CN110256357A - A kind of imidazoles molecule and preparation method thereof with bactericidal activity - Google Patents
A kind of imidazoles molecule and preparation method thereof with bactericidal activity Download PDFInfo
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- CN110256357A CN110256357A CN201910292116.XA CN201910292116A CN110256357A CN 110256357 A CN110256357 A CN 110256357A CN 201910292116 A CN201910292116 A CN 201910292116A CN 110256357 A CN110256357 A CN 110256357A
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- Prior art keywords
- ethyl acetate
- imidazoles
- reaction
- organic phase
- added
- Prior art date
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- Granted
Links
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 24
- 150000002460 imidazoles Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 135
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- -1 (methyl mercapto) (methylene) (amino) ethyl Chemical group 0.000 claims abstract description 31
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- YNEHBLLUZJTDOL-UHFFFAOYSA-N 2-methoxybenzenecarbothioamide Chemical compound COC1=CC=CC=C1C(N)=S YNEHBLLUZJTDOL-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 claims abstract description 14
- MNWSGMTUGXNYHJ-UHFFFAOYSA-N 2-methoxybenzamide Chemical compound COC1=CC=CC=C1C(N)=O MNWSGMTUGXNYHJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000009833 condensation Methods 0.000 claims abstract description 12
- 230000005494 condensation Effects 0.000 claims abstract description 12
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims abstract description 11
- JUOXYWXXPHUSAI-UHFFFAOYSA-N ethylamino acetate Chemical compound CCNOC(C)=O JUOXYWXXPHUSAI-UHFFFAOYSA-N 0.000 claims abstract description 11
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 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 abstract description 11
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZEVQPQCOLBCVSA-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1h-imidazole Chemical class C1=CC(OC)=CC=C1C1=NC=CN1 ZEVQPQCOLBCVSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- WYTRYIUQUDTGSX-UHFFFAOYSA-N 1-phenylpropan-2-ol Chemical compound CC(O)CC1=CC=CC=C1 WYTRYIUQUDTGSX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000012074 organic phase Substances 0.000 claims description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- 239000012071 phase Substances 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 5
- 230000001143 conditioned effect Effects 0.000 claims description 5
- 229960004756 ethanol Drugs 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 235000002639 sodium chloride Nutrition 0.000 claims description 5
- 229960002668 sodium chloride Drugs 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 2
- 229910052710 silicon Inorganic materials 0.000 claims 2
- 239000010703 silicon Substances 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 125000001309 chloro group Chemical class Cl* 0.000 claims 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 47
- 238000010790 dilution Methods 0.000 abstract description 4
- 239000012895 dilution Substances 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 239000004327 boric acid Substances 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 229960002523 mercuric chloride Drugs 0.000 description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- CNZIQHGDUXRUJS-CIGIFLASSA-N (2R,3S,5E,9R)-5-(1-hydroxyethylidene)-8,8-dimethyl-7,16-diazapentacyclo[9.6.1.02,9.03,7.015,18]octadeca-1(17),11(18),12,14-tetraene-4,6-dione Chemical compound C\C(O)=C1\C(=O)[C@@H]2[C@@H]3[C@@H](Cc4cccc5[nH]cc3c45)C(C)(C)N2C1=O CNZIQHGDUXRUJS-CIGIFLASSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 229920003026 Acene Polymers 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- SLYYZQLLDJDQGB-UHFFFAOYSA-N C(=O)N.C1(=CC=CC=C1)OC Chemical compound C(=O)N.C1(=CC=CC=C1)OC SLYYZQLLDJDQGB-UHFFFAOYSA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108010063919 Glucagon Receptors Proteins 0.000 description 1
- 102100040890 Glucagon receptor Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229940123690 Raf kinase inhibitor Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008361 aminoacetonitriles Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000004693 imidazolium salts Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 description 1
- 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention discloses a kind of imidazoles molecule and preparation method thereof with bactericidal activity, belongs to the synthesis technical field of antibacterials.Technical solution of the present invention main points are as follows: the imidazoles molecule has structureThe present invention passes through using P-methoxybenzoic acid as starting material, N- ethyl acetate base-reacts to obtain to methoxy benzamide under condensation reagent effect with ethyl aminoacetate in elder generation, react to obtain N- ethyl acetate base-with lawesson reagent again to methoxythiobenzamide, 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate is obtained with iodomethane reaction, then 2- ((cyclization after (4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate and formamide condensation, it hydrolyzes to obtain 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid again, esterification finally occurs with methyl benzyl carbinol and obtains target compound.Antibacterial activity test is carried out by micro doubling dilution, discovery target compound has certain antibacterial action.
Description
Technical field
The invention belongs to antibacterials synthesis technical fields, and in particular to a kind of imidazoles with bactericidal activity point
Son and preparation method thereof.
Background technique
Nitrogen-containing heterocycle compound is always a hot spot in energetic material research.Imidazole ring is a kind of important five yuan and contains
Nitrogen heterocyclic, all it can be seen that imidazole fragments in many natural products and compound with pharmacological activity.Many takes
Plant growth regulator, p38MAP and B.Raf kinase inhibitor, glucagon receptor are also used as imdazole derivatives.
In addition, all containing multiple functionalized imidazole ring in the drugs such as Losartan, Candesartan, Eprosartant.In view of imidazoles
The extensive use of class compound, being efficiently synthesized polysubstituted imidazoles has important meaning to the application for expanding imidazole derivative
Justice.
Early in 1858, Germany scientist Heinrich Debus synthesized three substitutions using second diketone, formaldehyde, amine for the first time
Imidazoles ring derivatives, but its yield is lower；2008, Kaila was from amidinothiourea, elder generation and primary amine under the action of mercuric chloride
Reaction generates guanyl guanidine, then the 12h that reacts under DBU alkaline condition with bromo ketone compound, generates 1,2,4,5- tetra- and replaces
Imidazolium compounds, the reaction time is longer, and the mercuric chloride catalyst toxicity used is larger；2017, Yu etc. was devised
A kind of N substitution 2- aminoacetonitriles raw material acts on building C-C coupling with boric acid under palladium catalyst and C-N is condensed tandem reaction, conjunction
At 1,2,4,5- tetra- substituted imidazole compounds, palladium catalyst is expensive, and industrial production cost is higher.In view of triazole acene
And the extensive use of phenodiazine Miscellaneous Derivatives and imdazole derivatives in medicine, this two heterocyclic compounds is synthesized with important
Meaning.Find there is the method for largely synthesizing this two classes compound to be reported, but the step of having is cumbersome, has by literature survey
To use expensive catalyst, some by-products are more, and therefore, exploring has step simple, mild condition, Atom economy high
Synthetic method becomes particularly significant.
Due to job specification.Hospital sewage has before harmless treatment containing a large amount of pathogenic microorganisms, chemistry
Evil object and radioactive pollutant etc. have great harmfulness to ambient enviroment, are to cause pollution of waterhead and outbreaks of infectious diseases stream
Capable Potential infection source.One of the important process that monitoring is health care is carried out to the sewage of medical institutions' discharge.Research
It was found that containing a large amount of Escherichia coli and staphylococcus aureus during hospital is anhydrous, therefore study to the two bacteria inhibitions
To handling, hospital is anhydrous to be of great significance good germ killing drugs very much.
The present invention is using P-methoxybenzoic acid as starting material, by five step such as amidation, aldol condensation, molecule inner ring condensation
Reaction obtains a kind of glyoxaline compound of structure novel, and has carried out antibacterial activity survey to Escherichia coli and Staphylococcus aureus
Examination.
Summary of the invention
The imidazoles molecule and its preparation that the technical problem to be solved by the present invention is to provide a kind of with bactericidal activity
Method.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of imidazoles with bactericidal activity
Molecule, it is characterised in that the compound has the following structure:
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of imidazoles with bactericidal activity
The preparation method of molecule, it is characterised in that specific steps are as follows:
(1), P-methoxybenzoic acid reacts to obtain N- ethyl acetate base-with ethyl aminoacetate under condensation reagent effect
To methoxy benzamide；
(2), N- ethyl acetate base-reacts to obtain with lawesson reagent N- ethyl acetate base-to first to methoxy benzamide
Oxygroup thiobenzamide；
(3), N- ethyl acetate base-obtains 2- (((4- methoxybenzene) to methoxythiobenzamide and iodomethane reaction
(methyl mercapto) (methylene) (amino) ethyl acetate；
(4), 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate and formamide condensation after cyclization,
It hydrolyzes to obtain 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid again；
(5), 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid and a methyl benzyl carbinol generation esterification obtain target
Compound.
It further limits, the detailed process of step (1) are as follows: P-methoxybenzoic acid, ethyl aminoacetate and a certain amount of
Condensation reagent be added in certain solvent, after mixing evenly under nitrogen protection, reacted under room temperature to methoxybenzene
Saturated sodium chloride solution washing reaction liquid is added into reaction solution, separates organic phase, water phase after mixing evenly for formic acid fully reacting
Glacial acetic acid is added and adjusts pH to neutrality, then is extracted with dichloromethane repeatedly, merges organic phase, is concentrated under reduced pressure, residue is passed through
Silica gel column chromatography is purified to obtain N- ethyl acetate base-to methoxy benzamide；The condensation reagent is O- benzo three
Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester or I-hydroxybenzotriazole；The solvent is methylene chloride or acetonitrile；
The inventory molar ratio of the P-methoxybenzoic acid and ethyl aminoacetate and condensation reagent is 1:1.1:1~1.5.
It further limits, the detailed process of step (2) are as follows: a certain amount of N- ethyl acetate base-to methoxybenzoyl
Amine and lawesson reagent are added in reaction dissolvent, are heated to certain temperature, are concentrated under reduced pressure under the conditions of ventilating system is good, so
After saturated sodium chloride solution is added, add methylene chloride after mixing evenly, continue stirring a period of time, separate organic phase, will
Residue is purified to obtain N- ethyl acetate base-to methoxythiobenzamide by column chromatography；The reaction dissolvent
For tetrahydrofuran or toluene；Inventory molar ratio of the N- ethyl acetate base-to methoxy benzamide and lawesson reagent
For 1:0.7；The reaction temperature is 60~80 DEG C.
Further limit, the detailed process of step (3) are as follows: N- ethyl acetate base-to methoxythiobenzamide and
Dehydrated alcohol is added in a certain amount of alkali compounds, and the ethanol solution dissolved with iodomethane is slowly added dropwise in certain reaction temperature, drips
It is stirred to react a period of time after adding, is washed with distilled water mixed liquor, then is extracted with ethyl acetate respectively repeatedly, merges organic
Phase, organic phase are washed twice by saturated sodium chloride solution, separate organic phase, obtained organic phase is done with anhydrous sodium sulfate
Dry, concentration, residue is purified to obtain 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (ammonia by silica gel column chromatography
Base) ethyl acetate；The alkali compounds is sodium methoxide, sodium ethoxide or potassium tert-butoxide；The N- ethyl acetate base-is to first
The inventory molar ratio of oxygroup thiobenzamide and alkali compounds and iodomethane is 1:1~1.2:3；The reaction temperature
It is -15~-10 DEG C.
Further limit, the detailed process of step (4) are as follows: in the reaction flask with stirring as under the conditions of -60 DEG C, nitrogen
Under the conditions of gas shielded, a certain amount of 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate and formamide
It is added in tetrahydrofuran, then the tetrahydrofuran solution dissolved with a certain amount of catalyst is added dropwise, it is anti-to raw material in -60 DEG C of conditioned responses
After answering completely, restore to room temperature, be extracted with ethyl acetate respectively repeatedly, merges organic phase, organic phase reduced pressure；In 0 DEG C of item
Under part, into concentrate, it is 2 or so that the hydrochloric acid that 2N is added dropwise, which adjusts reaction solution pH, and sodium chloride and water is added, adds sodium bicarbonate
Adjusting reaction solution pH is 6 to 7, and the sodium hydroxide solution that mass fraction is 10% is added dropwise, and room temperature reaction, pH is no more than 8；TLC prison
Raw material fully reacting is controlled, is cooled to -10 DEG C, is filtered after being stirred to react uniformly, obtains 2- (4- methoxyphenyl) -1H- imidazoles -4-
Carboxylic acid；The catalyst is two (trimethyl silicon substrate) Sodamides, double-(trimethyl silicon substrate) amine lithium or double-(trimethyl silicon substrate)
Potassamide；The 2- be (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate and formamide and catalyst
Inventory molar ratio is 1:2:2.
It further limits, the detailed process of step (5) are as follows: 2- (4- methoxyphenyl) -1H- miaow is added in reaction flask
Azoles -4- carboxylic acid and thionyl chloride are stirred to react a period of time at room temperature, are then evaporated off under vacuum condition again unreacted
Thionyl chloride adds methylene chloride, under the conditions of 10 DEG C, is added dropwise into reaction solution dissolved with a certain amount of methyl benzyl carbinol
Dichloromethane solution, the reaction was continued after dripping to raw material fully reacting, and water is added into reaction solution, after mixing evenly, separates
Organic phase, water phase are extracted with dichloromethane repeatedly again, merge organic phase, obtain after concentration and are recrystallized to give target chemical combination in methyl alcohol
Object；The inventory molar ratio of 2- (4- the methoxyphenyl) -1H- imidazoles -4- carboxylic acid and methyl benzyl carbinol is 1:1.
The invention has the benefit that the present invention has synthesized a kind of imidazoles point of structure novel by new method
Son, and antibacterial activity test discovery target compound is carried out with good antibacterial action by micro doubling dilution.
Detailed description of the invention
The nucleus magnetic hydrogen spectrum of Fig. 1 target compound
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In the reaction flask with blender, P-methoxybenzoic acid 15g, ethyl aminoacetate 11g and O- benzo three
Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester 48g is added in methylene chloride 300mL, is protected after mixing evenly in nitrogen
Under shield, 3.5h is reacted under room temperature, saturated sodium chloride solution 200mL washing reaction liquid is added into reaction solution, stirs 10min
After separate organic phase, water phase is added glacial acetic acid and adjusts pH to neutrality, then repeatedly with methylene chloride 100mL extraction, merging organic phase,
It is concentrated under reduced pressure, residue is purified into (eluant, eluent, petroleum ether: ethyl acetate=5:1) by silica gel column chromatography and obtains N- second
Acetoacetic ester base-is to methoxy benzamide 12.1g；1H NMR(400MHz,DMSO-d6): δ 8.47 (s, 1H), 7.74 (d, J=
8.0Hz,2H),6.93(dd,J1=8.0Hz, J2=4.0Hz, 2H), 4.20-4.14 (m, 4H), 3.77 (s, 3H), 1.24 (t, J1
=4.0Hz, J2=4.0Hz, 3H)13C NMR(101MHz,DMSO-d6):δ171.1,166.9,162.4,128.2,125.7,
113.8,61.5,54.8,41.7,14.1。
Embodiment 2
In the reaction flask with blender, P-methoxybenzoic acid 15g, ethyl aminoacetate 11g and O- benzo three
Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester 48g is added in acetonitrile 300mL, after mixing evenly under nitrogen protection,
2h is reacted under room temperature, saturated sodium chloride solution 200mL washing reaction liquid is added into reaction solution, is separated after stirring 10min
Organic phase, it is dense to neutrality, then, merging organic phase multiple with methylene chloride 200mL extraction, decompression that water phase addition glacial acetic acid adjusts pH
Residue is purified (eluant, eluent, petroleum ether: ethyl acetate=5:1) by silica gel column chromatography and obtains N- ethyl acetate by contracting
Base-is to methoxy benzamide 16.5g；1H NMR(400MHz,DMSO-d6): δ 8.47 (s, 1H), 7.74 (d, J=8.0Hz,
2H),6.93(dd,J1=8.0Hz, J2=4.0Hz, 2H), 4.20-4.14 (m, 4H), 3.77 (s, 3H), 1.24 (t, J1=
4.0Hz,J2=4.0Hz, 3H)13C NMR(101MHz,DMSO-d6):δ171.1,166.9,162.4,128.2,125.7,
113.8,61.5,54.8,41.7,14.1。
Embodiment 3
In the reaction flask with blender, P-methoxybenzoic acid 15g, ethyl aminoacetate 11g and EDCHCl
20g and I-hydroxybenzotriazole 20g are added in acetonitrile 400mL, after mixing evenly under nitrogen protection, are reacted under room temperature
5.2h, TLC monitor P-methoxybenzoic acid fully reacting, and saturated sodium chloride solution 200mL washing reaction is added into reaction solution
Liquid separates organic phase after stirring 10min, and water phase is added glacial acetic acid and adjusts pH to neutrality, then more with methylene chloride 200mL extraction
It is secondary, merge organic phase, be concentrated under reduced pressure, residue is purified into (eluant, eluent, petroleum ether: ethyl acetate by silica gel column chromatography
=5:1) N- ethyl acetate base-is obtained to methoxy benzamide 21.2g；1H NMR(400MHz,DMSO-d6):δ8.47(s,
1H), 7.74 (d, J=8.0Hz, 2H), 6.93 (dd, J1=8.0Hz, J2=4.0Hz, 2H), 4.20-4.14 (m, 4H), 3.77
(s,3H),1.24(t,J1=4.0Hz, J2=4.0Hz, 3H)13C NMR(101MHz,DMSO-d6):δ171.1,166.9,
162.4,128.2,125.7,113.8,61.5,54.8,41.7,14.1。
Embodiment 4
In the reaction flask with blender, P-methoxybenzoic acid 15g, ethyl aminoacetate 11g and EDCHCl
20g and I-hydroxybenzotriazole 13g are added in acetonitrile 400mL, after mixing evenly under nitrogen protection, are reacted under room temperature
Saturated sodium chloride solution 200mL washing reaction liquid is added into reaction solution by 5.2h, separates organic phase after stirring 10min, water phase adds
Enter glacial acetic acid and adjust pH to neutrality, then repeatedly with methylene chloride 200mL extraction, merge organic phase, reduced pressure passes through residue
It crosses silica gel column chromatography and is purified (eluant, eluent, petroleum ether: ethyl acetate=5:1) and obtain N- ethyl acetate base-to methoxybenzene
Formamide 17.7g；1H NMR(400MHz,DMSO-d6): δ 8.47 (s, 1H), 7.74 (d, J=8.0Hz, 2H), 6.93 (dd, J1
=8.0Hz, J2=4.0Hz, 2H), 4.20-4.14 (m, 4H), 3.77 (s, 3H), 1.24 (t, J1=4.0Hz, J2=4.0Hz,
3H).13C NMR(101MHz,DMSO-d6):δ171.1,166.9,162.4,128.2,125.7,113.8,61.5,54.8,
41.7,14.1。
Embodiment 5
In reaction flask, N- ethyl acetate base-is added to tetrahydro to methoxy benzamide 24g and lawesson reagent 28g
Furans 200mL, heating reflux reaction 2.5h, (lawesson reagent by-product has for reduced pressure under the conditions of ventilating system is good
Stench), saturated sodium chloride solution 130mL is then added, adds methylene chloride 100mL after mixing evenly, continues to stir
10min separates organic phase, by residue by column chromatography purified (silicagel column, eluant, eluent, petroleum ether: ethyl acetate=3:
1) N- ethyl acetate base-, is obtained to methoxythiobenzamide 18.5g；MS(ESI)m/z:254.3(M+H+)。
Embodiment 6
In reaction flask, N- ethyl acetate base-is added to toluene to methoxy benzamide 24g and lawesson reagent 28g
200mL is heated to 80 DEG C of reaction 1h, and (lawesson reagent by-product, which has, dislikes for reduced pressure under the conditions of ventilating system is good
It is smelly), saturated sodium chloride solution 130mL is then added, adds methylene chloride 100mL after mixing evenly, continues to stir 10min,
Organic phase is separated, residue is purified into (silicagel column, eluant, eluent, petroleum ether: ethyl acetate=3:1) by column chromatography, is obtained
To N- ethyl acetate base-to methoxythiobenzamide 21.6g；MS(ESI)m/z:254.3(M+H+)。
Embodiment 7
In the reaction flask with blender, N- ethyl acetate base-to methoxythiobenzamide 25g and sodium ethoxide
Dehydrated alcohol 180mL is added in 7g, and temperature of reaction system is down to -15~-10 DEG C, and the ethyl alcohol being slowly added dropwise dissolved with iodomethane 43g is molten
Liquid 200mL is stirred to react 3h after dripping, with distilled water 100mL cleaning mixture, then respectively with ethyl acetate 60mL extraction three
It is secondary, merge organic phase, organic phase is washed twice by saturated sodium-chloride 50mL solution, separates organic phase, the organic phase that will be obtained
It is dry with anhydrous sodium sulfate, concentration, residue purified by silica gel column chromatography (eluant, eluent, petroleum ether: ethyl acetate=7:
1) 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate 19.4g, is obtained；1H NMR(400MHz,
DMSO-d6): δ 7.71 (d, J=8.0Hz, 2H), 6.97 (dd, J1=8.0Hz, J2=4.0Hz, 2H), 4.26 (s, 2H), 4.19
(dd,J1=8.0Hz, J2=8.0Hz, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 1.24 (t, J1=4.0Hz, J2=4.0Hz,
3H),MS(ESI)m/z:268.4(M+H+)。
Embodiment 8
In the reaction flask with blender, N- ethyl acetate base-to methoxythiobenzamide 25g and sodium methoxide
Dehydrated alcohol 180mL is added in 5.5g, and temperature of reaction system is down to -15~-10 DEG C, the ethyl alcohol dissolved with iodomethane 43g is slowly added dropwise
Solution 200mL is stirred to react 3h after dripping, and is extracted with distilled water 100mL cleaning mixture, then respectively with ethyl acetate 60mL
Three times, merge organic phase, organic phase is washed twice by saturated sodium-chloride 50mL solution, separates organic phase, organic by what is obtained
It is mutually dry with anhydrous sodium sulfate, concentration, residue purified by silica gel column chromatography (eluant, eluent, petroleum ether: ethyl acetate=
7:1), 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate 14.9g is obtained；1H NMR(400MHz,
DMSO-d6): δ 7.71 (d, J=8.0Hz, 2H), 6.97 (dd, J1=8.0Hz, J2=4.0Hz, 2H), 4.26 (s, 2H), 4.19
(dd,J1=8.0Hz, J2=8.0Hz, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 1.24 (t, J1=4.0Hz, J2=4.0Hz,
3H),MS(ESI)m/z:268.4(M+H+)。
Embodiment 9
In the reaction flask with blender, N- ethyl acetate base-to methoxythiobenzamide 25g and the tert-butyl alcohol
Dehydrated alcohol 180mL is added in potassium 11g, and temperature of reaction system is down to -15~-10 DEG C, the ethyl alcohol dissolved with iodomethane 43g is slowly added dropwise
Solution 200mL, is stirred to react 3h after dripping, TLC monitors raw material fully reacting, with distilled water 100mL cleaning mixture, then divides
Not Yong ethyl acetate 60mL extraction three times, merge organic phase, organic phase is washed twice by saturated sodium-chloride 50mL solution, is separated
Organic phase, obtained organic phase is dry with anhydrous sodium sulfate, and concentration, residue is purified (elution by silica gel column chromatography
Agent, petroleum ether: ethyl acetate=7:1), obtain 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate
22.5g；1H NMR(400MHz,DMSO-d6): δ 7.71 (d, J=8.0Hz, 2H), 6.97 (dd, J1=8.0Hz, J2=4.0Hz,
2H),4.26(s,2H),4.19(dd,J1=8.0Hz, J2=8.0Hz, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 1.24 (t, J1
=4.0Hz, J2=4.0Hz, 3H), MS (ESI) m/z:268.4 (M+H+)。
Embodiment 10
In the reaction flask with blender, N- ethyl acetate base-to methoxythiobenzamide 25g and the tert-butyl alcohol
Dehydrated alcohol 180mL is added in potassium 13.5g, and temperature of reaction system is down to -15~-10 DEG C, the second dissolved with iodomethane 43g is slowly added dropwise
Alcoholic solution 200mL, is stirred to react 3h after dripping, TLC monitors raw material fully reacting, with distilled water 100mL cleaning mixture, then
Respectively three times with ethyl acetate 60mL extraction, merging organic phase, organic phase is washed twice by saturated sodium-chloride 50mL solution, point
From organic phase, obtained organic phase is dry with anhydrous sodium sulfate, and concentration, residue is purified by silica gel column chromatography and (is washed
De- agent, petroleum ether: ethyl acetate=7:1), obtain 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate
25.1g；1H NMR(400MHz,DMSO-d6): δ 7.71 (d, J=8.0Hz, 2H), 6.97 (dd, J1=8.0Hz, J2=4.0Hz,
2H),4.26(s,2H),4.19(dd,J1=8.0Hz, J2=8.0Hz, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 1.24 (t, J1
=4.0Hz, J2=4.0Hz, 3H), MS (ESI) m/z:268.4 (M+H+)。
Embodiment 11
In the reaction flask with stirring as under the conditions of -60 DEG C, under the conditions of nitrogen protection, 2- (((4- methoxybenzene)
(methyl mercapto) (methylene) (amino) ethyl acetate 27g and formamide 9g are added in tetrahydrofuran 120mL, then are added dropwise dissolved with two
The tetrahydrofuran solution 200mL of (trimethyl silicon substrate) Sodamide 37g has been reacted in -60 DEG C of conditioned response 7h, TLC monitoring raw materials
Quan Hou restores to merge organic phase respectively three times with ethyl acetate 120mL extraction to room temperature, and organic phase is concentrated under reduced pressure；In 0 DEG C of item
Under part, into concentrate, it is 2 or so that the hydrochloric acid that 2N is added dropwise, which adjusts reaction solution pH, and sodium chloride 20g is added, adds water 250mL,
It is 6 to 7 that sodium bicarbonate, which is added, and adjusts reaction solution pH, the sodium hydroxide solution that mass fraction is 10% is added dropwise, room temperature reaction, pH is not
More than 8；TLC monitors raw material fully reacting, is cooled to -10 DEG C, filters after being stirred to react 1h, obtains 2- (4- methoxyphenyl) -
1H- imidazoles -4- carboxylic acid 13.6g；Elemental analysis calculated value [C11H10N2O3]:C,60.55；H,4.62；N, 12.84. measured value: C,
60.39；H,4.71；N,12.75.
Embodiment 12
In the reaction flask with stirring as under the conditions of -60 DEG C, under the conditions of nitrogen protection, 2- (((4- methoxybenzene)
(methyl mercapto) (methylene) (amino) ethyl acetate 27g and formamide 9g are added in tetrahydrofuran 120mL, then be added dropwise dissolved with
The tetrahydrofuran solution 200mL of double-(trimethyl silicon substrate) amine lithium 33g (0.2mol), it is former in -60 DEG C of conditioned response 7h, TLC monitoring
After expecting fully reacting, restore to merge organic phase respectively three times with ethyl acetate 120mL extraction to room temperature, organic phase decompression is dense
Contracting；Under the conditions of 0 DEG C, into concentrate, it is 2 or so that the hydrochloric acid that 2N is added dropwise, which adjusts reaction solution pH, addition sodium chloride 20g, then plus
Enter water 250mL, it is 6 to 7 that sodium bicarbonate, which is added, and adjusts reaction solution pH, and the sodium hydroxide solution that mass fraction is 10%, room is added dropwise
Temperature reaction, pH are no more than 8；TLC monitors raw material fully reacting, is cooled to -10 DEG C, filters after being stirred to react 1h, obtains 2- (4- first
Phenyl) -1H- imidazoles -4- carboxylic acid 19.7g；Elemental analysis calculated value [C11H10N2O3]:C,60.55；H,4.62；N,
12.84. measured value: C, 60.39；H,4.71；N,12.75.
Embodiment 13
In the reaction flask with stirring as under the conditions of -60 DEG C, under the conditions of nitrogen protection, 2- (((4- methoxybenzene)
(methyl mercapto) (methylene) (amino) ethyl acetate 27g and formamide 9g are added in tetrahydrofuran 120mL, then be added dropwise dissolved with
The tetrahydrofuran solution 200mL of double-(trimethyl silicon substrate) potassamide 40g (0.2mol), in -60 DEG C of conditioned response 7h, TLC monitoring
After raw material fully reacting, restore to merge organic phase respectively three times with ethyl acetate 120mL extraction to room temperature, organic phase decompression is dense
Contracting；Under the conditions of 0 DEG C, into concentrate, it is 2 or so that the hydrochloric acid that 2N is added dropwise, which adjusts reaction solution pH, addition sodium chloride 20g, then plus
Enter water 250mL, it is 6 to 7 that sodium bicarbonate, which is added, and adjusts reaction solution pH, and the sodium hydroxide solution that mass fraction is 10%, room is added dropwise
Temperature reaction, pH are no more than 8；TLC monitors raw material fully reacting, is cooled to -10 DEG C, filters after being stirred to react 1h, obtains 2- (4- first
Phenyl) -1H- imidazoles -4- carboxylic acid 15.3g；Elemental analysis calculated value [C11H10N2O3]:C,60.55；H,4.62；N,
12.84. measured value: C, 60.39；H,4.71；N,12.75.
Embodiment 14
2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid 22g and thionyl chloride 100mL are added in reaction flask, in room
It is stirred to react 1h under the conditions of temperature, unreacted thionyl chloride is then evaporated off under vacuum condition again, adds methylene chloride 130mL,
Under the conditions of 10 DEG C, it is added dropwise into reaction solution dissolved with a dichloromethane solution 100mL of methyl benzyl carbinol 14g, drips subsequent
Continuous reaction 30min, TLC monitor raw material fully reacting, and water 100mL is added into reaction solution and separates organic phase after mixing evenly,
Water phase uses methylene chloride 50mL extraction repeatedly again, merges organic phase, obtains after concentration and is recrystallized to give target compound in methyl alcohol
27.5g；1H NMR(400MHz,DMSO-d6): δ 8.49 (s, 1H, NH-1H), 8.37 (s, 1H, CH-H), 8.17 (d, J=
8.0Hz,2H,Ar-2H),7.18(t,J1=8.0Hz, J2=8.0Hz, 1H, Ar-1H), 7.07-6.99 (m, 5H, Ar-5H),
3.81(s,3H,OCH3-3H),3.46(dd,J1=8.0Hz, J2=4.0Hz, 2H, CH2-2H),2.79(dd,J1=8.0Hz, J2
=4.0Hz, 2H, CH2-2H),2.28(s,3H,CH3-3H).MS(ESI)m/z:337.5(M+H+)；Elemental analysis calculated value
[C20H20N2O3]:C,71.41；H,5.99；N, 8.33. measured value: C, 71.09；H,5.93；N,8.51.
Embodiment 15
Antibacterial activity test
It is to shine the positive with Norfloxacin, using micro doubling dilution measurement target compound to staphylococcus aureus
With Escherichia coli antibacterial activity.Compound to be measured is dissolved in dimethyl sulfoxide, with micropipettor in 96 well culture plates
Upper two times of gradient dilution samples obtain the different quality strength solution of 0.125~128ug/mL, and bacterium solution, bacterial concentration 5 is added
×105CFU/mL.It is cultivated at 37 DEG C for 24 hours, record is as a result, if having bacterium growth orifice plate bottom to have a white precipitate, on 96 orifice plates
Not having concentration corresponding to last hole of precipitating in horizontally-arranged is just the MIC value of the medicine.
As can be seen from the above table, target compound is to the function and effect of Escherichia coli since the effect of Staphylococcus aureus is imitated
Fruit.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (8)
1. a kind of imidazoles molecule and preparation method thereof with bactericidal activity, it is characterised in that the imidazoles molecule
Structure are as follows:
2. the imidazoles molecule according to claim 1 with bactericidal activity, it is characterised in that the imidazoles
The specific preparation step of molecule are as follows:
(1), P-methoxybenzoic acid reacts to obtain N- ethyl acetate base-to first under condensation reagent effect with ethyl aminoacetate
Oxybenzamide；
(2), N- ethyl acetate base-reacts to obtain with lawesson reagent N- ethyl acetate base-to methoxyl group to methoxy benzamide
Thiobenzamide；
(3), N- ethyl acetate base-obtains 2- (((4- methoxybenzene) (first to methoxythiobenzamide and iodomethane reaction
Sulfenyl) (methylene) (amino) ethyl acetate；
(4), 2- ((cyclization after (4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate and formamide condensation, then water
Solution obtains 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid；
(5), 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid and a methyl benzyl carbinol generation esterification obtain target chemical combination
Object.
3. a kind of preparation method of imidazoles molecule with bactericidal activity according to claim 2, feature exist
Detailed process in step (1) are as follows: P-methoxybenzoic acid, ethyl aminoacetate and a certain amount of condensation reagent are added to one
Determine in solvent, after mixing evenly under nitrogen protection, is reacted under room temperature to P-methoxybenzoic acid fully reacting, Xiang Fanying
Saturated sodium chloride solution washing reaction liquid is added in liquid, separates organic phase after mixing evenly, water phase be added glacial acetic acid adjust pH to
Neutrality, then be extracted with dichloromethane repeatedly, merge organic phase, be concentrated under reduced pressure, residue is purified by silica gel column chromatography
N- ethyl acetate base-is obtained to methoxy benzamide；The condensation reagent is O- benzotriazole-N, N, N', N'- tetramethyl
Base urea tetrafluoro boric acid ester or I-hydroxybenzotriazole；The solvent is methylene chloride or acetonitrile；The P-methoxybenzoic acid
It is 1:1.1:1~1.5 with the inventory molar ratio of ethyl aminoacetate and condensation reagent.
4. a kind of preparation method of imidazoles molecule with bactericidal activity according to claim 2, feature exist
It can in the detailed process of step (2) are as follows: methoxy benzamide and lawesson reagent is added in a certain amount of N- ethyl acetate base-
Into reaction dissolvent, it is heated to certain temperature, is concentrated under reduced pressure under the conditions of ventilating system is good, saturated sodium-chloride is then added
Solution adds methylene chloride after mixing evenly, continues stirring a period of time, separates organic phase, and residue is chromatographed by column
Purified to obtain N- ethyl acetate base-to methoxythiobenzamide；The reaction dissolvent is tetrahydrofuran or toluene；
The N- ethyl acetate base-is 1:0.7 to the inventory molar ratio of methoxy benzamide and lawesson reagent；The reaction
Temperature is 60~80 DEG C.
5. a kind of preparation method of imidazoles molecule with bactericidal activity according to claim 2, feature exist
Detailed process in step (3) are as follows: N- ethyl acetate base-to methoxythiobenzamide and a certain amount of alkali compounds
Dehydrated alcohol is added, is stirred to react one section after certain reaction temperature is slowly added dropwise the ethanol solution dissolved with iodomethane, drips
Time is washed with distilled water mixed liquor, then is extracted with ethyl acetate respectively repeatedly, merges organic phase, organic phase is through supersaturated chlorine
Change sodium solution to wash twice, separate organic phase, obtained organic phase is dry with anhydrous sodium sulfate, and concentration, residue passes through silicon
Plastic column chromatography is purified to obtain 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate；The alkalinity
Compound is sodium methoxide, sodium ethoxide or potassium tert-butoxide；The N- ethyl acetate base-is to methoxythiobenzamide and alkalinity
The inventory molar ratio of compound and iodomethane is 1:1~1.2:3；The reaction temperature is -15~-10 DEG C.
6. a kind of preparation method of imidazoles molecule with bactericidal activity according to claim 2, feature exist
Detailed process in step (4) are as follows: in the reaction flask with stirring as under the conditions of -60 DEG C, under the conditions of nitrogen protection, one
Quantitative 2- (((4- methoxybenzene) (methyl mercapto) (methylene) (amino) ethyl acetate and formamide are added in tetrahydrofuran,
The tetrahydrofuran solution dissolved with a certain amount of catalyst is added dropwise again, after -60 DEG C of conditioned responses to raw material fully reacting, restores to room
Temperature is extracted with ethyl acetate repeatedly respectively, merges organic phase, and organic phase is concentrated under reduced pressure；Under the conditions of 0 DEG C, into concentrate, drop
Adding the hydrochloric acid of 2N to adjust reaction solution pH is 2 or so, and sodium chloride and water is added, and adds sodium bicarbonate adjusting reaction solution pH and arrives for 6
7, the sodium hydroxide solution that mass fraction is 10% is added dropwise, room temperature reaction, pH is no more than 8；It is cooled to -10 DEG C after reaction,
It is filtered after being stirred to react uniformly, obtains 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid；The catalyst is two (front threes
Base silicon substrate) Sodamide, double-(trimethyl silicon substrate) amine lithium or double-(trimethyl silicon substrate) potassamide；2- (((the 4- methoxyl group
Benzene) the inventory molar ratio of (methyl mercapto) (methylene) (amino) ethyl acetate and formamide and catalyst is 1:2:2.
7. a kind of preparation method of imidazoles molecule with bactericidal activity according to claim 2, feature exist
Detailed process in step (5) are as follows: 2- (4- methoxyphenyl) -1H- imidazoles -4- carboxylic acid is added in reaction flask and dichloro is sub-
Sulfone is stirred to react a period of time at room temperature, unreacted thionyl chloride is then evaporated off under vacuum condition again, adds two
The dichloromethane solution dissolved with a certain amount of methyl benzyl carbinol is added dropwise into reaction solution, is added dropwise under the conditions of 10 DEG C for chloromethanes
The reaction was continued after complete to raw material fully reacting, and water is added into reaction solution, after mixing evenly, separates organic phase, water phase uses two again
Chloromethanes extraction repeatedly, merges organic phase, obtains after concentration and is recrystallized to give target compound in methyl alcohol；2- (the 4- first
Phenyl) the inventory molar ratio of -1H- imidazoles -4- carboxylic acid and methyl benzyl carbinol is 1:1.
8. the antibacterial activity application of imidazoles molecule as described in claim 1.
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| CN102898425A (en) * | 2012-10-30 | 2013-01-30 | 黑龙江八一农垦大学 | 4,5-glyoxalidine [1,2-a] quinoline derivative and application of 4,5- glyoxalidine [1,2-a] quinoline derivative |
| CN106866539A (en) * | 2017-03-06 | 2017-06-20 | 黑龙江八农垦大学 | The alkyl imidazole derivative of 1 substituted-phenyl 2 and its application |
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| CN102898425A (en) * | 2012-10-30 | 2013-01-30 | 黑龙江八一农垦大学 | 4,5-glyoxalidine [1,2-a] quinoline derivative and application of 4,5- glyoxalidine [1,2-a] quinoline derivative |
| CN106866539A (en) * | 2017-03-06 | 2017-06-20 | 黑龙江八农垦大学 | The alkyl imidazole derivative of 1 substituted-phenyl 2 and its application |
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| DHAINAUT, ALAIN; TIZOT, ANDRE; RAIMBAUD, ERIC; LOCKHART, BRIAN: "Synthesis, Structure, and Neuroprotective Properties of Novel Imidazolyl Nitrones", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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