compounds represented by formula 1-9: R f = 0.16 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 1.01 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 3.22 (d, J = 6.8 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H) , 4.07 (d, J = 10.0 Hz, 1H), 4.16-4.26 (m, 1H), 6.50 (dd, J = 3.6, 2.0 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.37- 7.43 (m, 2 H), 7.52-7.58 (m, 3H) ppm; (minor) δ 1.27 (t, J = 7.2 Hz, 3H), 2.07 (s, 3H), 3.25-3.38 (m, 2H), 4.03 (d, J = 10.0 Hz, 1H), 4.16-4.26 (m, 3H), 6.48-6.52 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.37-7.43 (m, 2H), 7.52-7.58 (m, 3H) ppm; 13 C-NMR (major) δ 13.7, 29.6, 40.0, 41.8, 61.7, 64.2, 111.0, 112.4, 117.5, 118.6, 129.2, 132.1, 146.2, 146.6, 152.2, 167.4, 186.1, 201.3 ppm; (minor) δ 14.0, 30.0, 40.0, 41.6, 62.0, 64.0, 111.0, 112.4, 117.4, 118.5, 129.1, 132.3, 146.1, 146.5, 152.2, 167.8, 185.9, 200.9 ppm; IR 2223, 1715, 1670, 1469, 1364, 1267, 1230, 1148, 1014, 835, 750, 663, 596, 567 cm −1 ; HRMS (ESI) calcd for C 20 H 19 NO 5 Na [M + Na] + 376.1155, found 376.1159.
실시예 42: 하기 화학식 2-9로 표시되는 화합물(Ethyl 3-(4-cyanophenyl)-5-(furan-2-yl)-2,5-dioxopentanoate)의 제조Example 42: Preparation of the compound represented by Chemical Formula 2-9 (Ethyl 3- (4-cyanophenyl) -5- (furan-2-yl) -2,5-dioxopentanoate)
[화학식 2-9][Formula 2-9]
화학식 1-9로 표시되는 화합물(0.80 g, 2.27 mmol)을 아세트산(20 mL)에 녹이고 Mn(OAc)3·2H2O(60 mg, 0.23 mmol) 및 CoCl2(30 mg, 0.23 mmol)를 첨가하였다. 이 혼합물을 공기 하, 실온에서 24시간 동안 교반하고, 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 오일 타입의 화학식 2-9로 표시되는 화합물(0.23 g, 0.71 mmol)을 얻었다(수율 31%).The compound of formula 1-9 (0.80 g, 2.27 mmol) was dissolved in acetic acid (20 mL), and Mn (OAc) 3 .2H 2 O (60 mg, 0.23 mmol) and CoCl 2 (30 mg, 0.23 mmol) were added thereto. Added. The mixture was stirred for 24 hours at room temperature under air and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound represented by the formula (2-9) of the yellow oil type (0.23 g, 0.71 mmol) (yield 31%).
화학식 2-9로 표시되는 화합물의 데이터: Rf = 0.32 (hexane:EtOAc = 4:1); 1H-NMR δ 1.32(t,J = 7.2 Hz, 3H), 3.35 (dd, J = 18.0, 4.4 Hz, 1H), 3.87 (dd, J = 18.0, 10.0 Hz, 1H), 4.22-4.36 (m, 2H), 5.17 (dd, J = 10.4, 4.8 Hz, 1H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H), 7.22 (dd, J = 3.6, 0.8 Hz, 1H), 7.46-7.50 (m, 2H), 7.59 (dd, J = 1.6, 0.8 Hz, 1H), 7.63-7.67 (m, 2H) ppm; 13C-NMR δ 13.9, 42.3, 47.9, 62.9, 112.0, 112.6, 117.7, 118.3, 129.6, 132.8, 140.8, 146.8, 151.7, 160.0, 185.7, 191.2 ppm; IR 2227, 1729, 1670, 1469, 1394, 1260, 1230, 1163, 1081, 1036, 850, 768, 567 cm-1; HRMS (ESI) calcd for C18H15NO5Na [M+Na]+ 348.0842, found 348.0845.Data for the compound represented by Formula 2-9: R f = 0.32 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.32 (t, J = 7.2 Hz, 3H), 3.35 (dd, J = 18.0, 4.4 Hz, 1H), 3.87 (dd, J = 18.0, 10.0 Hz, 1H), 4.22-4.36 (m , 2H), 5.17 (dd, J = 10.4, 4.8 Hz, 1H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H), 7.22 (dd, J = 3.6, 0.8 Hz, 1H), 7.46-7.50 ( m, 2H), 7.59 (dd, J = 1.6, 0.8 Hz, 1H), 7.63-7.67 (m, 2H) ppm; 13 C-NMR δ 13.9, 42.3, 47.9, 62.9, 112.0, 112.6, 117.7, 118.3, 129.6, 132.8, 140.8, 146.8, 151.7, 160.0, 185.7, 191.2 ppm; IR 2227, 1729, 1670, 1469, 1394, 1260, 1230, 1163, 1081, 1036, 850, 768, 567 cm −1 ; HRMS (ESI) calcd for C 18 H 15 NO 5 Na [M + Na] + 348.0842, found 348.0845.
실시예 43: 하기 화학식 3-25로 표시되는 화합물(Ethyl 4-(4-cyanophenyl)-[2,2'-bifuran]-5-carboxylate)의 제조Example 43 Preparation of Compound (Ethyl 4- (4-cyanophenyl)-[2,2'-bifuran] -5-carboxylate) represented by Chemical Formula 3-25
[화학식 3-25][Formula 3-25]
화학식 2-9로 표시되는 화합물(65 mg, 0.20 mmol)을 아세트산 무수물(8 mL)에 녹인 용액에 진한 염산(1 mL)을 첨가하였다. 이 혼합물을 50 ℃에서 9 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물에 포화 Na2CO3 수용액을 가하여 중화 시킨 뒤, EtOAc로 추출하고, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-25로 표시되는 노란색 오일 타입의 화합물(15 mg, 0.049 mmol)을 얻었다(수율 24%).To the solution of the compound represented by the formula (2-9) (65 mg, 0.20 mmol) in acetic anhydride (8 mL) was added concentrated hydrochloric acid (1 mL). The mixture was heated at 50 ° C. for 9 hours and cooled to room temperature. The mixture was neutralized by adding saturated aqueous Na 2 CO 3 solution, extracted with EtOAc, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a yellow oil type compound (15 mg, 0.049 mmol) represented by Formula 3-25 (yield 24%).
화학식 3-25로 표시되는 화합물의 데이터: Rf = 0.55 (hexane:EtOAc = 4:1); 1H-NMR δ 1.31 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.53 (dd, J = 3.6, 1.6 Hz, 1H), 6.74 (s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 7.51 (dd, J = 1.6, 0.8 Hz 1H), 7.69-7.74 (m, 4H) ppm; 13C-NMR δ14.2, 61.2, 108.4, 108.9, 111.9. 112.0, 118.7, 130.1, 131.7, 134.2, 136.6, 143.0, 143.6, 144.7, 148.6, 158.7 ppm; IR 2225, 1707, 1528, 1416, 1379, 1282, 1178, 1111, 1014, 850, 813, 745 cm-1; HRMS (ESI) calcd for C18H13NO4Na [M+Na]+ 330.0737, found 330.0741.Data of compounds represented by formulas 3-25: R f = 0.55 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.31 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.53 (dd, J = 3.6, 1.6 Hz, 1H), 6.74 (s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 7.51 (dd, J = 1.6, 0.8 Hz 1H), 7.69-7.74 (m, 4H) ppm; 13 C-NMR δ 14.2, 61.2, 108.4, 108.9, 111.9. 112.0, 118.7, 130.1, 131.7, 134.2, 136.6, 143.0, 143.6, 144.7, 148.6, 158.7 ppm; IR 2225, 1707, 1528, 1416, 1379, 1282, 1178, 1111, 1014, 850, 813, 745 cm -1 ; HRMS (ESI) calcd for C 18 H 13 NO 4 Na [M + Na] + 330.0737, found 330.0741.
실시예 44: 하기 화학식 3-26으로 표시되는 화합물(Ethyl 3-(4-cyanophenyl)-5-(furan-2-yl)-1Example 44: Compound represented by the following formula 3-26 (Ethyl 3- (4-cyanophenyl) -5- (furan-2-yl) -1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-26][Formula 3-26]
화학식 2-9로 표시되는 화합물(65 mg, 0.20 mmol)을 아세트산(2 mL)에 녹이고 NH4OAc(30 mg, 0.40 mmol)와 sulfamic acid(2 mg, 0.02 mmol)를 첨가하였다. 이 혼합물을 실온에서 9시간 동안 교반하고, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음, 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체의 화학식 3-26으로 표시되는 화합물(28 mg, 0.092 mmol)을 얻었다(수율 46%).The compound represented by Formula 2-9 (65 mg, 0.20 mmol) was dissolved in acetic acid (2 mL), and NH 4 OAc (30 mg, 0.40 mmol) and sulfamic acid (2 mg, 0.02 mmol) were added thereto. The mixture was stirred at rt for 9 h and the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain a compound (28 mg, 0.092 mmol) represented by the formula 3-26 as a white solid (yield 46%).
화학식 3-26으로 표시되는 화합물의 데이터: Rf = 0.39 (hexane:EtOAc = 4:1); 1H-NMR δ 1.26 (t, J = 6.8 Hz, 3H), 4.29 (q, J = 6.4 Hz, 2H), 6.49 (dd, J = 3.2, 1.6 Hz, 1H), 6.53 (d, J = 3.2, 1H), 6.60 (d, J = 0.8, 1H), 7.46 (s, 1H), 7.64-7.71 (m, 4H), 9.46(s, 1H) ppm; 13C-NMR δ 14.2, 60.7, 106.0, 108.4, 110.6, 111.8, 118.1, 119.1, 127.2, 130.1, 131.1, 131.4, 139.6, 142.2, 145.9, 160.3 ppm; IR 3281, 2221, 1662, 1603, 1431, 1372, 1327, 1275, 1200, 1163, 1133, 1014, 962, 880, 827, 731, 589, 552 cm-1; HRMS (ESI) calcd for C18H14N2O3Na [M+Na]+ 329.0897, found 329.0900.Data of compounds represented by formula 3-26: R f = 0.39 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.26 (t, J = 6.8 Hz, 3H), 4.29 (q, J = 6.4 Hz, 2H), 6.49 (dd, J = 3.2, 1.6 Hz, 1H), 6.53 (d, J = 3.2 , 1H), 6.60 (d, J = 0.8, 1H), 7.46 (s, 1H), 7.64-7.71 (m, 4H), 9.46 (s, 1H) ppm; 13 C-NMR δ 14.2, 60.7, 106.0, 108.4, 110.6, 111.8, 118.1, 119.1, 127.2, 130.1, 131.1, 131.4, 139.6, 142.2, 145.9, 160.3 ppm; IR 3281, 2221, 1662, 1603, 1431, 1372, 1327, 1275, 1200, 1163, 1133, 1014, 962, 880, 827, 731, 589, 552 cm −1 ; HRMS (ESI) calcd for C 18 H 14 N 2 O 3 Na [M + Na] + 329.0897, found 329.0900.
실시예 45: 하기 화학식 3-27로 표시되는 화합물(Ethyl 3-(4-cyanophenyl)-5-(furan-2-yl)thiophene-2-carboxylate)의 제조Example 45 Preparation of Compound (Ethyl 3- (4-cyanophenyl) -5- (furan-2-yl) thiophene-2-carboxylate) represented by Chemical Formula 3-27
[화학식 3-27][Formula 3-27]
화학식 2-9로 표시되는 화합물(65 mg, 0.20 mmol)을 톨루엔(5 mL)에 녹인 다음 Lawesson’s Reagent(97 mg, 0.24 mmol)를 첨가하였다. 이 혼합물을 60 ℃에서 8 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 의 화학식 3-27로 표시되는 화합물(15 mg, 0.046 mmol)을 얻었다(수율 23%).The compound represented by Formula 2-9 (65 mg, 0.20 mmol) was dissolved in toluene (5 mL), and Lawesson's Reagent (97 mg, 0.24 mmol) was added thereto. The mixture was heated at 60 ° C. for 8 hours and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain a compound (15 mg, 0.046 mmol) represented by the formula 3-27 as a brown solid (yield 23%).
화학식 3-27로 표시되는 화합물의 데이터: Rf = 0.39 (hexane:EtOAc = 4:1); 1H-NMR δ 1.27(t,J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.50 (dd, J = 3.6, 2.0 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 7.19 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H)ppm; 13C-NMR δ 14.1, 61.3, 107.9, 111.7. 112.2, 119.0, 125.4, 130.0, 131.6, 131.7, 138.1, 140.3, 143.2, 146.7, 148.0, 161.6 ppm; IR 2229, 1715, 1439, 1372, 1260, 1223, 1118, 1081, 1014, 842, 760 cm-1; HRMS (ESI) calcd for C18H13NO3SNa [M+Na]+ 346.0508, found 346.0510.Data of compounds represented by formula 3-27: R f = 0.39 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.27 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7.2 Hz, 2H), 6.50 (dd, J = 3.6, 2.0 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 7.19 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H) ppm; 13 C-NMR δ 14.1, 61.3, 107.9, 111.7. 112.2, 119.0, 125.4, 130.0, 131.6, 131.7, 138.1, 140.3, 143.2, 146.7, 148.0, 161.6 ppm; IR 2229, 1715, 1439, 1372, 1260, 1223, 1118, 1081, 1014, 842, 760 cm -1 ; HRMS (ESI) calcd for C 18 H 13 NO 3 SNa [M + Na] + 346.0508, found 346.0510.
실시예 46: 하기 화학식 1-10으로 표시되는 화합물(Ethyl 2-acetyl-5-(furan-2-yl)-3-(2-methoxyphenyl)-5-oxopentanoate)의 제조Example 46 Preparation of a Compound (Ethyl 2-acetyl-5- (furan-2-yl) -3- (2-methoxyphenyl) -5-oxopentanoate) Represented by Chemical Formula 1-10
[화학식 1-10][Formula 1-10]
아르곤 분위기 하에서, 에틸 아세토아세테이트(5 mL, 39.0 mmol)와 (E)-1-(퓨란-2-일)-3-(2-메톡시페닐)-2-프로펜-1-온(1.40 g, 6.13 mmol)의 혼합물에 CeCl3.7H2O(220 mg, 0.61 mmol)와 NaI(92 mg, 0.61 mmol)를 첨가하였다. 상기 혼합물을 50 ℃에서 10시간 동안 교반한 뒤, 실온으로 식힌다. EtOAc로 묽힌 다음, 물로 씻고, 무수 Na2SO4로 수분을 제거 한 뒤, 거름종이로 거르고, 여과액을 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 흰색 고체의 화학식 1-10으로 표시되는 화합물(1.47 g, 4.10 mmol, 1.1:1 입체이성질체 혼합물)을 얻었다(수율 67%).Under argon atmosphere, ethyl acetoacetate (5 mL, 39.0 mmol) and ( E ) -1- (furan-2-yl) -3- (2-methoxyphenyl) -2-propen-1-one (1.40 g , 6.13 mmol) was added CeCl 3 .7H 2 O (220 mg, 0.61 mmol) and NaI (92 mg, 0.61 mmol). The mixture is stirred at 50 ° C. for 10 hours and then cooled to room temperature. Dilute with EtOAc, wash with water, remove water with anhydrous Na 2 SO 4 , filter with filter paper, and concentrate the filtrate under reduced pressure. The product was purified by silica gel flash column chromatography to obtain the compound (1.47 g, 4.10 mmol, 1.1: 1 stereoisomer mixture) of the white solid (yield 67%).
화학식 1-10으로 표시되는 화합물의 데이터: Rf = 0.17 (hexane:EtOAc = 4:1); 1H-NMR (major) δ 0.95 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.13 (d of A of ABq, J AB = 15.6, J d = 4.4 Hz, 1H), 3.30 (d of B of ABq, J AB = 15.6, J d = 8.4 Hz, 1H), 3.83 (s, 3H), 3.88 (q, J = 7.2 Hz, 2H), 4.28-4.38 (m, 1H), 4.38 (d, J = 10.8 Hz, 1H), 6.44-6.48 (m, 1H), 6.76-6.85 (m, 2H), 7.08-7.18 (m, 3H), 7.49-7.54 (m, 1H) ppm; (minor) δ = 1.25 (t, J = 7.2 Hz, 3H), 2.05 (s, 3H), 3.22 (d of A of ABq, J AB = 15.6, J d = 4.4 Hz, 1H), 3.43 (d of B of ABq, J AB = 15.6, J d = 9.2 Hz, 1H), 3.81 (s, 3H), 4.18 (dq, J d = 2.0, J q = 7.2 Hz, 2H), 4.28 (d, J = 10.4 Hz, 1H), 4.28-4.38 (m, 1H), 4.07-4.16 (m, 1H), 6.44-6.48 (m, 1H), 6.76-6.85 (m, 2H), 7.08-7.18 (m, 3H), 7.49-7.54 (m, 1H) ppm; 13C-NMR (major) δ 13.6, 29.7, 37.5, 40.5, 55.2, 61.0, 62.7, 110.7, 112.0, 117.2, 120.4, 127.7, 128.3, 130.4, 146.1, 152.6, 157.4, 168.8, 187.4, 202.8 ppm; (minor) δ 14.0, 29.3, 37.1, 40.7, 55.2, 61.4, 62.6, 110.9, 112.0, 117.1, 120.7, 127.3, 128.4, 146.2, 152.5, 130.1, 157.0, 168.1, 187.1, 202.5 ppm; IR 1737, 1715, 1670, 1491, 1469, 1357, 1237, 1148, 1118, 1088, 1021, 750 cm-1.Data for the compound represented by Formula 1-10: R f = 0.17 (hexane: EtOAc = 4: 1); 1 H-NMR (major) δ 0.95 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 3.13 (d of A of ABq, J AB = 15.6, J d = 4.4 Hz, 1H), 3.30 (d of B of ABq, J AB = 15.6, J d = 8.4 Hz, 1H), 3.83 (s, 3H), 3.88 (q, J = 7.2 Hz, 2H), 4.28-4.38 (m, 1H), 4.38 (d, J = 10.8 Hz, 1H), 6.44-6.48 (m, 1H), 6.76-6.85 (m, 2H), 7.08-7.18 (m, 3H), 7.49-7.54 (m, 1H) ppm; (minor) δ = 1.25 (t, J = 7.2 Hz, 3H), 2.05 (s, 3H), 3.22 (d of A of ABq, J AB = 15.6, J d = 4.4 Hz, 1H), 3.43 (d of B of ABq, J AB = 15.6, J d = 9.2 Hz, 1H), 3.81 (s, 3H), 4.18 (dq, J d = 2.0, J q = 7.2 Hz, 2H), 4.28 (d, J = 10.4 Hz, 1H), 4.28-4.38 (m, 1H), 4.07-4.16 (m, 1H), 6.44-6.48 (m, 1H), 6.76-6.85 (m, 2H), 7.08-7.18 (m, 3H), 7.49-7.54 (m, 1 H) ppm; 13 C-NMR (major) δ 13.6, 29.7, 37.5, 40.5, 55.2, 61.0, 62.7, 110.7, 112.0, 117.2, 120.4, 127.7, 128.3, 130.4, 146.1, 152.6, 157.4, 168.8, 187.4, 202.8 ppm; (minor) δ 14.0, 29.3, 37.1, 40.7, 55.2, 61.4, 62.6, 110.9, 112.0, 117.1, 120.7, 127.3, 128.4, 146.2, 152.5, 130.1, 157.0, 168.1, 187.1, 202.5 ppm; IR 1737, 1715, 1670, 1491, 1469, 1357, 1237, 1148, 1118, 1088, 1021, 750 cm -1 .
실시예 47: 하기 화학식 2d으로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(2-methoxyphenyl)-2,5-dioxopentanoate)의 제조Example 47 Preparation of a Compound Represented by Chemical Formula 2d (Ethyl 5- (furan-2-yl) -3- (2-methoxyphenyl) -2,5-dioxopentanoate)
[화학식 2d][Formula 2d]
화학식 1-10으로 표시되는 화합물(850 mg, 2.37 mmol)을 아세트산(20 mL)에 녹이고 Mn(OAc)3·2H2O(64 mg, 0.24 mmol)과 CoCl2(31 mg, 0.24 mmol)를 첨가하였다. 이 혼합물을 공기 하, 실온에서 14시간 동안 교반하고, 감압 하에서 용매를 제거하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 연 노란색 오일 타입의 화학식 2-10으로 표시되는 화합물(120 mg, 0.35 mmol)을 얻었다(수율 15%).The compound of Formula 1-10 (850 mg, 2.37 mmol) was dissolved in acetic acid (20 mL), and Mn (OAc) 3 .2H 2 O (64 mg, 0.24 mmol) and CoCl 2 (31 mg, 0.24 mmol) were added thereto. Added. The mixture was stirred for 14 h at room temperature under air and the solvent was removed under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a compound (120 mg, 0.35 mmol) represented by the formula 2-10 as a pale yellow oil type (yield 15%).
화학식 2-10으로 표시되는 화합물의 데이터: 1H-NMR δ 1.17 (t, J = 7.2 Hz, 3H), 3.13 (dd, J = 18.0, 4.8 Hz, 1H), 3.76 (dd, J = 18.0, 8.8 Hz, 1H), 3.80 (s, 3H), 4.10-4.23 (m, 2H), 5.20 (dd, J = 8.8, 4.8 Hz, 1H), 6.50-6.53 (m, 1H), 6.85-6.95 (m, 2H), 7.16-7.28 (m, 3H), 7.54-7.57 (m, 1H) ppm.Data for compounds represented by Formulas 2-10: 1 H-NMR δ 1.17 (t, J = 7.2 Hz, 3H), 3.13 (dd, J = 18.0, 4.8 Hz, 1H), 3.76 (dd, J = 18.0, 8.8 Hz, 1H), 3.80 (s, 3H), 4.10-4.23 (m, 2H), 5.20 (dd, J = 8.8, 4.8 Hz, 1H), 6.50-6.53 (m, 1H), 6.85-6.95 (m , 2H), 7.16-7.28 (m, 3H), 7.54-7.57 (m, 1H) ppm.
실시예 48: 하기 화학식 3-28로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(2-methoxyphenyl)-2,5-dioxopentanoate)의 제조Example 48: Preparation of the compound represented by Chemical Formula 3-28 (Ethyl 5- (furan-2-yl) -3- (2-methoxyphenyl) -2,5-dioxopentanoate)
[화학식 3-28][Formula 3-28]
화학식 2-10으로 표시되는 화합물(112 mg, 0.34 mmol)을 아세트산 무수물(8 mL)에 녹인 용액에 진한 염산(1 mL)을 첨가하였다. 이 혼합물을 50 ℃에서 9 시간 동안 가열하고 실온으로 냉각하였다. 이 혼합물에 포화 Na2CO3 수용액을 가하여 중화 시킨 뒤, EtOAc로 추출하고, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 생성물을 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 화학식 3-28로 표시되는 노란색 오일 타입의 화합물(6.5 mg, 0.02 mmol)을 얻었다(수율 6%).Concentrated hydrochloric acid (1 mL) was added to a solution of the compound represented by Formula 2-10 (112 mg, 0.34 mmol) in acetic anhydride (8 mL). The mixture was heated at 50 ° C. for 9 hours and cooled to room temperature. The mixture was neutralized by adding saturated aqueous Na 2 CO 3 solution, extracted with EtOAc, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The product was purified by silica gel flash column chromatography to obtain a yellow oil type compound represented by the formula (3-28) (6.5 mg, 0.02 mmol) (yield 6%).
화학식 3-28로 표시되는 화합물의 데이터: Data: Rf = 0.63 (hexane:EtOAc = 4:1); 1H-NMR δ 1.21 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.51 (dd, J = 3.2, 2.0 Hz, 1H), 6.74 (s, 1H), 6.84 (d, J = 3.2 Hz, 1H), 6.94-7.02 (m, 2H), 7.33-7.37 (m, 2H), 7.47 (dd, J = 1.2, 0.8 Hz, 1H) ppm; 13C-NMR δ 14.1, 55.5, 60.6, 108.0, 110.2, 110.7, 111.7, 120.1, 121.2, 129.7, 131.4, 132.1, 139.0, 143.0, 145.5, 147.8, 156.8, 159.1 ppm; IR 1715, 1461, 1290, 1252, 1178, 1103, 1021, 753 cm-1.Data of compounds represented by formula 3-28: Data: R f = 0.63 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.21 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.51 (dd, J = 3.2, 2.0 Hz, 1H), 6.74 (s, 1H), 6.84 (d, J = 3.2 Hz, 1H), 6.94-7.02 (m, 2H), 7.33-7.37 (m, 2H), 7.47 (dd, J = 1.2, 0.8 Hz, 1H) ppm; 13 C-NMR δ 14.1, 55.5, 60.6, 108.0, 110.2, 110.7, 111.7, 120.1, 121.2, 129.7, 131.4, 132.1, 139.0, 143.0, 145.5, 147.8, 156.8, 159.1 ppm; IR 1715, 1461, 1290, 1252, 1178, 1103, 1021, 753 cm -1 .
실시예 49: 하기 화학식 3-29로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(2-methoxyphenyl)-1Example 49: Compound represented by Chemical Formula 3-29 (Ethyl 5- (furan-2-yl) -3- (2-methoxyphenyl) -1 HH -pyrrole-2-carboxylate)의 제조-pyrrole-2-carboxylate)
[화학식 3-29][Formula 3-29]
화학식 2-10으로 표시되는 화합물(84 mg, 0.25 mmol)을 아세트산(3 mL)에 녹이고 NH4OAc(39 mg, 0.50 mmol)와 sulfamic acid(2.5 mg, 0.03 mmol)를 첨가하였다. 이 혼합물을 40 ℃에서 4시간 동안 교반하고, 실온으로 식힌 뒤, 용매를 감압 하에서 제거하였다. 이를 EtOAc로 묽히고 물로 씻은 다음, 무수 Na2SO4로 수분을 제거하여 거른 뒤, 농축하여 생성물을 얻었다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 노란색 고체의 화학식 3-29로 표시되는 화합물(48 mg, 0.15 mmol)을 얻었다(수율 62%).The compound represented by Formula 2-10 (84 mg, 0.25 mmol) was dissolved in acetic acid (3 mL), and NH 4 OAc (39 mg, 0.50 mmol) and sulfamic acid (2.5 mg, 0.03 mmol) were added thereto. The mixture was stirred at 40 ° C. for 4 hours, cooled to room temperature and the solvent was removed under reduced pressure. It was diluted with EtOAc, washed with water, filtered off with anhydrous Na 2 SO 4 , filtered and concentrated to give the product. This was purified by silica gel flash column chromatography to obtain a compound (48 mg, 0.15 mmol) represented by the formula (3-29) as a yellow solid (yield 62%).
화학식 3-29로 표시되는 화합물의 데이터: Rf = 0.27 (hexane:EtOAc = 4:1); 1H-NMR δ 1.15 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 6.46 (dd, J = 3.6, 2.0 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.92-6.99 (m, 2H), 7.25-7.33 (m, 2H), 7.43 (t, J = 0.8, 1H), 9.32 (br s, 1H) ppm; 13C-NMR δ 14.1, 55.4, 60.1, 105.2, 109.5, 110.5, 111.7, 119.4, 119.9, 124.3, 126.6, 128.6, 131.6, 141.7, 146.8, 157.0, 161.0 ppm; IR 3295, 1670, 1491, 1461, 1439, 1282, 1251, 1163, 1133, 1111, 1051, 1021, 813, 753 cm-1.Data of compounds represented by formula 3-29: R f = 0.27 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.15 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 6.46 (dd, J = 3.6, 2.0 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.92-6.99 (m, 2H), 7.25-7.33 (m, 2H), 7.43 (t, J = 0.8, 1H), 9.32 (br s, 1H) ppm; 13 C-NMR δ 14.1, 55.4, 60.1, 105.2, 109.5, 110.5, 111.7, 119.4, 119.9, 124.3, 126.6, 128.6, 131.6, 141.7, 146.8, 157.0, 161.0 ppm; IR 3295, 1670, 1491, 1461, 1439, 1282, 1251, 1163, 1133, 1111, 1051, 1021, 813, 753 cm -1 .
실시예 50: 하기 화학식 3-30으로 표시되는 화합물(Ethyl 5-(furan-2-yl)-3-(2-methoxyphenyl)thiophene-2-carboxylate)의 제조Example 50 Preparation of the Compound (Ethyl 5- (furan-2-yl) -3- (2-methoxyphenyl) thiophene-2-carboxylate) represented by Chemical Formula 3-30
[화학식 3-30][Formula 3-30]
화학식 2-10으로 표시되는 화합물(112 mg, 0.34 mmol)을 톨루엔(5 mL)에 녹인 다음 Lawesson’s Reagent(164 mg, 0.40 mmol)를 첨가하였다. 이 혼합물을 50 ℃에서 하루 동안 가열하고 실온으로 냉각하였다. 이 혼합물을 포화 NaHCO3 수용액으로 퀀치하고, EtOAc로 추출하였다. 유기 상을 H2O 및 브라인(brine)으로 세척, 무수 Na2SO4로 건조, 여과 및 감압 하에서 농축하였다. 이를 실리카 겔 플래시 컬럼 크로마토그래피로 정제하여 갈색 고체 의 화학식 3-30으로 표시되는 화합물(49 mg, 0.15 mmol)을 얻었다(수율 44%).The compound represented by Formula 2-10 (112 mg, 0.34 mmol) was dissolved in toluene (5 mL), and Lawesson's Reagent (164 mg, 0.40 mmol) was added thereto. This mixture was heated at 50 ° C. for 1 day and cooled to room temperature. This mixture was quenched with saturated aqueous NaHCO 3 solution and extracted with EtOAc. The organic phase was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. This was purified by silica gel flash column chromatography to obtain a compound (49 mg, 0.15 mmol) represented by the formula (3-30) as a brown solid (yield 44%).
화학식 3-30으로 표시되는 화합물의 데이터: Rf = 0.26 (hexane:EtOAc = 4:1); 1H-NMR δ 1.18(t,J = 7.2 Hz, 3H), 3.77 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 6.47 (dd, J = 3.6, 2.0 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.93-7.02 (m, 2H), 7.20 (s, 1H), 7.25-7.37 (m, 2H), 7.44 (d, J = 1.6 Hz, 1H) ppm; 13C-NMR δ 14.0, 55.5, 60.7, 107.1, 110.7, 112.0, 120.1, 125.1, 126.5, 126.8, 129.4, 130.5, 136.7, 142.6, 144.7, 148.7, 156.7, 162.0 ppm; IR 1715, 1491, 1461, 1431, 1252, 1103, 1081, 1021, 753 cm-1.Data of compounds represented by formula 3-30: R f = 0.26 (hexane: EtOAc = 4: 1); 1 H-NMR δ 1.18 (t, J = 7.2 Hz, 3H), 3.77 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 6.47 (dd, J = 3.6, 2.0 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.93-7.02 (m, 2H), 7.20 (s, 1H), 7.25-7.37 (m, 2H), 7.44 (d, J = 1.6 Hz, 1H) ppm; 13 C-NMR δ 14.0, 55.5, 60.7, 107.1, 110.7, 112.0, 120.1, 125.1, 126.5, 126.8, 129.4, 130.5, 136.7, 142.6, 144.7, 148.7, 156.7, 162.0 ppm; IR 1715, 1491, 1461, 1431, 1252, 1103, 1081, 1021, 753 cm -1 .
이상 본 발명자에 의해서 이루어진 발명을 상기 실시예에 따라 구체적으로 설명하였지만, 본 발명은 상기 실시예에 한정되는 것은 아니고 그 요지를 이탈하지 않는 범위에서 여러 가지로 변경 가능한 것은 물론이다.As mentioned above, although the invention made by this inventor was demonstrated concretely according to the said Example, this invention is not limited to the said Example and can be variously changed in the range which does not deviate from the summary.
Claims (21)
[화학식 3]
상기 화학식 3 중에서,
R1, R2, R3는 서로 독립적으로 NO2, OMe, Br, F 또는 CN이고;
R4는 탄소수 1~3의 알킬기이며;
X 및 Y는 독립적으로 O, S 또는 N-R이고;
R은 H 또는 질소의 보호기이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula (3):
[Formula 3]
In Formula 3,
R 1 , R 2 , R 3 are independently of each other NO 2 , OMe, Br, F or CN;
R 4 is an alkyl group having 1 to 3 carbon atoms;
X and Y are independently O, S or NR;
R is a protecting group of H or nitrogen.
[화학식 3a]
상기 화학식 3a 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula (3a):
[Formula 3a]
In Formula 3a,
Y is O, S or NH.
[화학식 3b]
상기 화학식 3b 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound containing a phenyl substituent represented by the formula (3b):
[Formula 3b]
In Formula 3b,
Y is O, S or NH.
[화학식 3c]
상기 화학식 3c 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula (3c):
[Formula 3c]
In Formula 3c,
Y is O, S or NH.
[화학식 3d]
상기 화학식 3d 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula 3d:
[Formula 3d]
In Formula 3d,
Y is O, S or NH.
[화학식 3e]
상기 화학식 3e 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula (3e):
[Formula 3e]
In Formula 3e,
Y is O, S or NH.
[화학식 3f]
상기 화학식 3f 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound containing a phenyl substituent represented by the formula 3f:
[Formula 3f]
In Formula 3f,
Y is O, S or NH.
[화학식 3g]
상기 화학식 3g 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula 3g:
[Formula 3g]
In Formula 3g,
Y is O, S or NH.
[화학식 3h]
상기 화학식 3h 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula 3h:
[Formula 3h]
In Formula 3h,
Y is O, S or NH.
[화학식 3i]
상기 화학식 3i 중에서,
Y는 O, S 또는 NH이다.
A bi-heteroaromatic compound comprising a phenyl substituent represented by Formula 3i:
[Formula 3i]
In Formula 3i,
Y is O, S or NH.
[화학식 3j]
상기 화학식 3j 중에서,
Y는 O, S 또는 NH이다.
Bi-heteroaromatic compound comprising a phenyl substituent represented by the formula (3j):
[Formula 3j]
In Formula 3j,
Y is O, S or NH.
[화학식 2a]
상기 화학식 2a 중에서,
X는 O, S 또는 NBz이다.
1,4-dicarbonyl compound represented by the following formula (2a):
[Formula 2a]
In Formula 2a,
X is O, S or NBz.
[화학식 2b]
상기 화학식 2b 중에서,
R은 NO2, OMe, Br 또는 F이다.
1,4-dicarbonyl compound represented by the following formula (2b):
[Formula 2b]
In Formula 2b,
R is NO 2 , OMe, Br or F.
[화학식 2c]
상기 화학식 2c 중에서,
X는 S 또는 O 이다.
1,4-dicarbonyl compound represented by the following formula (2c):
[Formula 2c]
In Formula 2c,
X is S or O.
[화학식 2d]
1,4-dicarbonyl compound represented by the following formula (2d):
[Formula 2d]
[화학식 1]
(b) 상기 (a)단계에서 제조된 1,5-디카르보닐 화합물을 망간 및 코발트를 포함하는 금속촉매의 존재 하에서 탈아세틸화 반응시켜 하기 화학식 2로 표시되는 1,4-디카르보닐 화합물을 합성하는 단계; 및
[화학식 2]
(c) 상기 (b)단계에서 합성된 1,4-디카르보닐 화합물을 Paal-Knorr 합성법으로 반응시켜 하기 화학식 3으로 표시되는 화합물을 제조하는 단계
[화학식 3]
상기 화학식 1 내지 화학식 3 중에서,
R1, R2, R3는 서로 독립적으로 NO2, OMe, Br, F 또는 CN이고;
R4는 탄소수 1~3의 알킬기이며;
X 및 Y는 독립적으로 O, S 또는 N-R이고;
R은 H 또는 질소의 보호기이다.
를 포함하는 바이-헤테로아로마틱 화합물의 합성방법.
(a) preparing an 1,5-dicarbonyl compound represented by Chemical Formula 1 by reacting an alpha, beta-unsaturated carbonyl compound including an acetoacetic ester compound and a phenyl substituent;
[Formula 1]
(b) a 1,4-dicarbonyl compound represented by the following Chemical Formula 2 by deacetylation of the 1,5-dicarbonyl compound prepared in step (a) in the presence of a metal catalyst containing manganese and cobalt; Synthesizing; And
[Formula 2]
(c) preparing a compound represented by the following Chemical Formula 3 by reacting the 1,4-dicarbonyl compound synthesized in step (b) by Paal-Knorr synthesis
[Formula 3]
In Formula 1 to Formula 3,
R 1 , R 2 , R 3 are independently of each other NO 2 , OMe, Br, F or CN;
R 4 is an alkyl group having 1 to 3 carbon atoms;
X and Y are independently O, S or NR;
R is a protecting group of H or nitrogen.
Method for synthesizing bi-heteroaromatic compound comprising a.
상기 (b)단계에서 탈아세틸화 반응은 1,5-디카르보닐 화합물을 아세트산에 용해시킨 후, 5~10 mol% Mn(OAc)3·2H2O 및 2~5 mol% CoCl2를 첨가하여 실시되는 바이-헤테로아로마틱 화합물의 합성방법.
The method of claim 16,
In the step (b), the deacetylation reaction is performed by dissolving the 1,5-dicarbonyl compound in acetic acid, and then adding 5-10 mol% Mn (OAc) 3 · 2H 2 O and 2-5 mol% CoCl 2 . Method for synthesizing bi-heteroaromatic compound carried out by.
상기 (b)단계에서 탈아세틸화 반응은 25~60℃의 온도에서 1~48시간 동안 실시되는 바이-헤테로아로마틱 화합물의 합성방법.
The method of claim 16,
Deacetylation in step (b) is a method for synthesizing a bi-heteroaromatic compound is carried out for 1 to 48 hours at a temperature of 25 ~ 60 ℃.
상기 (c)단계에서 반응은 50~100℃에서 0.5~10시간 동안 실시되는 바이-헤테로아로마틱 화합물의 합성방법.
The method of claim 16,
The reaction in step (c) is a method for synthesizing a bi-heteroaromatic compound is carried out for 50 to 100 ℃ for 0.5 to 10 hours.
상기 (c)단계에서 반응 시 황산, 로손 시약(2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide), 암모늄아세테이트(NH4OAc)와 설파믹 산(sulfamic acid) 및 이들의 조합으로부터 선택되는 적어도 1종을 첨가하는 바이-헤테로아로마틱 화합물의 합성방법.
The method of claim 16,
In the step (c), sulfuric acid, Lawson's reagent (2,4-Bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide), ammonium acetate (NH 4 OAc) and sulfa A method for synthesizing a bi-heteroaromatic compound, wherein at least one selected from sulfamic acid and combinations thereof is added.
상기 (b)단계 및 (c)단계는 원-포트 연속반응방식으로 수행되는 바이-헤테로아로마틱 화합물의 합성방법.The method of claim 16,
Step (b) and step (c) is a method for synthesizing a bi-heteroaromatic compound is carried out in a one-pot continuous reaction method.
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