CN105218501A - 含哌嗪环的香豆素类衍生物及其制备与在抗菌药物中的应用 - Google Patents
含哌嗪环的香豆素类衍生物及其制备与在抗菌药物中的应用 Download PDFInfo
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- CN105218501A CN105218501A CN201410319763.2A CN201410319763A CN105218501A CN 105218501 A CN105218501 A CN 105218501A CN 201410319763 A CN201410319763 A CN 201410319763A CN 105218501 A CN105218501 A CN 105218501A
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- piperazine
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- piperazine ring
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 54
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 10
- 229940088710 antibiotic agent Drugs 0.000 title claims description 6
- 150000001893 coumarin derivatives Chemical class 0.000 title abstract 4
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 150000004775 coumarins Chemical class 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- VXIXUWQIVKSKSA-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000000638 solvent extraction Methods 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- -1 mono-substituted piperazine Chemical class 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims 1
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 14
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 9
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- PWZDJIUQHUGFRJ-UHFFFAOYSA-N 1-(2-chlorophenyl)piperazine Chemical group ClC1=CC=CC=C1N1CCNCC1 PWZDJIUQHUGFRJ-UHFFFAOYSA-N 0.000 description 2
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical group ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 description 2
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical group C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- UDQMXYJSNNCRAS-UHFFFAOYSA-N 2,3-dichlorophenylpiperazine Chemical group ClC1=CC=CC(N2CCNCC2)=C1Cl UDQMXYJSNNCRAS-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
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Abstract
含哌嗪环的香豆素类衍生物,它具有如下通式。实验证明,含哌嗪环的香豆素类衍生物对革兰氏阳性菌金黄色葡萄球菌(S.aureus)和枯草芽孢杆菌(B.subtilis)有一定的抑制作用,而对革兰氏阴性菌铜绿假单胞(P.aeruginosa)和大肠杆菌(E.coli)几乎没有抑制作用。因此它们有可能用于制备抗菌的药物。本发明公开了含哌嗪环的香豆素类衍生物的制法。其中R1,R2分别如图所示。
Description
技术领域
本发明涉及含哌嗪环的香豆素类衍生物及其制备与在抗菌药物中的应用。
背景技术
香豆素及其衍生物广泛应用于医药工业、香料工业和农药工业中。天然香豆素衍生物特有的生物学和生理学性质,如抗菌、抗凝血作用、抗线胺的释放和降压作用。如4-羟基香豆素类化合物能抑制凝血因子在肝脏的合成,是一种口服抗凝药物。
哌嗪是一类碱性基团,其毒性小,易形成多个氢键或离子键,常能有效地调节药物的脂水分配系数和酸碱平衡常数。将其引入分子,能有效地增加分子的碱性和水溶性,从而增强分子的活性。研究表明,含哌嗪且N-取代的化合物常显示出广泛的生物活性,如抗微生物、抗高血压、抗癌、消炎和止痛等。哌嗪化合物在抗疟、抗菌、抗结核、抗真菌和抗病毒等抗微生物领域都有较好的活性。
本发明基于香豆素的抗菌活性,对其引入不同取代基的N-单取代哌嗪进行修饰,合成出一系列含哌嗪环的香豆素类衍生物,并对它们进行抗菌活性测试。
发明内容
本发明涉及含哌嗪环的香豆素类衍生物及其制备与在抗菌药物中的应用。
本发明的技术方案如下:
一类含哌嗪环的香豆素衍生物,其特征是它有如下通式:
其中R1,R2分别为:
一种制备上述的含哌嗪环的香豆素类衍生物1-14的方法,其特征是它由下列步骤组成:
步骤1:称取一定量的4-羟基香豆素溶解在适量的乙腈里,再按一定比例往其中加入一定量的环氧氯丙烷,加入适量碳酸钾,搅拌回流反应。反应毕,减压蒸发溶剂,所得固体加水溶解,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,所得固体干燥后,直接用于下一步反应。
步骤2:称取步骤1中所得固体、N-单取代的哌嗪、碳酸铯(Cs2CO3)、按适当比例溶解在一定量的二甲基甲酰胺(DMF)中,搅拌回流反应。反应毕,趁热将反应液倒入水中,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,层析或者重结晶得到本发明的含哌嗪环的4-羟基香豆素类衍生物1-14。
一种制备上述的含哌嗪环的4香豆素类衍生物15-24的方法,其特征是它由下列步骤组成:
步骤1:称取一定量的N-单取代的哌嗪、溴乙酸、碳酸铯按适当比例溶解在一定量的DMF中,搅拌回流反应。反应毕,趁热将反应液倒入水中,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,所得固体干燥后,直接用于下一步反应。
步骤2:称取步骤1中所得固体、4-羟基香豆素、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)、1-羟基-苯并-三氮唑(HOBt)按适当比例溶解在一定量的二氯甲烷中,搅拌回流反应。反应毕,分别用水、氢氧化钠溶液和饱和食盐水依次多次洗反应液,有机层用无水硫酸钠干燥,减压蒸发溶剂,重结晶得到本发明的含哌嗪环的4-羟基香豆素类衍生物15-24。
上述制法中,步骤1中所述有机溶剂,为乙酸乙酯,石油醚,甲苯,二氯甲烷,氯仿,四氢呋喃中之一,或任意两者混合液。步骤2中所述层析,是采用200-300目柱层析硅胶柱,洗脱液为一定比例的无水乙酸乙酯和石油醚。
本发明的含哌嗪环的香豆素类衍生物对革兰氏阳性菌细菌具有明显的抑制作用。因此本发明的含哌嗪环的香豆素类衍生物可以应用于制备抗菌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:4-(2-羟基-3-(4-苯基哌嗪-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物1)的制备
称取香豆素10mmol,环氧氯丙烷12mmol,碳酸钾适量溶解在一定量的乙腈中,70-80℃下搅拌回流6-10h.反应毕,减压蒸发溶剂,所得固体加水溶解,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,所得固体干燥后,直接用于下一步反应。
称取上述中所得固体1mmol,N-苯基哌嗪1mmol,碳酸铯1mmol,溶解在5-10mlDMF中,90-100℃下搅拌回流5-10h,反应毕,趁热将反应液倒入水中,用乙酸乙酯萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,重结晶得到目标产物。产物为白色固体。产率67%,mp:80-82℃.1HNMR(400MHz,CDCl3)δ:7.59-7.86(t,J=3.98Hz,1H,ArH),7.54-7.58(m,1H,ArH),7.26-7.34(m,4H,ArH),6.91-6.96(t,J=9.58Hz,2H,ArH),6.87-6.89(d,J=7.32Hz,1H,ArH),5.72(s,1H),4.26-4.30(m,1H,CH),4.13-4.20(m,2H,CH2),3.71(s,1H,-OH),3.21-3.30(br,4H,-CH2CH2-),2.73-2.94(m,2H,CH2),2.63-2.73(br,4H,-CH2CH2-).ESI-MS:381.21(C22H25N2O4,[M+H]+),Anal.CalcdforC22H24N2O4:C,69.46;H,6.36;N,7.36%;Found:C,69.48;H,6.34;N,7.40%.
实施例二:4-(2-羟基-3-(4-苄基-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物2)的制备
制备方法同实施例一。以N-苄基哌嗪代替苯基哌嗪。产物为黄色油状物。产率48%.1HNMR(400MHz,CDCl3)δ:7.86-7.88(m,1H,ArH),7.56-7.60(m,1H,ArH),7.36-7.37(d,J=4.4Hz,5H,ArH),7.32-7.33(t,J=2.1Hz,1H,ArH),7.31(s,1H,ArH),7.28-7.30(m,1H,CH),5.73(s,1H),4.21-4.26(m,1H,OH),4.12-4.20(m,2H,CH2),3.57(s,2H,CH2),2.78(s,2H,CH2),2.64-2.67(t,J=6.16Hz,4H,-CH2CH2-),2.47-2.61(m,4H,-CH2CH2-).ESI-MS:395.15(C23H27N2O4,[M+H]+),Anal.CalcdforC23H26N2O4:C,70.03;H,6.64;N,7.10%;Found:C,70.05;H,6.62;N,7.09%.
实施例三:4-(3-(4-(2,4-二甲基苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物3)的制备
制备方法同实施例一。以N-(2,4-二甲基苯基)哌嗪代替苯基哌嗪。产物为棕色油状物。产率52%。1HNMR(400MHz,CDCl3)δ:7.85-7.87(t,J=3.96Hz,1H,ArH),7.54-7.58(m,1H,ArH),7.28-7.34(m,1H,ArH),6.93-7.01(m,3H,ArH),5.72(s,1H),4.24-4.29(m,1H,CH),4.14-4.17(m,2H,CH2),2.93-2.97(m,4H,-CH2CH2-),2.89-2.91(d,J=9.32Hz,2H,CH2),2.62-2.66(m,4H,-CH2CH2-),2.78(s,6H,2CH3).ESI-MS:409.26(C24H29N2O4,[M+H]+).Anal.CalcdforC24H28N2O4:C,70.57;H,6.91;N,6.86%;Found:C,70.57;H,6.92;N,6.88%.
实施例四:4-(2-羟基-3-(4-(4-硝基苯基)哌嗪-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物4)的制备
制备方法同实施例一。以N-(4-硝基苯基)哌嗪代替苯基哌嗪。产物为黄色固体。产率58%。mp:170-172℃.1HNMR(400MHz,CDCl3)δ:8.19-8.21(d,J=9.32Hz,2H,ArH),7.87-7.89(d,J=8.08Hz,1H,ArH),7.39(s,1H,ArH),7.36-7.37(d,J=4.92Hz,2H,ArH),6.90-6.92(d,J=9.24Hz,2H,ArH),5.78(s,1H);4.41-4.43(d,J=9.2Hz,1H,CH),4.23-4.24(d,J=4.48Hz,2H,CH2),3.60(s,4H,-CH2CH2-),3.02(s;2H,CH2),2.85(s,4H,-CH2CH2-).ESI-MS:426.22(C22H24N3O6,[M+H]+).Anal.CalcdforC22H23N3O6:C,62.11;H,5.45;N,9.88%;Found:C,62.12;H,5.43;N,9.89%.
实施例五:4-(2-羟基-3-(4-(2-甲氧基苯基)哌嗪-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物5)的制备
制备方法同实施例一。以N-(2-甲氧基苯基)哌嗪代替苯基哌嗪。产物为棕色油状物。产率43%。1HNMR(400MHz,CDCl3)δ:7.89(s,1H,ArH),7.56-7.89(m,1H,ArH),7.29-7.35(m,3H,ArH),7.20-7.24(t,J=8.16Hz,1H,ArH),6.58-6.60(m,1H,CH),6.46-6.51(m,2H,ArH),5.75(s,1H),4.23-4.33(m,1H,OH),4.13-4.23(m,2H,CH2),3.83(s,3H,CH3),3.22-3.31(m,4H,-CH2CH2-),2.88-2.93(m,2H,CH2),2.62-2.74(m,4H,-CH2CH2-).ESI-MS:411.12(C23H27N2O5,[M+H]+).Anal.CalcdforC23H26N2O5:C,67.30;H,6.38;N,6.82%;Found:C,67.33;H,6.35;N,6.84%.
实施例六:4-(2-羟基-3-(4-(3-甲氧基苯基)哌嗪-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物6)的制备
制备方法同实施例一。以N-(3-甲氧基苯基)哌嗪代替苯基哌嗪。产物为白色粉末状固体。产率61%。mp:208-210℃.1HNMR(400MHz,CDCl3)δ:7.87-7.89(d,J=7.6Hz,1H,ArH),7.55-7.59(t,J=7.44Hz,1H,ArH),7.19-7.34(m,3H,ArH),6.46-6.59(m,3H,ArH),5,75(s,1H),4.29-4.30(d,J=3.96Hz,1H,CH),4.15-4.19(t,J=7.98Hz,2H,CH2),3.82(s,3H,CH3),3.26(s,4H,-CH2CH2-,),2.88-2.89(d,J=4.28Hz,2H,CH2),2.66-2.70(t,J=8.28Hz,4H,-CH2CH2-).ESI-MS:411.12(C23H27N2O5,[M+H]+).Anal.CalcdforC23H26N2O5:C,67.30;H,6.38;N,6.82%;Found:C,67.32;H,6.40;N,6.80%.
实施例七:4-(2-羟基-3-(4-(4-甲氧基苯基)哌嗪-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物7)的制备
制备方法同实施例一。以N-(4-甲氧基苯基)哌嗪代替苯基哌嗪。产物为棕色粉末状固体。产率43%。mp:120-122℃.1HNMR(400MHz,CDCl3)δ:7.89-7.91(m,1H,ArH);7.58-7.62(m,1H,ArH);7.33-7.38(m,2H,ArH);6.94-6.97(m,2H,ArH);6.90-6.91(d,J=2.36Hz,2H,ArH);6.89(s,1H,CH);5.76(s,1H);4.35-4.38(m,1H,OH);4.20-4.24(m,2H,CH2);3.81-3.82(d,J=3.84Hz,4H,-CH2CH2-);3.20-3.24(m,4H,-CH2CH2-);2.99-3.02(m,2H,CH2);2.73-2.82(m,3H,CH3).ESI-MS:411.12(C23H27N2O5,[M+H]+).Anal.CalcdforC23H26N2O5:C,67.30;H,6.38;N,6.82%;Found:C,67.30;H,6.37;N,6.84%.
实施例八:4-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物8)的制备
制备方法同实施例一。以N-(2,3-二氯苯基)哌嗪代替苯基哌嗪。产物为黄色粉末状固体。产率55%。Mp:176-178℃.1HNMR(400MHz,CDCl3)δ:7.89-7.91(d,J=7.84Hz,1H,ArH),7.59-7.63(t,J=7.78Hz,1H,ArH),7.33-7.39(m,2H,ArH),7.21-7.23(d,J=6.88Hz,2H,ArH),7.01-7.03(t,J=3.4Hz,1H,ArH),5.77(s,1H),4.31-4.34(m,1H,CH),4.21-4.22(d,J=4.96Hz,2H,CH2),3.78(s,1H,OH),3.17-3.22(t,J=2.32Hz,4H,-CH2CH2-);2.99(s,2H,CH2),2.73-2.78(m,4H,-CH2CH2-).ESI-MS:449.15(C22H23C12N2O4,[M+H]+).Anal.CalcdforC22H22C12N2O4:C,58.81;H,4.94;N,6.23%;Found:C,58.80;H,4.95;N,6.22%.
实施例九:4-(3-(4-(3,4-二氯苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物9)的制备
制备方法同实施例一。以N-(3,4-二氯苯基)哌嗪代替苯基哌嗪。产物为棕色粉末状固体。产率62%。Mp:82-85℃.1HNMR(400MHz,CDCl3)δ:7.88-7.90(d,J=7.84Hz,1H),7.59-7.63(m,1H,ArH),7.32-7.38(m,3H,ArH),7.01(d,J=2.72Hz,1H,ArH),6.78-6.81(m,1H,ArH),5.76(s,1H),4.30-4.34(m,1H,CH),4.17-4.25(m,2H,CH2),3.68-3.75(m,1H,OH),3.25-3.29(m,4H,-CH2CH2-),2.90-2.95(m,2H,CH2),2.66-2.77(m,4H,-CH2CH2-).ESI-MS:449.15(C22H23C12N2O4,[M+H]+).Anal.CalcdforC22H22C12N2O4:C,58.81;H,4.94;N,6.23%;Found:C,58.83;H,4.91;N,6.20%.
实施例十:4-(3-(4-(2-氯苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物10)的制备
制备方法同实施例一。以N-(2-氯苯基)哌嗪代替苯基哌嗪。产物为淡黄色油状物。产率47%。1HNMR(400MHz,CDCl3)δ:7.89-7.91(m,1H,ArH),7.57-7.62(m,1H,ArH);7.40-7.42(m,1H,ArH),7.28-7.34(m,3H,ArH),7.09-7.11(m,1H,ArH),7.01-7.05(m,1H,ArH),5.76(s,1H),4.29-4.36(m,1H,CH),4.17-4.25(m,2H,CH2),3.75-3.78(t,J=4.90Hz,1H,OH),3.17(s,4H,-CH2CH2-),2.96-2.98(t,J=4.98Hz,2H,CH2),2.68-2.77(m,4H,-CH2CH2-).ESI-MS:415.21(C22H24ClN2O4,[M+H]+).Anal.CalcdforC22H23ClN2O4:C,63.69;H,5.59;N,6.75%;Found,C,63.66;H,5.61;N,6.74%.
实施例十一:4-(3-(4-(3-氯苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物11)的制备
制备方法同实施例一。以N-(3-氯苯基)哌嗪代替苯基哌嗪。产物为棕色油状物。产率51%。1HNMR(400MHz,CDCl3)δ:7.88-7.90(m,1H,ArH),7.58-7.62(m,1H,ArH),7.30-7.36(m,2H,ArH),7.20-7.24(t,J=8.1Hz,1H,ArH),6.92-6.93(t,J=2.06Hz,1H,ArH),6.78-6.89(m,2H,ArH),5.75-5.78(d,J=9.48Hz,1H),4.29-4.35(m,1H,CH),4.16-4.24(m,2H,CH2),3.67-3.68(d,J=4.2Hz,1H,OH),3.25-3.33(m,4H,-CH2CH2-),2.89-2.94(m,2H,CH2),2.65-2.77(m,4H,-CH2CH2-).ESI-MS:415.21(C22H24ClN2O4,[M+H]+).Anal.CalcdforC22H23ClN2O4:C,63.69;H,5.59;N,6.75%;Found:C,63.69;H,5.57;N,6.78%.
实施例十二:4-(3-(4-(2-氟苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物12)的制备
制备方法同实施例一。以N-(2-氟苯基)哌嗪代替苯基哌嗪。产物为黄色油状物。产率47%。1HNMR(400MHz,CDCl3)δ:7.88-7.89(d,J=7.84Hz,1H,ArH),7.57-7.61(t,J=7.72Hz,1H,ArH),7.34-7.36(d,J=9.6Hz;2H,ArH),7.08-7.13(m,2H,ArH),6.98-7.01(d,J=14.24Hz,2H,ArH),5.76(s,1H),4.30-4.31(d,j=3.72Hz,1H,CH),4.20-4.21(d,j=5.52Hz,2H,CH2),3.75(s,1H,OH),3.19-3.25(t,J=10.32Hz,4H,-CH2CH2-),2.93-2.94(d,J=4.84Hz,2H,CH2),2.70-2.75(t,J=9.32Hz,4H,-CH2CH2-).ESI-MS:399.07(C22H24FN2O4,[M+H]+).Anal.CalcdforC22H23FN2O4:C,66.32;H,5.82;F,N,7.03%;Found:C,66.31;H,5.82;N,7.05%.
实施例十三:4-(3-(4-(4-氟苯基)哌嗪-1-基)-2-羟基丙氧基)-2H-苯并吡喃-2-酮(化合物13)的制备
制备方法同实施例一。以N-(4-氟苯基)哌嗪代替苯基哌嗪。产物为黄色油状物。产率50%。1HNMR(400MHz,CDCl3)δ:7.88-7.90(m,1H,ArH),7.57-7.61(m,1H,ArH),7.31-7.36(m,2H,ArH),7.05-7.13(m,2H,ArH),6.97-7.02(m,2H,ArH),5.76(s,1H),4.28-4.34(m,1H,CH),4.16-4.24(m,2H,CH2),3.74-3.78(m,1H,OH),3.15-3.24(m,4H,-CH2CH2-),2.92-2.97(m,2H,CH2),2.65-2.75(m,4H,-CH2CH2-).ESI-MS:399.07(C22H24FN2O4,[M+H]+).Anal.CalcdforC22H23FN2O4:C,66.32;H,5.82;N,7.03%;Found:C,66.34;H,5.79;N,7.02%.
实施例十四:4-(2-羟基-3-(4-(3-三氟甲基苯基)哌嗪-1-基)丙氧基)-2H-苯并吡喃-2-酮(化合物14)的制备
制备方法同实施例一。以N-N-(3-三氟甲基苯基)哌嗪代替苯基哌嗪。产物为黄色固体。产率52%。mp:93-96℃.1HNMR(400MHz,CDCl3)δ:7.84-7.86(m,1H,ArH),7.54-7.58(m,1H,ArH),7.29-7.38(m,3H,ArH),7.07-7.12(t,j=10.44HZ,3H,ArH),5.72(s,1H),4.25-4.30(m,1H,CH),4.13-4.4.21(m,2H,CH2),3.57-3.66(m,1H,OH),3.25-3.34(m,4H,-CH2CH2-),2.87-2.92(m,2H,CH2),2.61-2.70(m,4H,-CH2CH2-).ESI-MS:449.09(C23H24F3N2O4,[M+H]+).Anal.CalcdforC23H23F3N2O4:C,61.60;H,5.17;N,6.25%;Found:C,61.58;H,5.18;N,6.27%.
实施例十五:4-(2-(4-(4-氯苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物15)的制备
称取1mmolN-(4-氯苯基)哌嗪、1.2mmol溴乙酸、1mmol碳酸铯溶解在10mLDMF中,搅拌回流反应。反应毕,趁热将反应液倒入水中,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,所得固体干燥后,直接用于下一步反应。
称取步骤1中所得固体1mmol、4-羟基香豆素1mmol、0.5mmolHOBt、1.5mmolEDC溶解在25mL二氯甲烷中,搅拌回流反应。反应毕,分别用水、氢氧化钠溶液和饱和食盐水依次多次洗反应液,有机层用无水硫酸钠干燥,减压蒸发溶剂,重结晶得目标产物。白色固体,产率:57%。mp:173-175℃.1HNMR(400MHz,DMSO)δ:7.88-7.90(t,J=7.84Hz,1H,ArH),7.68-7.72(t,J=7.84Hz,1H,ArH),7.40-7.46(m,3H,ArH),7.31-7.33(d,J=7.4Hz,1H,ArH),7.16-7.18(d,J=7.12Hz,1H,ArH),7.09-7.11(d,J=7.72Hz,1H,ArH),5.98(s,1H),5.25(s,2H,CH2),3.62-3.66(m,4H,-CH2CH2-),2.99-3.66(t,J=11.32Hz,4H,-CH2CH2-).ESI-MS:399.13(C21H20ClN2O4,[M+H]+).Anal.CalcdforC21H19ClN2O4:C,63.24;H,4.80;N,7.02%;Found:C,63.22;H,4.81;N,7.04%.
实施例十六:4-(2-(4-(2,4-二甲基苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物16)的制备
制备方法同实施例十五。以N-(2,4-二甲基苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:66%。mp:185-188℃.1HNMR(400MHz,DMSO)δ:7.88-7.90(d,J=7.8Hz,1H,ArH),7.67-7.69(d,J=7.4Hz,1H,ArH),7.39-7.45(m,2H,ArH),6.90-7.00(m,3H,ArH),5.97(s,1H);5.24(s,2H,CH2),3.59-3.63(d,J=17.88Hz,4H,-CH2CH2-),2.79-2.85(d,J=23.56Hz,4H,-CH2CH2-),2.22-2.25(d,J=11.92Hz,6H,2CH3).ESI-MS:393.15(C23H24N2O4,[M+H]+).Anal.CalcdforC23H24N2O4:C,70.39;H,6.16;N,7.14%;Found:C,70.40;H,6.18;N,7.12%.
实施例十七:4-(2-(4-(4-硝基苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物17)的制备
制备方法同实施例十五。以N-(4-硝基苯基)哌嗪代替N-(4-氯苯基)哌嗪。黄色固体,产率:52%。mp:202-204℃.1HNMR(400MHz,DMSO)δ:8.05-8.07(d,J=8.36Hz,1H,ArH);7.91-7.93(d,J=6.88Hz,1H);7.63-7.78(d,J=8.32Hz,1H,ArH);7.52-7.63(m,1H,ArH);7.35-7.45(m,1H,ArH);7.23-7.28(m,1H,ArH);6.94-7.00(m,2H,ArH);6.82-6.85(m,1H,ArH),5.91(s,1H);3.77(s,2H,ArH);3.60-3.62(t,J=4.84Hz,4H,-CH2CH2-);3.22-3.25(t,J=5.08Hz,4H,-CH2CH2-).ESI-MS:410.21(C21H20N3O6,[M+H]+).Anal.CalcdforC21H19N3O6:C,61.61;H,4.68;N,10.26%;Found:C,61.58;H,4.65;N,10.28%.
实施例十八:4-(2-(4-(2-甲氧基苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物18)的制备
制备方法同实施例十五。以N-(2-甲氧基苯基)哌嗪代替N-(4-氯苯基)哌嗪。粉红色固体,产率:63%,mp:145-147℃.1HNMR(400MHz,DMSO)δ:7.89(s,1H,ArH),7.69(s,1H,ArH),7.43(s,2H,ArH),6.91-6.98(d,J=29.96Hz,ArH),5.96(s,1H),5.23(s,2H,CH2),3.81(s,3H,CH3),3.62(s,4H,-CH2CH2-),2.97-3.02(d,J=20.56Hz,4H,-CH2CH2-).ESI-MS:395.17(C22H23N2O5,[M+H]+).Anal.CalcdforC22H22N2O5:C,66.99;H,5.62;N,7.10%;Found:C,66.97;H,5.64;N,7.11%.
实施例十九:4-(2-(4-(3-甲氧基苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物19)的制备
制备方法同实施例十五。以N-(3-甲氧基苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:67%,mp:220-222℃.1HNMR(400MHz,DMSO)δ:7.87-7.89(d,J=7.84Hz,1H,ArH),7.67-7.71(t,J=7.8Hz,1H,ArH),7.39-7.45(m,2H,ArH),7.12-7.16(t,J=8.18Hz,1H,ArH),6.56-6.58(m,1H,ArH),6.50(s,1H,ArH),6.40-6.43(m,1H,ArH),5.97(s,1H),5.25(s,2H,CH2),3.73(s,3H,CH3),3.59-3.62(m,4H,-CH2CH2-),3.16-3.23(t,J=14.06Hz,4H,-CH2CH2-).ESI-MS:395.17(C22H23N2O5,[M+H]+).Anal.CalcdforC22H22N2O5:C,66.99;H,5.62;N,7.10%;Found:C,66.70;H,5.60,N,7.08%.
实施例二十:4-(2-(4-(4-甲氧基苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物20)的制备
制备方法同实施例十五。以N-(4-甲氧基苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:66%,mp:205-207℃.1HNMR(400MHz,DMSO)δ:7.93-7.95(m,1H,ArH),7.60-7.64(m,1H,ArH),7.35-7.39(m,2H,ArH),6.98(s,2H,ArH),6.90-6.92(d,J=8.84Hz,2H,ArH),5.73(s,1H),4.96(s,2H,CH2),3.89(s,2H,CH2),3.83(s,3H,CH3),3.72(s,2H,CH2),3.16(s,4H,-CH2CH2-).ESI-MS:395.17(C22H23N2O5,[M+H]+).Anal.CalcdforC22H22N2O5:C,66.99;H,5.62;N,7.10%;Found:C,66.97;H,5.63;N,7.11%.
实施例二十一:4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物21)的制备
制备方法同实施例十五。以N-(2,3-二氯苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:57%,mp:174-176℃.1HNMR(400MHz,DMSO)δ:7.88-7.90(m,1H,ArH),7.67-7.72(m,1H,ArH),7.40-7.45(m,2H,ArH),7.35-7.36(t,J=2.62Hz,2H,ArH),7.16-7.19(m,1H,ArH),5.98(s,1H),5.25(s,2H,CH2),3.63-3.66(m,4H,-CH2CH2-),3.00-3.06(t,J=13.2Hz,4H,-CH2CH2-).ESI-MS:433.09(C21H19Cl2N2O4,[M+H]+).Anal.CalcdforC21H18Cl2N2O4:C,58.21;H,4.19;N,6.47%;Found:C,58.20;H,4.17;N,6.48%.
实施例二十二:4-(2-(4-(2-氯苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物22)的制备
制备方法同实施例十五。以N-(2-氯苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:59%,mp:172-175℃.1HNMR(400MHz,DMSO)δ:7.88-7.90(m,1H,ArH),7.67-7.71(m,1H,ArH),7.41-7.46(m,3H,ArH),7.31-7.40(m,1H,ArH),7.16-7.18(m,1H,ArH),7.07-7.11(m,1H,ArH),5.98(s,1H),5.25(s,2H,CH2),3.63-3.66(m,4H,-CH2CH2-),3.00-3.05(t,J=11.12Hz,4H,-CH2CH2-).ESI-MS:399.13(C21H20ClN2O4,[M+H]+).Anal.CalcdforC21H19ClN2O4:C,63.24;H,4.80;N,7.02%;Found:C,63.26;H,4.76;N,7.01%.
实施例二十三:4-(2-(4-(3-氯苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物23)的制备
制备方法同实施例十五。以N-(3-氯苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:63%,mp:197-199℃.1HNMR(400MHz,DMSO)δ:7.87(d,J=1.44Hz,1H,ArH),7.67-7.72(m,1H,ArH),7.40-7.45(m,2H,ArH),7.07-7.11(t,J=8.86Hz,2H,ArH),6.99-7.02(m,2H,ArH),5.97(s,1H),5.24(s,2H,CH2),3.60-3.64(m,4H,-CH2CH2-);3.10-3.17(t,J=14.36Hz,4H,-CH2CH2-).ESI-MS:399.13(C21H20ClN2O4,[M+H]+).Anal.CalcdforC21H19ClN2O4:C,63.24;H,4.80;N,7.02%;Found:C,63.22,H,4.76,N,7.05%.
实施例二十四:4-(2-(4-(3-三氟甲基苯基)哌嗪-1-基)-2-氧代乙氧基)-2H-苯并吡喃-2-酮(化合物24)的制备
制备方法同实施例十五。以N-(3-三氟甲基苯基)哌嗪代替N-(4-氯苯基)哌嗪。白色固体,产率:67%,mp:159-161℃.1HNMR(400MHz,DMSO)δ:7.87-7.90(m,1H,ArH),7.67-7.71(m,1H,ArH),7.45-7.48(t,J=5.54Hz,1H,ArH),7.39-7.43(t,J=7.16Hz,2H,ArH),7.23-7.28(t,J=11.02Hz,2H,ArH),7.11-7.13(d,J=7.16Hz,1H,ArH),5.98(s,1H),5.26(s,2H,CH2),3.63-3.64(t,J=5.24Hz,4H,-CH2CH2-),3.28-3.29(d,J=4.6Hz,4H,-CH2CH2-).ESI-MS:433.15(C22H20F3N2O4,[M+H]+).Anal.CalcdforC22H19F3N2O4:C,61.11;H,4.43;N,6.48%;Found:C,61.12;H,4.40;N,6.45%.
实施例二十五:含哌嗪环的香豆素类衍生物抗菌活性研究
1.实验材料和方法
1.1药品与试剂
Mueller-Hinton培养基(牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中)、氯霉素、青霉素、DMSO、MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名为噻唑蓝)、异丙醇、盐酸、均为分析纯试剂、合成的化合物1-6、PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.12H2O2.9g,KH2PO40.2g,NaCl8.0g,KCl0.2g,蒸馏水1000mL)。
1.2菌种
大肠杆菌(E.coli)、金黄色葡萄球菌(S.aureus)、枯草芽孢杆菌(B.subtilis)、铜绿假单胞菌(P.aeruginosa)
1.3实验方法
1.3.1培养基的配制
取牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中,加热煮沸溶解,分装,121℃高压灭菌15分钟备用。
1.3.2试验菌的培养
在无菌室内,取大肠杆菌,金黄色葡萄球菌,枯草芽孢杆菌和铜绿假单胞菌四种试验菌株,于酒精灯下用接种针分别在四种试验菌株斜面上,刮取少量斜面菌苔,用一定量的无菌水制成菌悬液,然后取一定量加到已融化又冷却至50℃左右的MH培养基中,摇匀,即刻倒入无菌培养皿中,待充分冷凝后用胶塞密封后,于37℃培养18-24h备用。吸取菌液1mL,用MH培养基按1∶1000稀释,使菌液浓度约为105cfu/mL。
1.3.3抗菌实验:
将待测药品溶于DMSO中配制成2mg/mL的溶液,然后用二倍稀释法将药品稀释成一定浓度梯度(50μg/mL,25μg/mL,12.5μg/mL,6.25μg/mL,3.125μg/mL)与DMSO中。于灭菌微量滴定板第一条中分别加入100μL的培养基,第二条为阳性对照,加入100μL菌悬液。其余的孔中加入90μL的菌悬液和10μL的药物溶液。每个药物溶液浓度平行3次。在微量滴定板底部标明细菌名称。将处理完的培养皿于37℃培养24h,观察。
1.3.4MIC的测定
在每个微量滴定板都可以直观的测定其MIC值之后,在板的每个孔中加入50μLPBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.2H2O2.9g,KH2PO40.2g,NaCl8.0g,KCl0.2g,蒸馏水1000mL),其中包含2mgMTT/mL。在室温下继续孵育4-5h。将孔中的物质移出并加入100μL含有5%1mol/LHCl的异丙醇来萃取染料。继续在室温下赋育12h,于酶标仪测定各孔光吸收(OD值),测定波长550nm。根据各孔OD值计算药物对细菌生长的最小抑制浓度。
最小抑制浓度(minimuminhibitoryconcentration,MIC):在特定环境下孵育24小时,可抑制某种微生物出现明显增长的最低药物浓度即最小抑制浓度,根据测定的光密度(OD值),制作细菌生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的MIC见表1所示
2.实验结果
表1本发明所列含哌嗪环的香豆素类衍生物对细菌的抑制MIC值(μg/mL)
阳性对照:PenicillinG
结果表明:含哌嗪环的香豆素类衍生物对革兰氏阳性菌金黄色葡萄球菌(S.aureus)和枯草芽孢杆菌(B.subtilis)有一定的抑制作用,而对革兰氏阴性菌铜绿假单胞菌(P.aeruginosa)和大肠杆菌(E.coli)几乎没有抑制作用。
Claims (6)
1.一类含哌嗪环的香豆素类衍生物,其特征是它具有以下通式:
其中R1,R2分别为:
2.一种权利要求1中所述的含哌嗪环的香豆素类衍生物1-14的制法,其特征是由以下步骤组成:
步骤1:称取一定量的4-羟基香豆素溶解在适量的乙腈里,再按一定比例往其中加入一定量的环氧氯丙烷,加入适量碳酸钾,搅拌回流反应。反应毕,减压蒸发溶剂,所得固体加水溶解,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,所得固体干燥后,直接用于下一步反应。
步骤2:称取步骤1中所得固体、N-单取代的哌嗪、碳酸铯(Cs2CO3)、按适当比例溶解在一定量的二甲基甲酰胺(DMF)中,搅拌回流反应。反应毕,趁热将反应液倒入水中,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,层析或者重结晶得到本发明的含哌嗪环的4-羟基香豆素类衍生物。
3.一种制备上述的含哌嗪环的香豆素类衍生物15-24的方法,其特征是它由下列步骤组成:
步骤1:称取一定量的N-单取代的哌嗪、溴乙酸、碳酸铯按适当比例溶解在一定量的DMF中,搅拌回流反应。反应毕,趁热将反应液倒入水中,用有机溶剂萃取多次,收集萃取液,无水硫酸钠干燥,减压蒸发溶剂,所得固体干燥后,直接用于下一步反应。
步骤2:称取步骤1中所得固体、4-羟基香豆素、HOBt、EDCI按适当比例溶解在一定量的二氯甲烷中,搅拌回流反应。反应毕,分别用水、氢氧化钠溶液和饱和食盐水依次多次洗反应液,有机层用无水硫酸钠干燥,减压蒸发溶剂,重结晶得到本发明的含哌嗪环的4-羟基香豆素类衍生物15-24。
4.根据权利要求2所述制法,其步骤1中所述有机溶剂,为乙酸乙酯,石油醚,甲苯,二氯甲烷,氯仿,四氢呋喃中之一,或任意两者混合液。
5.根据权利要求2所述制法,其步骤2中所述层析,是采用200-300目硅胶柱,洗脱剂为无水乙酸乙酯和石油醚一定比例的混合溶剂。
6.权利要求1所述的含哌嗪环的香豆素类衍生物在制备抗菌药物中的应用。
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