CN111747904A - 一种多氟烯基取代的恶唑化合物及其制备方法 - Google Patents
一种多氟烯基取代的恶唑化合物及其制备方法 Download PDFInfo
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- CN111747904A CN111747904A CN202010666373.8A CN202010666373A CN111747904A CN 111747904 A CN111747904 A CN 111747904A CN 202010666373 A CN202010666373 A CN 202010666373A CN 111747904 A CN111747904 A CN 111747904A
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- Prior art keywords
- phenylvinyl
- acetamide
- substituted
- benzamide
- vinyl
- Prior art date
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- -1 oxazole compound Chemical class 0.000 title claims abstract description 130
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000004440 column chromatography Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000001514 detection method Methods 0.000 claims abstract description 6
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 230000000975 bioactive effect Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- IXRNQIKIVWWFBH-UHFFFAOYSA-N n-(1-phenylethenyl)acetamide Chemical compound CC(=O)NC(=C)C1=CC=CC=C1 IXRNQIKIVWWFBH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- YLILOFLECOVRJP-UHFFFAOYSA-N n-[1-(4-cyanophenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C(C#N)C=C1 YLILOFLECOVRJP-UHFFFAOYSA-N 0.000 claims description 4
- QQTXDQXKSNMHPM-UHFFFAOYSA-N 2-methyl-N-(1-phenylethenyl)propanamide Chemical compound CC(C)C(=O)NC(=C)c1ccccc1 QQTXDQXKSNMHPM-UHFFFAOYSA-N 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- WWPSNILIVNXHJL-UHFFFAOYSA-N N-[1-(4-butylphenyl)ethenyl]acetamide Chemical compound CCCCC1=CC=C(C(=C)NC(C)=O)C=C1 WWPSNILIVNXHJL-UHFFFAOYSA-N 0.000 claims description 3
- YNTNVGBAXOSQRB-UHFFFAOYSA-N N-[1-(4-iodophenyl)ethenyl]acetamide Chemical compound IC1=CC=C(C=C1)C(=C)NC(C)=O YNTNVGBAXOSQRB-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 229950001902 dimevamide Drugs 0.000 claims description 3
- 125000005610 enamide group Chemical group 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- XTYDFMVGAZPQBZ-UHFFFAOYSA-N n-[1-(4-nitrophenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C([N+]([O-])=O)C=C1 XTYDFMVGAZPQBZ-UHFFFAOYSA-N 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical class CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 2
- CHOJEKYEZPCDFE-UHFFFAOYSA-N 2,2-dimethyl-n-(1-phenylethenyl)propanamide Chemical compound CC(C)(C)C(=O)NC(=C)C1=CC=CC=C1 CHOJEKYEZPCDFE-UHFFFAOYSA-N 0.000 claims description 2
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 2
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 claims description 2
- SKDORDVTQPQSRH-UHFFFAOYSA-N N-(3-methylbut-1-en-2-yl)acetamide Chemical compound C(C(=C)NC(=O)C)(C)C SKDORDVTQPQSRH-UHFFFAOYSA-N 0.000 claims description 2
- FSBBMVZPLLEQRS-UHFFFAOYSA-N N-[1-(4-ethylphenyl)ethenyl]acetamide Chemical compound C(C)C1=CC=C(C=C1)C(=C)NC(C)=O FSBBMVZPLLEQRS-UHFFFAOYSA-N 0.000 claims description 2
- MXSGZJLAIFQOIL-UHFFFAOYSA-N N-[1-(4-tert-butylphenyl)ethenyl]acetamide Chemical compound C(C)(=O)NC(=C)C1=CC=C(C=C1)C(C)(C)C MXSGZJLAIFQOIL-UHFFFAOYSA-N 0.000 claims description 2
- 150000003869 acetamides Chemical class 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical class CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- QGXBDMJGAMFCBF-LUJOEAJASA-N epiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-LUJOEAJASA-N 0.000 claims description 2
- 229960003399 estrone Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000006343 heptafluoro propyl group Chemical group 0.000 claims description 2
- 125000006303 iodophenyl group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- HGJBCPCDLGWOSE-UHFFFAOYSA-N n-(1-naphthalen-1-ylethenyl)acetamide Chemical compound C1=CC=C2C(C(=C)NC(=O)C)=CC=CC2=C1 HGJBCPCDLGWOSE-UHFFFAOYSA-N 0.000 claims description 2
- YDNZMDGXIHCQTN-UHFFFAOYSA-N n-(1-phenylethenyl)benzamide Chemical compound C=1C=CC=CC=1C(=C)NC(=O)C1=CC=CC=C1 YDNZMDGXIHCQTN-UHFFFAOYSA-N 0.000 claims description 2
- YPIDOFMLPMJTJX-UHFFFAOYSA-N n-(1-phenylethenyl)propanamide Chemical compound CCC(=O)NC(=C)C1=CC=CC=C1 YPIDOFMLPMJTJX-UHFFFAOYSA-N 0.000 claims description 2
- LWCASYBTPPNMOQ-UHFFFAOYSA-N n-(3,3-dimethylbut-1-en-2-yl)acetamide Chemical compound CC(=O)NC(=C)C(C)(C)C LWCASYBTPPNMOQ-UHFFFAOYSA-N 0.000 claims description 2
- DGOOUXUKZWVHDP-UHFFFAOYSA-N n-(3-phenylprop-1-en-2-yl)acetamide Chemical compound CC(=O)NC(=C)CC1=CC=CC=C1 DGOOUXUKZWVHDP-UHFFFAOYSA-N 0.000 claims description 2
- OQFXOFQCLBQHKK-UHFFFAOYSA-N n-[1-(4-bromophenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C(Br)C=C1 OQFXOFQCLBQHKK-UHFFFAOYSA-N 0.000 claims description 2
- DVUMGIDOTXJYIW-UHFFFAOYSA-N n-[1-(4-chlorophenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C(Cl)C=C1 DVUMGIDOTXJYIW-UHFFFAOYSA-N 0.000 claims description 2
- SQNJXYSUGKGTPB-UHFFFAOYSA-N n-[1-(4-fluorophenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C(F)C=C1 SQNJXYSUGKGTPB-UHFFFAOYSA-N 0.000 claims description 2
- WBXRIHAXVFNDKL-UHFFFAOYSA-N n-[1-(4-methoxyphenyl)ethenyl]acetamide Chemical compound COC1=CC=C(C(=C)NC(C)=O)C=C1 WBXRIHAXVFNDKL-UHFFFAOYSA-N 0.000 claims description 2
- WSMPLUKWVPUMKQ-UHFFFAOYSA-N n-[1-(4-methylphenyl)ethenyl]acetamide Chemical compound CC(=O)NC(=C)C1=CC=C(C)C=C1 WSMPLUKWVPUMKQ-UHFFFAOYSA-N 0.000 claims description 2
- FSNXYJBYYNRTMG-UHFFFAOYSA-N n-but-1-en-2-ylacetamide Chemical compound CCC(=C)NC(C)=O FSNXYJBYYNRTMG-UHFFFAOYSA-N 0.000 claims description 2
- RFGFCICNGCPXQJ-UHFFFAOYSA-N n-prop-1-en-2-ylacetamide Chemical compound CC(=C)NC(C)=O RFGFCICNGCPXQJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 claims description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940080818 propionamide Drugs 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- DUIGXCNVYKDLER-UHFFFAOYSA-N O=C(C1=CC=NC=C1)NC=CC1=CC=CC=C1 Chemical compound O=C(C1=CC=NC=C1)NC=CC1=CC=CC=C1 DUIGXCNVYKDLER-UHFFFAOYSA-N 0.000 claims 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 229910052731 fluorine Inorganic materials 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- PGRFXXCKHGIFSV-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I PGRFXXCKHGIFSV-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
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- 239000003208 petroleum Substances 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
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- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 2
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Abstract
本发明公开了一种多氟烯基取代的恶唑化合物及其制备方法。本发明通过将由N‑酰基烯胺化合物与全氟烷基碘化物混合而成的反应原料加入到碱促进剂以及溶剂中,在空气氛围、室温条件下搅拌反应1~24小时,TLC检测确定反应进程,反应结束后得到反应液;最后将所述反应液依次经过洗涤、萃取和干燥处理,再通过柱层析分离得到多氟烯基取代的恶唑化合物。本发明制备方法中所需原料简单易得,具有多样的官能团耐受性和底物范围,且能引入天然产物和药物活性分子骨架;本发明制备方法反应条件温和,无需昂贵的过渡金属催化剂,符合绿色、经济化学的要求;本发明制备方法无需预先构建合成五元恶唑杂环,具有最高的步骤经济性。
Description
技术领域
本发明属于有机化学及药物化学领域,尤其涉及一种多氟烯基取代的恶唑化合物及其制备方法。
背景技术
恶唑环由于其特殊结构,五元环中同时含有氧和氮原子,展现出独特的生物活性和材料性能。例如,已报道的恶唑化合物具有抗真菌、抗结核、抗惊厥、降血压、镇痛消炎等活性。目前,含恶唑骨架的药物分子已运用于临床上的包括:Linezolid(利奈唑胺),可用于治疗革兰氏阳性(G+)球菌引起的感染;Pristinamycin(普那霉素),对多种细菌感染具有较好的治疗效果;Calyculin A(钙霉素A)蛋白磷酸酯酶抑制剂,能够克服临床上的耐药性,在治疗感染疾病方面具有无可替代的地位。并且,恶唑化合物也可作为重要的合成子和中间体参与有机反应,它还是一类重要的有机光电材料核心分子。因此,如何高效、便捷合成此类化合物引起了有机化学家的广泛兴趣。
作为有机氟化学与杂环化学的交叉产物,含氟杂环化合物因其优异的性能在当今新药研制、农药创制以及光、电、热、磁等功能材料等研究领域扮演着重要角色。但是,自然界中含氟化合物的种类稀少,如何方便、温和、高效、安全地将含氟基团引入到杂环化合物中已成为合成研究的前沿热点。含氟恶唑化合物的获得一般是通过在已有杂环中直接导入氟原子。在杂环上直接氟化的化学选择性及区域选择性一般较差,不仅需要较为苛刻的反应条件,还需要预先制备特定结构的恶唑化合物。
目前,通过断裂多个碳氟键,在反应过程中形成恶唑环并完成多氟烯基化的例子还未见报道。因此,通过分子间串联环化反应,一步合成新型多氟烯基取代恶唑化合物就十分有研究价值。
发明内容
本发明的首要目的在于提供一种多氟烯基取代恶唑化合物,为新型恶唑骨架分子在医药、材料邻域的研究提供新的研究对象。
本发明的再一目的在于提供上述多氟烯基取代恶唑化合物的制备方法,旨在克服现有合成技术中所存在的各种缺陷。
本发明是这样实现的,一种多氟烯基取代的恶唑化合物,该化合物的化学结构式如下式(Ⅰ)所示:
式(Ⅰ)中,R1包括C1~C5烷基、C1~C4全氟取代烷基、金刚烷基、苄基、苯基、Cl~C5烷基取代的苯基、Cl~C5烷氧基取代的苯基、卤素取代的苯基、氰基取代的苯基、硝基取代的苯基、烷氧羰基取代的苯基、1-萘基、2-萘基、呋喃基、2-吡啶基、4-吡啶基以及生物活性分子衍生基团;
R2包括C1~C5烷基、苄基、苯基、Cl~C5烷基取代的苯基、Cl~C5烷氧基取代的苯基、卤素取代的苯基、氰基取代的苯基、硝基取代的苯基、烷氧羰基取代的苯基、1-萘基、2-萘基、呋喃基、2-吡啶基、4-吡啶基以及生物活性分子衍生基团;
n为不小于1的自然数。
优选地,所述C1~C5烷基包括甲基、乙基、丙基、异丙基、叔丁基、戊基;
所述C1~C4全氟取代烷基包括三氟甲基、五氟乙基、七氟丙级、全氟丁基;
所述卤素取代的苯基包括氟苯基、氯苯基、溴苯基、碘苯基;
所述生物活性分子衍生基团包括雌酚酮、表雄酮、生育酚衍生苯基。
优选地,所述n为1~8的自然数。
本发明进一步公开了上述多氟烯基取代的恶唑化合物的制备方法,该方法包括以下步骤:
(1)将由N-酰基烯胺化合物与全氟烷基碘化物混合而成的反应原料加入到碱促进剂以及溶剂中,在空气氛围、20~90℃温度条件下搅拌反应1~24小时,TLC检测确定反应进程,反应结束后得到反应液;其中,所述N-酰基烯胺化合物、全氟烷基碘化物、碱促进剂、溶剂的摩尔体积比为1mmol:(2~3)mmol:(1~3)mmol:(2~5)mL;
(2)将所述反应液依次经过洗涤、萃取和干燥处理,再通过柱层析分离得到多氟烯基取代的恶唑化合物。
优选地,在步骤(1)中,所述N-酰基烯胺化合物包括N-(1-苯基乙烯基)乙酰胺、N-(1-苯基乙烯基)丙酰胺、N-(1-苯基乙烯基)丁酰胺、N-(1-苯基乙烯基)异丁酰胺、N-(1-苯基乙烯基)新戊酰胺、N-(1-苯基乙烯基)戊酰胺、N-(1-苯基乙烯基)三氟甲基取代乙酰胺、N-(1-苯基乙烯基)五氟乙基取代丙酰胺、N-(1-苯基乙烯基)七氟丙基取代丁酰胺、N-(1-苯基乙烯基)七氟丁基取代戊酰胺、2-苯基-N-(1-苯基乙烯基)乙酰胺、N-(1-苯基乙烯基)苯甲酰胺、N-(1-苯基乙烯基)金刚烷基酰胺、4-甲基-N-(1-苯基乙烯基)苯甲酰胺、4-乙基-N-(1-苯基乙烯基)苯甲酰胺、4-丙基-N-(1-苯基乙烯基)苯甲酰胺、4-丁基-N-(1-苯基乙烯基)苯甲酰胺、4-叔丁基-N-(1-苯基乙烯基)苯甲酰胺、4-戊基-N-(1-苯基乙烯基)苯甲酰胺、4-甲氧基-N-(1-苯基乙烯基)苯甲酰胺、4-乙氧基-N-(1-苯基乙烯基)苯甲酰胺、4-丙氧基-N-(1-苯基乙烯基)苯甲酰胺、4-丁氧基-N-(1-苯基乙烯基)苯甲酰胺、4-叔丁氧基-N-(1-苯基乙烯基)苯甲酰胺、4-戊氧基-N-(1-苯基乙烯基)苯甲酰胺、4-氟-N-(1-苯基乙烯基)苯甲酰胺、4-氯-N-(1-苯基乙烯基)苯甲酰胺、4-溴-N-(1-苯基乙烯基)苯甲酰胺、4-碘-N-(1-苯基乙烯基)苯甲酰胺、3-溴-N-(1-苯基乙烯基)苯甲酰胺、2-溴-N-(1-苯基乙烯基)苯甲酰胺、4-乙氧羰基-N-(1-苯基乙烯基)苯甲酰胺、4-氰基-N-(1-苯基乙烯基)苯甲酰胺、4-硝基-N-(1-苯基乙烯基)苯甲酰胺、N-(1-苯基乙烯基)-1-萘甲酰胺、N-(1-苯基乙烯基)-2-萘甲酰胺、N-(1-苯基乙烯基)呋喃甲酰胺、N-(1-苯基乙烯基)-2-吡啶甲酰胺、N-(1-苯基乙烯基)-4-吡啶甲酰胺、N-(丙-1-烯-2-基)乙酰胺、N-(丁-1-烯-2-基)乙酰胺、N-(戊-1-烯-2-基)乙酰胺、N-(己-1-烯-2-基)乙酰胺、N-(庚-1-烯-2-基)乙酰胺、N-(3-甲基丁-1-烯-2-基)乙酰胺、N-(3,3-双甲基丁-1-烯-2-基)乙酰胺、N-(3-苯基丙-1-烯-2-基)乙酰胺、N-(1-对甲基苯基乙烯基)乙酰胺、N-(1-对乙基苯基乙烯基)乙酰胺、N-(1-对丙基苯基乙烯基)乙酰胺、N-(1-对丁基苯基乙烯基)乙酰胺、N-(1-对叔丁基苯基乙烯基)乙酰胺、N-(1-对戊基苯基乙烯基)乙酰胺、N-(1-(4-甲氧基苯基)乙烯基)乙酰胺、N-(1-(4-乙氧基苯基)乙烯基)乙酰胺、N-(1-(4-丙氧基苯基)乙烯基)乙酰胺、N-(1-(4-丁氧基苯基)乙烯基)乙酰胺、N-(1-(4-叔丁氧基苯基)乙烯基)乙酰胺、N-(1-(4-戊氧基苯基)乙烯基)乙酰胺、N-(1-(4-氟苯基)乙烯基)乙酰胺、N-(1-(4-氯苯基)乙烯基)乙酰胺、N-(1-(4-溴苯基)乙烯基)乙酰胺、N-(1-(4-碘苯基)乙烯基)乙酰胺、N-(1-(4-氰基苯基)乙烯基)乙酰胺、N-(1-(4-硝基苯基)乙烯基)乙酰胺、N-(1-(4-乙氧羰基苯基)乙烯基)乙酰胺、N-(1-(萘-1-基)乙烯基)乙酰胺、N-(2-(萘-1-基)乙烯基)乙酰胺、N-(2-(呋喃-1-基)乙烯基)乙酰胺、N-(2-(吡啶-1-基)乙烯基)乙酰胺、N-(4-(吡啶-1-基)乙烯基)乙酰胺以及生物活性分子衍生烯酰胺。
优选地,在步骤(1)中,所述全氟烷基碘化物包括全氟烷基碘乙烷、全氟烷基碘丙烷、全氟烷基碘丁烷、全氟烷基碘戊烷、全氟烷基碘己烷、全氟烷基碘庚烷、全氟烷基碘辛烷、全氟烷基碘壬烷、全氟烷基碘癸烷。
优选地,在步骤(1)中,所述碱促进剂包括吡啶、三乙烯二胺、二异丙胺、三乙胺、二氮杂二环、二氮杂二环、二异丙胺基钠、氢化钠、碳酸铯、碳酸钾、碳酸铵、磷酸钾、醋酸钠、氢氧化钠以及氢氧化锂;
所述溶剂包括二甲亚砜、乙腈、叔丁醇、硝基甲烷、乙醇、甲苯、四氢呋喃、环己烷以及乙酸乙酯。
优选地,所述碱促进剂为二氮杂二环;所述溶剂为二甲亚砜。
优选地,在步骤(1)中,所述N-酰基烯胺化合物、全氟烷基碘化物和碱促进剂的摩尔比为1:2:2.5。
优选地,在步骤(1)中,反应温度为25℃。
本发明克服现有技术的不足,提供一种多氟烯基取代恶唑化合物及其制备方法,本发明利用含氟砌块在构建杂环时引入氟原子,由于在反应过程中直接构建恶唑骨架的同时引入氟原子或含氟基团,能反应条件温和、高效、高区域选择性地合成含氟杂环化合物。更具体的,本发明采用一锅法原理,通过将由N-酰基烯胺化合物与全氟烷基碘化物混合而成的反应原料加入到碱促进剂以及溶剂中,在空气氛围、室温条件下搅拌反应1~24小时,TLC检测确定反应进程,反应结束后得到反应液;最后将所述反应液依次经过洗涤、萃取和干燥处理,再通过柱层析分离得到多氟烯基取代的恶唑化合物。N-酰基烯胺化合物与全氟烷基碘化物之间的合成过程如下所示:
在无过渡金属参与条件下,本发明通过简单将N-酰基烯胺化合物与全氟烷基碘化物混合、搅拌,基于分子间环化-脱氟串联机理(多氟烷基碘化物两个C-F键和一个C-I键切断,形成了新的C-O键和C-C键),以及在构建目标恶唑五元杂环的同时引入区域选择性多氟烯烃的方式(多氟烯基区位选择性的形成在恶唑C5位上),高效的合成氟烯基取代恶唑化合物。
在本发明制备方法中,通过调控反应物的比例、所选碱的种类、反应进行的溶剂和反应温度等一系列条件,可高效合成一系列多氟烯基取代恶唑化合物。其中,本发明制备方法的条件筛选过程中,对不同的碱促进剂,如:吡啶、三乙烯二胺、二异丙胺、三乙胺、二氮杂二环、二氮杂二环以及二异丙胺基钠、氢化钠、碳酸铯、碳酸钾、碳酸铵、磷酸钾、醋酸钠、氢氧化钠、氢氧化锂均能得到预期结果,但二氮杂二环效果最优;N-酰基烯胺化合物与全氟烷基碘化物之间不同的比例1:(1~3)之间,以1:2最优;对不同的溶剂,如:二甲亚砜、乙腈、叔丁醇、硝基甲烷、乙醇、甲苯、四氢呋喃、环己烷、乙酸乙酯均能得到预期产物,但二甲亚砜效果最优;20~90℃范围内的不同温度下均能得到目标产物,25℃室温最优。
相比于现有技术的缺点和不足,本发明具有以下有益效果:
(1)本发明制备方法中所采用的原料烯酰胺和多氟烷基碘化物简单易得,具有多样的官能团耐受性和底物范围,且能引入天然产物和药物活性分子骨架;
(2)本发明制备方法反应条件温和,无需昂贵的过渡金属催化剂,仅仅使用有机碱作为促进剂,符合绿色、经济化学的要求;
(3)本发明制备方法无需预先构建合成五元恶唑杂环,具有最高的步骤经济性。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
(1)将1mmol的N-酰基烯胺化合物(0.162克)、2mmol的全氟碘代烷烃(0.692克)、2.5mmol的碱促进剂(0.381克)加入到规格为10mL的试管反应管中,再往反应管中加入5mL二甲亚砜作溶剂,封口密闭,室温(25℃)下搅拌反应24小时,得到多氟烯基取代恶唑化合物;其中,N-酰基烯胺化合物为N-(1-苯基乙烯基)乙酰胺,氟碘代烷烃为全氟碘代丁烷;碱促进剂为二氮杂二环;
(2)在步骤(1)反应结束后,将反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件:固定相为300~400目硅胶粉,流动相为乙酸乙酯(A)和石油醚(B),流动相变化程序(A:B)为1:50→1:10,得到0.315克反应产物1。
对上述反应产物进行表征,结果为:无色液体;1H NMR(400MHz,Chloroform-d):δ=7.74–7.66(m,2H),7.47–7.38(m,3H),2.56(d,J=2.3Hz,3H)ppm.
根据表征数据可知,制得的反应产物1为2-甲基-5-(全氟丁基-1-烯-1-基)-4-苯基恶唑(纯度>95%);对产品产率进行计算,结果为93%。
实施例2~78
实施例2~78与上述实施例1基本相同,差别之处如下表1所示:
表1实施例2~78
实施例79
(1)将由1mmolN-酰基烯胺化合物与3mmol全氟烷基碘化物混合而成的反应原料加入到3mmol碱促进剂以及5mL四氢呋喃溶剂中,在空气氛围、90℃温度条件下搅拌反应24小时,TLC检测确定反应进程,反应结束后得到反应液;其中,N-酰基烯胺化合物为N-(1-苯基乙烯基)乙酰胺,氟碘代烷烃为全氟碘代丁烷;碱促进剂为二氮杂二环;
(2)在步骤(1)反应结束后,将反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件:固定相为300~400目硅胶粉,流动相为乙酸乙酯(A)和石油醚(B),流动相变化程序(A:B)为1:50→1:10,得到反应产物。
实施例80
(1)将由1mmol N-酰基烯胺化合物与2mmol全氟烷基碘化物混合而成的反应原料加入到1mmol碱促进剂以及2mL乙腈溶剂中,在空气氛围、20℃温度条件下搅拌反应1小时,TLC检测确定反应进程,反应结束后得到反应液;其中,N-酰基烯胺化合物为N-(1-苯基乙烯基)乙酰胺,氟碘代烷烃为全氟碘代丁烷;碱促进剂为二氮杂二环;
(2)在步骤(1)反应结束后,将反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件:固定相为300~400目硅胶粉,流动相为乙酸乙酯(A)和石油醚(B),流动相变化程序(A:B)为1:50→1:10,得到反应产物。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种多氟烯基取代的恶唑化合物,其特征在于,该化合物的化学结构式如下式(Ⅰ)所示:
式(Ⅰ)中,R1包括C1~C5烷基、C1~C4全氟取代烷基、金刚烷基、苄基、苯基、Cl~C5烷基取代的苯基、Cl~C5烷氧基取代的苯基、卤素取代的苯基、氰基取代的苯基、硝基取代的苯基、烷氧羰基取代的苯基、1-萘基、2-萘基、呋喃基、2-吡啶基、4-吡啶基以及生物活性分子衍生基团;
R2包括C1~C5烷基、苄基、苯基、Cl~C5烷基取代的苯基、Cl~C5烷氧基取代的苯基、卤素取代的苯基、氰基取代的苯基、硝基取代的苯基、烷氧羰基取代的苯基、1-萘基、2-萘基、呋喃基、2-吡啶基、4-吡啶基以及生物活性分子衍生基团;
n为不小于1的自然数。
2.如权利要求1所述的多氟烯基取代的恶唑化合物,其特征在于,所述C1~C5烷基包括甲基、乙基、丙基、异丙基、叔丁基、戊基;
所述C1~C4全氟取代烷基包括三氟甲基、五氟乙基、七氟丙级、全氟丁基;
所述卤素取代的苯基包括氟苯基、氯苯基、溴苯基、碘苯基;
所述生物活性分子衍生基团包括雌酚酮、表雄酮、生育酚衍生苯基。
3.如权利要求1所述的多氟烯基取代的恶唑化合物,其特征在于,所述n为1~8的自然数。
4.权利要求1~3任一项所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,该方法包括以下步骤:
(1)将由N-酰基烯胺化合物与全氟烷基碘化物混合而成的反应原料加入到碱促进剂以及溶剂中,在空气氛围、20~90℃温度条件下搅拌反应1~24小时,TLC检测确定反应进程,反应结束后得到反应液;其中,所述N-酰基烯胺化合物、全氟烷基碘化物、碱促进剂、溶剂的摩尔体积比为1mmol:(2~3)mmol:(1~3)mmol:(2~5)mL;
(2)将所述反应液依次经过洗涤、萃取和干燥处理,再通过柱层析分离得到多氟烯基取代的恶唑化合物。
5.如权利要求4所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,在步骤(1)中,所述N-酰基烯胺化合物包括N-(1-苯基乙烯基)乙酰胺、N-(1-苯基乙烯基)丙酰胺、N-(1-苯基乙烯基)丁酰胺、N-(1-苯基乙烯基)异丁酰胺、N-(1-苯基乙烯基)新戊酰胺、N-(1-苯基乙烯基)戊酰胺、N-(1-苯基乙烯基)三氟甲基取代乙酰胺、N-(1-苯基乙烯基)五氟乙基取代丙酰胺、N-(1-苯基乙烯基)七氟丙基取代丁酰胺、N-(1-苯基乙烯基)七氟丁基取代戊酰胺、2-苯基-N-(1-苯基乙烯基)乙酰胺、N-(1-苯基乙烯基)苯甲酰胺、N-(1-苯基乙烯基)金刚烷基酰胺、4-甲基-N-(1-苯基乙烯基)苯甲酰胺、4-乙基-N-(1-苯基乙烯基)苯甲酰胺、4-丙基-N-(1-苯基乙烯基)苯甲酰胺、4-丁基-N-(1-苯基乙烯基)苯甲酰胺、4-叔丁基-N-(1-苯基乙烯基)苯甲酰胺、4-戊基-N-(1-苯基乙烯基)苯甲酰胺、4-甲氧基-N-(1-苯基乙烯基)苯甲酰胺、4-乙氧基-N-(1-苯基乙烯基)苯甲酰胺、4-丙氧基-N-(1-苯基乙烯基)苯甲酰胺、4-丁氧基-N-(1-苯基乙烯基)苯甲酰胺、4-叔丁氧基-N-(1-苯基乙烯基)苯甲酰胺、4-戊氧基-N-(1-苯基乙烯基)苯甲酰胺、4-氟-N-(1-苯基乙烯基)苯甲酰胺、4-氯-N-(1-苯基乙烯基)苯甲酰胺、4-溴-N-(1-苯基乙烯基)苯甲酰胺、4-碘-N-(1-苯基乙烯基)苯甲酰胺、3-溴-N-(1-苯基乙烯基)苯甲酰胺、2-溴-N-(1-苯基乙烯基)苯甲酰胺、4-乙氧羰基-N-(1-苯基乙烯基)苯甲酰胺、4-氰基-N-(1-苯基乙烯基)苯甲酰胺、4-硝基-N-(1-苯基乙烯基)苯甲酰胺、N-(1-苯基乙烯基)-1-萘甲酰胺、N-(1-苯基乙烯基)-2-萘甲酰胺、N-(1-苯基乙烯基)呋喃甲酰胺、N-(1-苯基乙烯基)-2-吡啶甲酰胺、N-(1-苯基乙烯基)-4-吡啶甲酰胺、N-(丙-1-烯-2-基)乙酰胺、N-(丁-1-烯-2-基)乙酰胺、N-(戊-1-烯-2-基)乙酰胺、N-(己-1-烯-2-基)乙酰胺、N-(庚-1-烯-2-基)乙酰胺、N-(3-甲基丁-1-烯-2-基)乙酰胺、N-(3,3-双甲基丁-1-烯-2-基)乙酰胺、N-(3-苯基丙-1-烯-2-基)乙酰胺、N-(1-对甲基苯基乙烯基)乙酰胺、N-(1-对乙基苯基乙烯基)乙酰胺、N-(1-对丙基苯基乙烯基)乙酰胺、N-(1-对丁基苯基乙烯基)乙酰胺、N-(1-对叔丁基苯基乙烯基)乙酰胺、N-(1-对戊基苯基乙烯基)乙酰胺、N-(1-(4-甲氧基苯基)乙烯基)乙酰胺、N-(1-(4-乙氧基苯基)乙烯基)乙酰胺、N-(1-(4-丙氧基苯基)乙烯基)乙酰胺、N-(1-(4-丁氧基苯基)乙烯基)乙酰胺、N-(1-(4-叔丁氧基苯基)乙烯基)乙酰胺、N-(1-(4-戊氧基苯基)乙烯基)乙酰胺、N-(1-(4-氟苯基)乙烯基)乙酰胺、N-(1-(4-氯苯基)乙烯基)乙酰胺、N-(1-(4-溴苯基)乙烯基)乙酰胺、N-(1-(4-碘苯基)乙烯基)乙酰胺、N-(1-(4-氰基苯基)乙烯基)乙酰胺、N-(1-(4-硝基苯基)乙烯基)乙酰胺、N-(1-(4-乙氧羰基苯基)乙烯基)乙酰胺、N-(1-(萘-1-基)乙烯基)乙酰胺、N-(2-(萘-1-基)乙烯基)乙酰胺、N-(2-(呋喃-1-基)乙烯基)乙酰胺、N-(2-(吡啶-1-基)乙烯基)乙酰胺、N-(4-(吡啶-1-基)乙烯基)乙酰胺以及生物活性分子衍生烯酰胺。
6.如权利要求4所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,在步骤(1)中,所述全氟烷基碘化物包括全氟烷基碘乙烷、全氟烷基碘丙烷、全氟烷基碘丁烷、全氟烷基碘戊烷、全氟烷基碘己烷、全氟烷基碘庚烷、全氟烷基碘辛烷、全氟烷基碘壬烷、全氟烷基碘癸烷。
7.如权利要求4所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,在步骤(1)中,所述碱促进剂包括吡啶、三乙烯二胺、二异丙胺、三乙胺、二氮杂二环、二氮杂二环、二异丙胺基钠、氢化钠、碳酸铯、碳酸钾、碳酸铵、磷酸钾、醋酸钠、氢氧化钠以及氢氧化锂;
所述溶剂包括二甲亚砜、乙腈、叔丁醇、硝基甲烷、乙醇、甲苯、四氢呋喃、环己烷以及乙酸乙酯。
8.如权利要求7所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,所述碱促进剂为二氮杂二环;所述溶剂为二甲亚砜。
9.如权利要求4所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,在步骤(1)中,所述N-酰基烯胺化合物、全氟烷基碘化物和碱促进剂的摩尔比为1:2:2.5。
10.如权利要求4所述的多氟烯基取代的恶唑化合物的制备方法,其特征在于,在步骤(1)中,反应温度为25℃。
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CN115043787B (zh) * | 2022-07-20 | 2023-10-24 | 西安交通大学 | 一种2,4,5-三取代噁唑类化合物的制备方法 |
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