CN104370738A - 木豆素结构类似物及其在制备抗菌药物中的应用 - Google Patents
木豆素结构类似物及其在制备抗菌药物中的应用 Download PDFInfo
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- CN104370738A CN104370738A CN201410570796.4A CN201410570796A CN104370738A CN 104370738 A CN104370738 A CN 104370738A CN 201410570796 A CN201410570796 A CN 201410570796A CN 104370738 A CN104370738 A CN 104370738A
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- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 3
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- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims 1
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- 229910052731 fluorine Inorganic materials 0.000 abstract description 2
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
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- HCKWDQNSOKQKEN-UHFFFAOYSA-N methyl 3,5-dibromo-2,4-dimethoxy-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C(Br)=C(OC)C(Br)=C1OC HCKWDQNSOKQKEN-UHFFFAOYSA-N 0.000 description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
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- 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 4
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- UPYJDHOYTVQONH-RMKNXTFCSA-N methyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)-6-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]benzoate Chemical compound COC(=O)c1c(O)c(CC=C(C)C)c(OC)cc1\C=C\c1ccc(cc1)C(F)(F)F UPYJDHOYTVQONH-RMKNXTFCSA-N 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- AZCVLZAZCNZVBP-VMPITWQZSA-N 2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)-6-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]benzoic acid Chemical compound OC1=C(C(=O)O)C(=CC(=C1CC=C(C)C)OC)\C=C\C1=CC=C(C=C1)C(F)(F)F AZCVLZAZCNZVBP-VMPITWQZSA-N 0.000 description 3
- GVTAWVYBBHISNM-VMPITWQZSA-N 6-[(E)-2-(4-chlorophenyl)ethenyl]-2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)benzoic acid Chemical compound ClC1=CC=C(/C=C/C2=CC(=C(C(=C2C(=O)O)O)CC=C(C)C)OC)C=C1 GVTAWVYBBHISNM-VMPITWQZSA-N 0.000 description 3
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 3
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- MCVVUJPXSBQTRZ-ONEGZZNKSA-N methyl (e)-but-2-enoate Chemical compound COC(=O)\C=C\C MCVVUJPXSBQTRZ-ONEGZZNKSA-N 0.000 description 3
- VIFJIGAMXYFWTB-ONEGZZNKSA-N methyl 2-[(E)-2-(2,4-difluorophenyl)ethenyl]-6-hydroxy-4-methoxybenzoate Chemical compound COC(C1=C(C=C(C=C1O)OC)\C=C\C1=C(C=C(C=C1)F)F)=O VIFJIGAMXYFWTB-ONEGZZNKSA-N 0.000 description 3
- ILSAXRVYGGDHRU-QPJJXVBHSA-N methyl 2-[(E)-2-(4-fluorophenyl)ethenyl]-4,6-dimethoxybenzoate Chemical compound COC(=O)c1c(OC)cc(OC)cc1\C=C\c1ccc(F)cc1 ILSAXRVYGGDHRU-QPJJXVBHSA-N 0.000 description 3
- FGHOOWCKIFEXRR-ZZXKWVIFSA-N methyl 2-[(E)-2-(4-fluorophenyl)ethenyl]-6-hydroxy-4-methoxybenzoate Chemical compound COC(=O)c1c(O)cc(OC)cc1\C=C\c1ccc(F)cc1 FGHOOWCKIFEXRR-ZZXKWVIFSA-N 0.000 description 3
- JXPVPONHNCYDOL-ZZXKWVIFSA-N methyl 2-hydroxy-4-methoxy-6-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]benzoate Chemical compound COC(C1=C(C=C(C=C1\C=C\C1=CC=C(C=C1)C(F)(F)F)OC)O)=O JXPVPONHNCYDOL-ZZXKWVIFSA-N 0.000 description 3
- XDWPXHLEPLZIKA-VOTSOKGWSA-N methyl 6-[(E)-2-(2,4-difluorophenyl)ethenyl]-2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)benzoate Chemical compound FC1=C(/C=C/C2=CC(=C(C(=C2C(=O)OC)O)CC=C(C)C)OC)C=CC(=C1)F XDWPXHLEPLZIKA-VOTSOKGWSA-N 0.000 description 3
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- PFVPJOAAHSOENR-UHFFFAOYSA-N 2-hydroxy-4-methoxy-6-methylbenzoic acid methyl ester Chemical compound COC(=O)C1=C(C)C=C(OC)C=C1O PFVPJOAAHSOENR-UHFFFAOYSA-N 0.000 description 2
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- WVJJSTACRDCAMR-AATRIKPKSA-N 6-[(E)-2-(2,4-difluorophenyl)ethenyl]-2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)benzoic acid Chemical compound FC1=C(/C=C/C2=CC(=C(C(=C2C(=O)O)O)CC=C(C)C)OC)C=CC(=C1)F WVJJSTACRDCAMR-AATRIKPKSA-N 0.000 description 2
- MFKZKBCPPHOYBX-MDZDMXLPSA-N 6-[(E)-2-(2-fluorophenyl)ethenyl]-2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)benzoic acid Chemical compound FC1=C(/C=C/C2=CC(=C(C(=C2C(=O)O)O)CC=C(C)C)OC)C=CC=C1 MFKZKBCPPHOYBX-MDZDMXLPSA-N 0.000 description 2
- QUWBPUXZKXOCQM-CMDGGOBGSA-N 6-[(E)-2-(3-fluorophenyl)ethenyl]-2-hydroxy-4-methoxy-3-(3-methylbut-2-enyl)benzoic acid Chemical compound FC=1C=C(/C=C/C2=CC(=C(C(=C2C(=O)O)O)CC=C(C)C)OC)C=CC=1 QUWBPUXZKXOCQM-CMDGGOBGSA-N 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 2
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- CUEBJJIQAYCHGH-MDZDMXLPSA-N methyl 2,4-dimethoxy-6-[(e)-2-phenylethenyl]benzoate Chemical compound COC(=O)C1=C(OC)C=C(OC)C=C1\C=C\C1=CC=CC=C1 CUEBJJIQAYCHGH-MDZDMXLPSA-N 0.000 description 2
- WTUMSOUJLOIOFI-ZZXKWVIFSA-N methyl 2-[(E)-2-(4-chlorophenyl)ethenyl]-6-hydroxy-4-methoxybenzoate Chemical compound ClC1=CC=C(/C=C/C2=C(C(=O)OC)C(=CC(=C2)OC)O)C=C1 WTUMSOUJLOIOFI-ZZXKWVIFSA-N 0.000 description 2
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- RVUFOQGJUHERLT-CMDGGOBGSA-N methyl 2-hydroxy-4-methoxy-6-[(e)-2-phenylethenyl]benzoate Chemical compound COC(=O)C1=C(O)C=C(OC)C=C1\C=C\C1=CC=CC=C1 RVUFOQGJUHERLT-CMDGGOBGSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
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Abstract
本发明属于医药领域，公开了一种木豆素结构类似物及其在制备抗菌药物中的应用。所述木豆素结构类似物，具有式Ⅰ所示结构：其中，R1为-H或-CH3；R2为-H、异戊烯基或香叶基；R3为-CH3或R4为-H、-F、-Cl、-OCH3、-CF3或-CN，且不限定其在苯环上取代的个数。本发明以木豆素为先导化合物，对C-1位羧基、C-3位异戊烯基和芳香B环进行修饰和改造，设计合成了一系列木豆素衍生物，尤其是含氟木豆素衍生物。所得化合物抗菌活性更好、毒副作用更小、安全性更高，可应用于制备抗菌药物中，特别是对耐药菌有良好的抗菌活性，尤其是对耐甲氧西林金黄色葡萄球菌，优于阳性对照药，这在此类化合物中是第一次被发现。
Description
技术领域
本发明属于医药领域，特别涉及一种木豆素结构类似物及其在制备抗菌药物中的应用。
背景技术
超级病菌是一种耐药性细菌，更为科学的称谓应该是“产NDM-1耐药细菌引”，即携带有NDM-1基因，能够编码Ⅰ型新德里金属β-内酰胺酶，对绝大多数抗生素(替加环素、多粘菌素除外)不再敏感的细菌。最近发现的“产NDM-1耐药细菌”与传统“超级细菌”相比，其耐药性已经不再是仅仅针对数种抗生素具有“多重耐药性”，而是对绝大多数抗生素均不敏感，这被称为“泛耐药性”(pan-drug resistance，PDR)(参见国外医药抗生素分册，2011，32(6)，254-258)。因此，在细菌感染的治疗中迫切需要具有全新骨架和新作用机制的新型抗菌药物。
木豆素是从木豆叶中提取分离到的芪类化合物，具有显著的抗肿瘤、降血糖、降血脂、抗病毒、抗骨质疏松、抗股骨头坏死等活性。研究发现，木豆素对金黄色葡萄球菌、表皮葡萄球菌、枯草芽孢杆菌等革兰氏阳性菌具有较强的抗菌活性，MIC值为13～25μg/mL(参见Food Chemistry,121(2010),1150-1155)。对耐甲氧西林金黄色葡萄球菌同样显示了良好的抗菌活性，能够显著地杀死细菌，优于青霉素等阳性对照药。木豆素作为天然活性化合物，毒性较小。为了开发比木豆素抗菌活性更好、毒副作用更小、安全性更高的候选药物，本发明以木豆素为先导化合物，对C-1位羧基、C-3位异戊烯基和芳香B环进行修饰和改造，设计合成了系列木豆素结构类似化合物并对其体外抗菌活性进行测试。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种木豆素结构类似物。
本发明的另一目的在于提供所述木豆素结构类似物在制备抗菌药物中的应用。本发明的木豆素结构类似物抗菌活性更好、毒副作用更小、安全性更高，特别是对革兰氏阳性菌及其耐药菌具有良好的活性。尤其是对耐甲氧西林金黄色葡萄球菌，优于阳性对照药。这在此类化合物中是第一次被发现。
本发明的目的通过下述方案实现：
一种木豆素结构类似物，具有式Ⅰ所示结构：
其中，R1为-H或-CH3；
R2为-H、异戊烯基或香叶基；
R3为-CH3或
R4为-H、-F、-Cl、-OCH3、-CF3或-CN，且不限定其在苯环上取代的个数。
优选地，所述木豆素结构类似物具有下述所示结构：
本发明木豆素结构类似物的合成路线如下所示：
合成路线1：
如合成路线1所示，具体地，乙酰乙酸甲酯和巴豆酸甲酯在碱性条件下缩合得到化合物2；化合物2经溴取代，得到化合物3；化合物3在甲基化试剂作用下，得到化合物4；化合物4与溴代试剂反应，得到化合物5；化合物5与亚磷酸三乙酯发生Arbuzov反应，得到化合物6；化合物6在醋酸钯的作用下脱去溴，得到化合物7；化合物7与醛通过Witting-honor反应，得到A系列化合物；A系列化合物在BCl3等卤化硼试剂的作用下脱甲基得到B系列化合物；B系列化合物在NaH作用下与卤代烷反应(或者通过Stile偶联反应制得)，得到R1为-CH3的C系列化合物；C系列化合物在碱性条件下水解，得到R1为-H的本发明的木豆素结构类似物，即D系列的化合物。将A化合物直接在碱性条件下水解得到E系列的化合物。将2加入碘加入醇中加热，然后将得到的产物与卤代烃反应，得到C8、D8。
更具体地，所述合成方法包括以下步骤：
(1)将金属Na溶于无水甲醇等醇类物质中(也可以直接用甲醇钠、乙醇钠代替)，加入乙酰乙酸甲酯，加热回流反应0.5～3h，冷却至20～50℃，滴加巴豆酸甲酯，滴加完毕后，加热回流反应5～12h，蒸出甲醇，剩余物加到冰水中，调pH值至酸性，萃取，得到化合物2；
(2)将化合物2溶于酸中，20～60℃条件下，滴加三倍当量的液溴反应1h，常温条件下反应18h，冰水浴析出，过滤，收集滤饼，干燥得到化合物3；
(3)将化合物3溶于丙酮中，加入K2CO3、NaCO3等碳酸盐、硫酸二甲酯或碳酸二甲酯或碘甲烷等甲基化试剂，加热回流反应2～8h，蒸出丙酮，剩余物加入到NaOH或者其他碱性溶液中，萃取。有机层洗涤，干燥，过滤，蒸出溶剂，剩余物硅胶柱层析得化合物4；
(4)将化合物4溶于氯仿、四氯化碳等有机溶剂中，分批加入BPO等自由基引发剂和NBS混合物(也可以用其他溴代试剂代替)，光照条件下回流反应，过滤，收集滤液，滤液洗涤，干燥，过滤，蒸出溶剂，得到化合物5；
(5)将化合物5溶于烷基亚磷酸酯中，加热回流反应2～6h，柱层析得化合物6；
(6)将化合物6溶于有机溶剂中，加入乙酸钯、碳酸钾或其他碳酸盐，加热回流反应2～8h，得到化合物7；
(7)将5-冠醚-5或者其他相转移催化剂加入到无水THF中，加入NaH，缓慢滴加化合物7和相关的醛，反应0.5～2h后移至常温条件下反应1～3h，后处理柱层析得到化合物A；
(8)将化合物A溶于二氯甲烷中，-20℃条件下加入BCl3反应3h，蒸出二氯甲烷，剩余物萃取，有机层洗涤，干燥，过滤，蒸出溶剂，剩余物硅胶柱层析得本发明化合物B；
(9)将化合物B加入到无水甲苯或者苯中，加入NaH等金属氢化物，再加入卤代烷烃，升温至60～90℃反应3～8h。将反应液萃取三次，有机层饱和食盐水洗涤，柱层析，得R1为-CH3的本发明化合物C；
(10)将化合物10加入到醇和水的混合溶液中，加入KOH等碱，加热回流反应2～4h，冷却至室温，加入适量的酸将反应液调至酸性，析出白色固体，得到R1为-H的本发明化合物D。
进一步地，(1)将化合物B加入到醇和水的混合溶液中，加入加入KOH等碱，加热回流反应2～4h，冷却至室温，加入适量的酸将反应液调至酸性，析出白色固体，得到R1为-H，R2为-H，R4分别为-H、-OCH3、-F的本发明化合物E1、E2、E3。
(2)将化合物2溶于100mL醇中，加入一定量的I2，加热反应2～6h。得到无色固体，将此无色固体与卤代烃，NaH加热反应2～6h得到C8、D8。
上述本发明的木豆素结构类似物抗菌活性更好、毒副作用更小、安全性更高，可应用于制备抗菌药物中，特别是对耐药菌有良好的抗菌活性，对耐甲氧西林金黄色葡萄球菌(MRSA)具有良好的活性。
优选地，本发明的木豆素结构类似物可应用于制备抗金黄色葡萄球菌药物中。
所述的药物指含有本发明所述木豆素结构类似物或其药用盐和溶剂化物中的至少一种。公知的，化合物的溶剂化形式与盐通常并不影响化合物自身的生物学活性。
所述的药物可含有一种或多种药学上可接受的载体或赋形剂。
本发明相对于现有技术，具有如下的优点及有益效果：
(1)本发明以木豆素为先导化合物，对C-1位羧基、C-3位异戊烯基和芳香B环进行修饰和改造，设计合成了一系列木豆素衍生物，尤其是含氟木豆素衍生物。
(2)本发明所得化合物抗菌活性更好、毒副作用更小、安全性更高，可应用于制备抗菌药物中，特别是对耐药菌有良好的抗菌活性。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1：2,4-二甲氧基-6-亚磷酸二乙酯甲基苯甲酸甲酯的合成(化合物7的合成)
经以下反应步骤实现：
(1)2-羰基-4-羟基-6-甲基-环己-3-烯碳酸甲酯的合成(化合物2)
将4.0g(0.175mol)金属Na溶于250mL无水甲醇中，常温条件下加入乙酰乙酸甲酯18g(0.155mol)，加热回流1h。冷却至48℃，在此条件下缓慢滴加巴豆酸甲酯16g(0.160mol)，滴加完毕后，加热回流反应10h。蒸出甲醇，剩余物加到100mL冰水中，用10％的盐酸调pH值至2，乙酸乙酯(100mL×3)萃取。有机层用饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物用石油醚/乙酸乙酯重结晶得白色固体18.2g，产率为64％。1H NMR(300MHz,DMSO-D6)：δ11.38(s,1H),5.23(s,1H),3.64(s,3H),3.11(d,J＝10.8Hz,1H),2.44-2.20(m,2H),0.95(d,J＝6.0Hz,3H).ESI-MS(m/z):207.3[M+Na]+.
(2)2,4-二羟基-3,5-二溴-6-甲基苯甲酸甲酯的合成(化合物3)
将15g(0.081mol)化合物2溶于150mL冰乙酸中，45℃条件下，滴加液溴39g(0.243mol)的冰乙酸溶液50mL，在此条件下反应1h后，转移至常温条件下反应18h。将反应液加入到冰水中，有大量白色固体析出，过滤，收集滤饼，干燥，剩余物经硅胶柱层析(石油醚/丙酮)得白色固体25g，产率为93％。1H NMR(300MHz,DMSO-D6)：δ10.38(s,1H),3.83(s,3H),2.30(s,3H).13C NMR(75MHz,DMSO-D6)：δ168.11,153.52,152.94,135.99,115.59,106.05,99.80,52.94,21.56.ESI-MS(m/z):363.3[M+Na]+.
(3)2,4-二甲氧基-3,5-二溴-6-甲基苯甲酸甲酯的合成(化合物4)
将20g(0.059mol)化合物3溶于200mL丙酮中，加入24.4g(0.177mol)K2CO3，硫酸二甲酯22.3g(0.177mol)，加热回流反应4h。蒸出丙酮，剩余物加入到50mL 10％的NaOH溶液中，乙酸乙酯(100mL×3)萃取。有机层用饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯)得无色固体20.62g，产率为95％。1H NMR(300MHz,CDCl3)：δ3.90(s,1H),3.84(s,1H),3.83(s,1H),2.29(s,3H).13C NMR(75MHz,CDCl3)：δ166.75,155.96,154.16,135.95,127.32,116.80,110.93,62.17,60.36,52.61,20.48.ESI-MS(m/z):391.2[M+Na]+.
(4)2,4-二甲氧基-3,5-二溴-6-溴甲基苯甲酸甲酯的合成(化合物5)
将18g(0.049mol)化合物4溶于200mL四氯化碳中，分批加入1.0g(0.004mol)BPO和9.15g(0.051mol)NBS的混合物，在100W光照条件下回流反应6h，过滤，收集滤液，滤液依次用饱和NaHCO3溶液、饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物硅胶柱层析得无色固体17.6g，产率为80.6％。1H NMR(300MHz,CDCl3)：δ4.59(s,2H),3.97(s,3H),3.88(s,3H),3.88(s,3H).13C NMR(75MHz,CDCl3)：δ165.89,156.89,155.10,135.17,127.19,116.99,114.75,62.44,60.70,53.02,29.20.ESI-MS(m/z):469.2[M+Na]+.
(5)2,4-二甲氧基-3,5-二溴-6-亚磷酸二乙酯甲基苯甲酸甲酯的合成(化合物6)
将15g(33.6mmol)化合物5溶于13mL亚磷酸三乙酯中，加热回流反应2h，减压蒸出过量的亚磷酸三乙酯，剩余物硅胶柱层析(石油醚/丙酮)，得到无色液体14.3g，产率为84％。1H NMR(300MHz,CDCl3)：δ3.95(m,4H),3.84(s,3H),3.78(s,6H),3.60(d,J＝22.7Hz,2H),1.17(t,J＝7.1Hz,6H).13C NMR(75MHz,CDCl3)：δ166.19,166.17,156.65,156.60,155.53,155.48,131.89,131.76,126.89,126.82,118.01,117.92,113.10,113.03,62.27,62.18,60.43,52.64,32.22,30.38,16.30,16.22.ESI-MS(m/z):505.4[M+H]+.
(6)2,4-二甲氧基-6-亚磷酸二乙酯甲基苯甲酸甲酯的合成(化合物7)
将12g(23.8mmol)化合物6溶于150mL正丁醇中，加入乙酸钯125mg，碳酸钾6.5g(47.6mmol)，加热回流反应6h。过滤，收集滤液，减压蒸出正丁醇，剩余物经硅胶柱层析(石油醚/丙酮)得无色油状液体7g，产率为85％。1H NMR(300MHz,CDCl3)：δ6.52(t,J＝2.4Hz,1H),6.34(t,J＝2.1Hz,1H),4.07-3.91(m,4H),3.84(s,3H),3.78(s,3H),3.76(s,3H),3.28(d,J＝22.3Hz,2H),1.22(t,J＝7.1Hz,6H).ESI-MS(m/z):347.0[M+H]+.
实施例2：(E)-2,4-二甲氧基-6-(2'-氟苯乙烯基)苯甲酸甲酯(化合物A1)
将60mg 15-冠醚-5加入到30mL无水THF中，加入440mg(11mmol，含量60％)NaH，0℃搅拌10min，缓慢滴加3.5g(10mmol)化合物7和2-氟苯甲醛1.24g(10mmol)的THF混合溶液，30min后移至常温条件下反应3h。蒸出THF，剩余物加入到20mL饱和氯化铵溶液中，二氯甲烷(50mL×3)萃取，有机层用饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯)得白色固体2.9g，产率为92％。1H NMR(300MHz,CDCl3)：δ7.55(td,J＝7.7,1.7Hz,1H),7.25(dt,J＝4.5,3.9Hz,1H),7.20(d,J＝1.7Hz,2H),7.17-7.02(m,2H),6.80(d,J＝2.1Hz,1H),6.43(d,J＝2.1Hz,1H),3.94(s,3H),3.88(s,3H),3.83(s,3H).13C NMR(75MHz,CDCl3)：δ168.44,161.61,158.26,137.45,129.41,129.30,127.71,127.65,127.39,127.34,124.82,124.66,124.30,124.25,123.99,123.94,116.02,115.96,115.67,101.53,98.31,56.00,55.51,52.36.ESI-MS(m/z):317.1[M+H]+.
实施例3：(E)-2-羟基-4-甲氧基-6-(2'-氟苯乙烯基)苯甲酸甲酯的合成(化合物B1)
将2g(6.3mmol)化合物A1溶于50mL二氯甲烷中，-20℃条件下加入10mL的BCl3的二氯甲烷溶液(1mol/L)，并在此条件下反应2h。蒸出溶剂，剩余物加入到饱和的NaHCO3中，二氯甲烷(50mL×3)萃取，有机层饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯)得白色固体1.71g，产率为90％。1H NMR(300MHz,CDCl3)：δ11.72(s,1H),7.80(d,J＝16.1Hz,1H),7.57(td,J＝7.6,1.7Hz,1H),7.32-7.22(m,1H),7.13(m,2H),6.95(d,J＝16.1Hz,1H),6.66(d,J＝2.6Hz,1H),6.47(d,J＝2.6Hz,1H),3.97(s,3H),3.87(s,3H).13C NMR(75MHz,CDCl3)：δ171.60,165.15,164.19,142.79,132.43,132.36,129.07,128.96,127.64,127.59,125.30,125.14,124.29,124.24,123.34,123.30,116.07,115.78,108.14,103.98,100.38,55.52,52.25.ESI-MS(m/z):303.5[M+H]+.
实施例4：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(2'-氟苯乙烯基)苯甲酸甲酯的合成(化合物C1)
将1.51g(5mmol)化合物B1加入到50mL无水甲苯中，加入240mg(6mmol，含量60％)NaH和异戊烯基溴0.89g(6mmol)，升温至78℃反应4h。将反应液加入到20mL饱和NaHCO3中，乙醚(50mL×3)萃取，有机层用饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物经硅胶柱层析(环己烷/乙酸乙酯)得白色固体0.81g，产率为44％。1H NMR(300MHz,CDCl3)：δ7.80(d,J＝16.2Hz,1H),7.57(td,J＝7.6,1.6Hz,1H),7.25(m,1H),7.20-7.04(m,2H),6.92(d,J＝16.1Hz,1H),6.62(s,1H),5.29-5.13(m,1H),3.94(s,3H),3.93(s,3H),3.39(d,J＝7.0Hz,2H),1.80(s,3H),1.69(s,3H).13C NMR(75MHz,CDCl3)：δ171.89,162.12,161.46,161.38,140.23,133.13,133.06,131.94,128.96,128.85,127.45,127.40,125.42,125.26,124.31,124.26,122.41,122.04,116.89,116.05,115.76,104.54,102.94,55.70,52.24,25.87,22.16,17.84.ESI-MS(m/z):371.2[M+H]+；HRMS(ESI):Calcd for[M+H]+C22H24FO4,371.16531；found,371.16547.
实施例5：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(2'-氟苯乙烯基)苯甲酸的合成(化合物D1)
将0.37g(1mmol)化合物C1加入到乙醇15mL和水6mL的混合溶液中，加入168mg(3mmol)KOH，加热回流反应2h。冷却至室温，用10％的盐酸调pH至2，析出大量白色固体，过滤，收集滤饼，所得粗产物经硅胶柱层析(石油醚/丙酮)得白色固体329mg，产率为92.5％。1H NMR(300MHz,Acetone-d6):δ8.10(d,J＝16.2Hz,1H),7.73(td,J＝7.7,1.7Hz,1H),7.40-7.30(m,1H),7.28-7.13(m,2H),7.08(d,J＝16.2Hz,1H),6.86(s,1H),5.38-5.07(m,1H),4.01(s,3H),3.37(d,J＝7.2Hz,2H),1.78(s,3H),1.65(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.24,162.08,161.55,140.73,133.13,133.07,130.74,129.28,129.16,127.66,127.62,125.44,125.28,124.58,124.53,122.25,122.16,122.12,116.28,115.79,115.49,104.05,102.70,55.34,25.02,21.80,17.00.ESI-MS(m/z):357.3[M+H]+.HRMS(ESI):Calcd for[M+H]+C21H22FO4,357.14966；found,357.14944.
实施例6：(E)-2,4-二甲氧基-6-(3'-氟苯乙烯基)苯甲酸甲酯(化合物A2)
以化合物7为原料，制备方法同实施例7，原料用量的摩尔比与实施例7相同，得到白色固体A2，产率为88％。1H NMR(300MHz,CDCl3)：δ7.30(td,J＝7.9,5.9Hz,1H),7.22(d,J＝7.8Hz,1H),7.19-7.13(m,1H),7.12-6.91(m,3H),6.74(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),3.92(s,3H),3.87(s,3H),3.82(s,3H).13C NMR(75MHz,CDCl3)：δ168.38,158.33,139.25,139.15,137.13,130.56,130.52,130.21,130.09,126.80,122.72,122.68,116.00,115.02,114.74,113.27,112.98,101.63,98.33,56.04,55.52,52.43.ESI-MS(m/z):317.2[M+H]+.
实施例7：(E)-2-羟基-4-甲氧基-6-(3'-氟苯乙烯基)苯甲酸甲酯的合成(化合物B2)
以化合物A2为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得到白色固体，产率为90％。1H NMR(300MHz,CDCl3)：δ11.72(s,1H),7.80(d,J＝16.1Hz,1H),7.57(td,J＝7.6,1.7Hz,1H),7.32-7.22(m,1H),7.16-7.25(m,2H),6.95(d,J＝16.1Hz,1H),6.66(d,J＝2.6Hz,1H),6.47(d,J＝2.6Hz,1H),3.97(s,3H),3.87(s,3H).13C NMR(75MHz,CDCl3)：δ171.53,165.22,164.17,142.30,139.82,139.72,131.21,130.26,130.14,129.61,129.58,122.68,122.65,114.76,114.48,113.03,112.74,108.16,103.92,100.40,55.50,52.36.ESI-MS(m/z):303.5[M+Na]+.
实施例8：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(3'-氟苯乙烯基)苯甲酸甲酯的合成(化合物C2)
以化合物B2为原料，制备方法同实施例9，原料用量摩尔比与实施例9相同，得到白色固体C2，产率为40％。1H NMR(300MHz,CDCl3)：δ11.72(s,1H),7.74(d,J＝15.9Hz,1H),7.44-7.15(m,3H),7.06-6.92(m,1H),6.75(d,J＝15.9Hz,1H),6.61(s,1H),3.96(s,3H),3.95(s,3H),3.41(d,J＝7.1Hz,2H),1.82(s,3H),1.71(s,3H).13C NMR(75MHz,CDCl3)：δ171.82,161.52,161.36,139.95,139.85,139.79,132.03,131.99,130.25,130.14,128.84,122.56,122.53,121.98,116.99,114.65,114.36,113.01,112.72,104.53,102.92,55.69,52.36,25.86,22.16,17.84.ESI-MS(m/z):371.4[M+H]+；HRMS(ESI):Calcd for[M+H]+C22H24FO4,371.16531；found,371.16427.
实施例9：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(3'-氟苯乙烯基)苯甲酸的合成(化合物D2)
以化合物C2为原料，制备方法同实施例10，原料用量摩尔比与实施例10相同，得到白色固体D2，产率为94％。1H NMR(300MHz,Acetone-d6)：δ8.08(d,J＝16.1Hz,1H),7.54-7.26(m,3H),7.16-6.95(m,2H),6.88(s,1H),5.30-5.13(m,1H),3.99(s,3H),3.36(d,J＝7.3Hz,2H),1.78(s,3H),1.65(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.21,162.02,161.46,140.55,140.42,131.93,130.72,130.51,130.40,128.88,122.80,122.77,122.26,116.22,114.25,113.97,112.82,112.53,104.20,102.60,55.32,25.01,21.80,16.99.ESI-MS(m/z):357.3[M+H]+；HRMS(ESI):Calcd for[M+H]+C21H22FO4,357.14966；found,357.14994.
实施例10：(E)-2,4-二甲氧基-6-(4'-氯苯乙烯基)苯甲酸甲酯(化合物A3)
以化合物7为原料，制备方法同实施例7，原料用量摩尔比与实施例7相同，得到得白色固体3.09g，产率为93％。1H NMR(300MHz,CDCl3)：δ7.44-7.36(m,1H),7.35-7.28(m,1H),7.07(d,J＝16.1Hz,1H),6.97(d,J＝16.1Hz,1H),6.74(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),3.92(s,1H),3.87(s,1H),3.83(s,1H).13CNMR(75MHz,CDCl3)：δ168.43,161.60,158.34,137.27,135.39,133.69,130.44,128.87,127.96,126.06,115.94,101.60,98.22,56.04,55.50,52.38.ESI-MS(m/z):333.3[M+H]+.
实施例11：(E)-2-羟基-4-甲氧基-6-(4'-氯苯乙烯基)苯甲酸甲酯(化合物B3)
以化合物A3为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得白色固体1.64g，产率为86％。1H NMR(300MHz,CDCl3)：δ11.66(s,1H),7.65(d,J＝16.0Hz,1H),7.46-7.38(m,2H),7.37-7.29(m,2H),6.74(d,J＝15.9Hz,1H),6.60(d,J＝2.6Hz,1H),6.44(d,J＝2.6Hz,1H),3.94(s,3H),3.84(s,3H).13C NMR(75MHz,CDCl3)：δ171.53,165.18,164.18,142.47,135.92,133.43,130.49,129.54,128.91,127.81,108.07,103.93,100.34,55.51,52.31.ESI-MS(m/z):319.3[M+H]+.
实施例12：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(4'-氯苯乙烯基)苯甲酸甲酯的合成(化合物C3)
以化合物2-3为原料，制备方法同实施例2，原料用量摩尔比与实施例2相同，得到白色固体C3产率为43.4％。1H NMR(300MHz,CDCl3)：δ11.68(s,1H),7.68(d,J＝15.9Hz,1H),7.43(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.72(d,J＝15.9Hz,1H),6.58(s,1H),5.22(t,J＝7.0Hz,1H),3.38(d,J＝7.0Hz,2H),1.80(s,3H),1.69(s,3H).13C NMR(75MHz,CDCl3)：δ171.83,161.49,161.35,139.94,136.04,133.30,131.97,131.31,128.92,128.77,127.75,121.99,116.89,104.51,102.85,55.68,52.32,25.86,22.16,17.84.ESI-MS(m/z):409.3[M+Na]+.
实施例13：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(4'-氯苯乙烯基)苯甲酸的合成(化合物D3)
以化合物C3为原料，制备方法同实施例3，原料用量摩尔比与实施例3相同，得到白色固体D3产率92％。1H NMR(300MHz,Acetone-d6)：δ12.29(s,1H),8.01(d,J＝16.1Hz,1H),7.59(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),7.01(d,J＝16.0Hz,1H),6.86(s,1H),5.22(t,J＝7.1Hz,1H),3.98(s,3H),3.36(d,J＝7.1Hz,2H),1.78(s,3H),1.65(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.23,162.10,161.53,140.60,136.68,132.65,131.18,130.72,128.89,128.72,128.13,122.28,116.17,103.94,102.61,55.31,25.03,21.81,17.01.ESI-MS(m/z):395.3[M+Na]+；HRMS(ESI):Calcd for[M+H]+C21H22ClO4,373.12011；found,373.11735.
实施例14：(E)-2,4-二甲氧基-6-(3'-氰基苯乙烯基)苯甲酸甲酯(化合物A4)
以化合物7为原料，制备方法同实施例9，原料用量摩尔比与实施例9相同，得白色固体3.23g，产率为87％。1H NMR(300MHz,CDCl3)：δ7.69(dd,J＝7.4,6.2Hz,2H),7.54(dt,J＝7.6,1.3Hz,1H),7.45(t,J＝7.7Hz,1H),7.15(d,J＝16.2Hz,1H),6.98(d,J＝16.1Hz,1H),6.73(d,J＝2.1Hz,1H),6.44(d,J＝2.1Hz,1H),3.93(s,3H),3.88(s,3H),3.83(s,3H).13C NMR(75MHz,CDCl3)：δ168.25,161.69,158.48,138.14,136.77,131.18,130.70,130.26,129.52,129.29,128.21,118.44,116.10,112.96,101.83,98.66,56.09,55.55,52.48.ESI-MS(m/z):324.3[M+H]+.
实施例15：(E)-2-羟基-4-甲氧基-6-(3'-氰基苯乙烯基)苯甲酸甲酯的合成(化合物B4)
以化合物A4为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得到白色固体B4，产率为92％。1H NMR(300MHz,CDCl3)：δ11.64(s,1H),7.80-7.63(m,3H),7.54(dt,J＝7.6,1.3Hz,1H),7.47(d,J＝7.7Hz,1H),6.73(d,J＝16.0Hz,1H),6.58(d,J＝2.4Hz,1H),6.45(d,J＝2.6Hz,1H),3.94(s,3H),3.84(s,3H).13C NMR(75MHz,CDCl3)：δ171.30,165.24,164.21,141.81,138.66,132.54,130.93,130.76,129.95,129.57,128.37,118.77,112.98,108.36,103.91,100.66,55.55,52.44.ESI-MS(m/z):310.3[M+H]+.
实施例16：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(3'-氰基苯乙烯基)苯甲酸甲酯的合成(化合物C4)
以化合物B4为原料，制备方法同实施例9，原料用量摩尔比与实施例9相同，得到白色固体C4，产率为36％。1H NMR(300MHz,CDCl3)：δ11.66(s,1H),7.72(d,J＝16.0Hz,1H),7.60(m,2H),7.55(dd,J＝6.4,1.3Hz,1H),7.48(t,J＝7.7Hz,1H),6.73(d,J＝16.0Hz,1H),6.57(s,1H),5.27-5.15(m,1H),3.94(s,3H),3.93(s,3H),3.38(d,J＝7.1Hz,2H),1.79(s,3H),1.68(s,3H).13C NMR(75MHz,CDCl3)：δ171.60,161.54,161.38,139.29,138.78,133.35,132.09,130.85,130.62,129.99,129.57,127.65,121.84,118.81,117.39,112.98,104.55,103.01,55.72,52.46,25.86,22.18,17.84.ESI-MS(m/z):378.0[M+H]+.HRMS(ESI):Calcd for[M+H]+C23H24NO4,378.16998；found,378.16907.
实施例17：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(3'-氰基苯乙烯基)苯甲酸的合成(化合物D4)
以化合物C4为原料，制备方法同实施例10，原料用量摩尔比与实施例10相同，得到白色固体D4，产率88％。1H NMR(300MHz,Acetone-d6)：δ8.16(d,J＝16.1Hz,1H),8.05-7.85(m,3H),7.65(m,2H),7.06(d,J＝16.1Hz,1H),6.88(s,1H),5.22(m,1H),3.99(s,3H),3.36(d,J＝7.2Hz,3H),1.78(s,3H),1.65(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.19,162.03,161.45,140.16,139.22,133.01,130.79,130.72,129.95,129.85,127.91,122.22,118.39,116.45,112.77,104.27,102.72,55.34,,25.02,21.82,17.00.ESI-MS(m/z):364.3[M+H]+.HRMS(ESI):Calcd for[M+H]+C22H22NO4,364.15433；found,364.15387.
实施例18：(E)-2,4-二甲氧基-6-(4'-三氟甲基苯乙烯基)苯甲酸甲酯(化合物A5)
以化合物7为原料，制备方法同实施例7，原料用量摩尔比与实施例7相同，得白色固体3.87g，产率为92％。1H NMR(300MHz,CDCl3)：δ7.56(q,J＝8.6Hz,4H),7.18(d,J＝16.1Hz,1H),7.03(d,J＝16.1Hz,1H),6.75(d,J＝2.1Hz,1H),6.43(d,J＝2.1Hz,1H),3.93(s,3H),3.86(s,3H),3.82(s,3H).13C NMR(75MHz,CDCl3)：δ168.33,161.66,158.41,140.35,136.96,130.16,128.02,126.89,125.69,125.64,125.59,125.54,116.10,101.77,98.50,56.02,55.48,52.38.ESI-MS(m/z):367.1[M+H]+.
实施例19：(E)-2-羟基-4-甲氧基-6-(4'-三氟甲基苯乙烯基)苯甲酸甲酯的合成的合成(化合物B5)
以化合物A5为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得到白色固体B5，产率为92％。1H NMR(300MHz,CDCl3)：δ11.71(s,1H),7.63(d,J＝15.9Hz,1H),7.47(m,1H),7.08(t,J＝8.7Hz,2H),6.78(d,J＝15.9Hz,1H),6.63(d,J＝2.4Hz,1H),6.46(d,J＝2.6Hz,1H),3.97(s,3H),3.87(s,3H).13C NMR(75MHz,CDCl3)：δ171.61,165.18,164.17,160.82,142.67,133.56,129.66,128.22,128.11,115.86,115.57,108.02,103.92,100.21,55.51,52.33.
实施例20：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(4'-三氟甲基苯乙烯基)苯甲酸甲酯的合成(化合物C5)
以化合物B5为原料，制备方法同实施例9，原料用量摩尔比与实施例9相同，得到白色固体C5，产率为34％。1H NMR(300MHz,CDCl3)：δ11.67(s,1H),7.80(d,J＝15.9Hz,1H),7.67-7.55(m,4H),6.78(d,J＝16.0Hz,1H),6.60(s,1H),5.22(m,1H),3.93(s,6H),3.39(d,J＝7.1Hz,2H),1.80(s,3H),1.69(s,3H).13C NMR(75MHz,CDCl3)：δ171.71,161.54,161.38,139.58,133.23,132.03,128.51,126.66,125.72,125.67,121.91,117.25,104.57,102.98,55.70,52.34,25.85,22.18,17.83ESI-MS(m/z):421.4[M+H]+.HRMS(ESI):Calcd for[M+H]+C23H24F3O4,421.16212；found,421.16102.
实施例21：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(4'-三氟甲基苯乙烯基)苯甲酸的合成(化合物D5)
以化合物C5为原料，制备方法同实施例10，原料用量摩尔比与实施例10相同，得到白色固体D5，产率93％。1H NMR(300MHz,CDCl3)：δ11.51(s,1H),7.92(d,J＝16.0Hz,1H),7.74-7.56(m,4H),6.83(d,J＝15.9Hz,1H),6.64(s,1H),5.20(t,J＝7.1Hz,1H),3.96(s,3H),3.38(d,J＝7.1Hz,2H),1.79(s,3H),1.69(s,3H).13C NMR(75MHz,CDCl3)：δ175.04,162.53,162.31,141.05,132.94,132.14,129.21,126.88,125.66,121.72,117.37,103.46,103.03,55.79,25.83,22.13,17.81.ESI-MS(m/z):429.3[M+Na]+.HRMS(ESI):Calcd for[M+H]+C22H22F3O4,407.14647；found,407.14422.
实施例22：(E)-2,4-二甲氧基-6-(4'-三氟甲基苯乙烯基)苯甲酸甲酯(化合物A6)
以化合物7为原料，制备方法同实施例7，原料用量摩尔比与实施例7相同，得白色固体3.87g，产率为92％。1H NMR(300MHz,CDCl3)δ7.56–7.43(m,1H),7.10(s,2H),6.92–6.77(m,2H),6.75(d,J＝2.0Hz,1H),6.42(d,J＝2.0Hz,1H),3.92(s,1H),3.87(s,1H),3.82(s,1H).13C NMR(75MHz,CDCl3)δ168.40,164.16,164.04,162.23,162.07,161.63,158.68,158.31,137.36,128.20,127.32,123.01,121.31,121.26,121.15,121.09,115.98,111.86,111.81,111.57,111.53,104.51,104.17,103.83,101.51,98.34,56.04,55.54,52.38.ESI-MS(m/z):335.3[M+H]+.
实施例23：(E)-2-羟基-4-甲氧基-6-(2',4'-二氟苯乙烯基)苯甲酸甲酯的合成(化合物B6)
以化合物A6为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得到白色固体B6，产率为95％。1H NMR(300MHz,CDCl3)δ11.70(s,1H)，7.72(d,J＝16.1Hz,1H),7.53(td,J＝8.6,6.5Hz,1H),6.97(d,J＝16.1Hz,1H),6.96–6.77(m,2H),6.63(d,J＝2.5Hz,1H),6.47(d,J＝2.6Hz,1H),3.96(s,3H),3.87(s,3H).13C NMR(75MHz,CDCl3)δ171.52,165.17,164.20,142.60,132.07,132.03,128.52,128.45,128.40,128.32,122.40,121.74,121.69,121.56,121.55,111.82,111.78,111.54,111.49,108.16,104.60,104.26,103.93,100.39,55.53,52.26.ESI-MS(m/z):321.1[M+H]+.
实施例24：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(2',4'-二氟苯乙烯基)苯甲酸甲酯的合成(化合物C6)
以化合物B6为原料，制备方法同实施例9，原料用量摩尔比与实施例9相同，得到白色固体C6，产率为34％。1H NMR(300MHz,CDCl3)δ11.67(s,1H),7.72(d,J＝16.1Hz,1H),7.56-7.49(m,1H),6.98–6.8(m,2H),6.83(d,J＝16.1Hz,1H),6.59(s,1H),5.24-5.20(m,1H),3.93(s,6H),3.38(d,J＝7.1Hz,2H),1.80(s,3H),1.68(s,3H).13C NMR(75MHz,CDCl3)δ171.80,161.47,161.38,140.05,132.75,131.97,128.27,128.14,121.99,121.51,118.16,111.83,111.47,104.56,104.51,104.23,103.88,102.89,55.69,52.25,25.86,22.16,17.83.ESI-MS(m/z):461.2[M+H]+.
实施例25：(E)-2-羟基-3-异戊烯基-4-甲氧基-6-(2',4'-二氟苯乙烯基)苯甲酸的合成(化合物D6)
以化合物C6为原料，制备方法同实施例10，原料用量摩尔比与实施例10相同，得到白色固体D6，产率为34％。1H NMR(300MHz,Acetone)δ8.05(d,J＝16.2Hz,1H),7.85–7.71(m,1H),7.13–7.06(m,2H),7.02(d,J＝16.1Hz,1H),6.85(s,1H),5.41–5.08(m,1H),4.00(s,3H),3.36(d,J＝7.2Hz,2H),1.78(s,3H),1.65(s,3H).13C NMR(75MHz,Acetone)δ173.19,163.59,162.08,161.56,158.30,140.61,132.98,130.76,128.88,122.22,121.98,121.23,116.31,111.88,111.79,111.64,111.59,104.23,104.00,103.89,103.54,102.71,55.34,25.02,21.80,16.99.
实施例26：(E)-2,4-二甲氧基-6-(4'-氟苯乙烯基)苯甲酸甲酯(化合物A7)
以化合物7为原料，制备方法同实施例7，原料用量摩尔比与实施例7相同，得白色固体2.8g，产率为89％。1H NMR(300MHz,CDCl3)：δ7.52-7.34(m,2H),7.13-6.83(m,4H),6.74(d,J＝2.1Hz,1H),6.40(d,J＝2.1Hz,1H),3.93(s,3H),3.83(s,3H),3.79(s,3H).13C NMR(75MHz,CDCl3)：δ168.48,161.58,158.29,137.36,133.13,133.08,130.49,128.41,128.30,125.16,125.13,115.87,115.75,115.46,101.53,97.97,55.89,55.37,52.26.ESI-MS(m/z):317.1[M+H]+.
实施例27：(E)-2-羟基-4-甲氧基-6-(4'-氟苯乙烯基)苯甲酸甲酯(化合物B7)
以化合物A7为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得白色固体1.75g，产率为92％。1H NMR(300MHz,CDCl3)：δ11.67(s,1H),7.60(d,J＝15.9Hz,1H),7.51-7.39(m,2H),7.06(t,J＝8.7Hz,2H),6.76(d,J＝15.9Hz,1H),6.60(d,J＝2.6Hz,1H),6.44(d,J＝2.6Hz,1H),3.94(s,3H),3.85(s,3H).13C NMR(75MHz,CDCl3)：δ171.58,165.18,164.18,142.67,133.57,129.65,128.21,128.10,115.84,115.55,107.99,103.94,100.23,55.49,52.29.ESI-MS(m/z):303.2[M+H]+.
实施例28：(E)-2-羟基-3-香叶基-4-甲氧基-6-(4'-氟苯乙烯基)苯甲酸甲酯的合成(化合物C7)
以化合物B7为原料，制备方法同实施例9，原料用量摩尔比与实施例9相同，得到白色固体C7，产率为38％。1H NMR(300MHz,CDCl3)：δ11.68(s,1H),7.63(d,J＝15.9Hz,1H),7.54-7.40(m,2H),7.07(t,J＝8.7Hz,2H),6.74(d,J＝16.0Hz,1H),6.59(s,1H),5.22(dd,J＝7.1,6.0Hz,1H),5.07(dd,J＝9.5,3.9Hz,3H),3.94(s,3H),3.92(s,3H),3.39(d,J＝7.0Hz,2H),1.79(s,3H),1.65(s,3H),1.58(s,3H).13C NMR(75MHz,CDCl3)：δ171.90,161.52,161.41,140.10,135.38,133.74,131.20,130.49,130.46,128.84,128.13,128.02,124.47,121.87,116.82,115.85,115.56,104.48,102.80,55.65,52.30,39.84,26.75,25.71,22.09,17.69,16.16.ESI-MS(m/z):439.2[M+H]+.HRMS(ESI):Calcd for[M+H]+C27H32FO4,439.22791；found,439.22682.
实施例29：(E)-2-羟基-3-香叶基-4-甲氧基-6-(4'-氟苯乙烯基)苯甲酸的合成(化合物D7)
以化合物C7为原料，制备方法同实施例10，原料用量摩尔比与实施例10相同，制备得到化合物D7(95％)。1H NMR(300MHz,Acetone-d6)：δ7.96(d,J＝16.0Hz,1H),7.62(dd,J＝8.7,5.5Hz,2H),7.16(t,J＝8.8Hz,2H),7.01(d,J＝16.0Hz,1H),6.86(s,1H),5.24(dd,J＝7.2,6.2Hz,1H),5.08(t,J＝6.8Hz,1H),3.99(s,3H),3.38(d,J＝7.2Hz,3H),1.79(s,3H),1.62(s,3H),1.56(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.33,163.91,163.10,162.13,161.67,161.55,160.75,160.66,140.80,134.38,134.32,130.69,130.29,129.02,128.47,128.36,124.26,122.26,116.06,115.57,115.28,103.95,102.53,55.31,39.64,26.51,24.95,21.74,16.82,15.34.ESI-MS(m/z):425.3[M+H]+.HRMS(ESI):Calcd for[M+H]+C26H30FO4,425.21226；found,425.21404.
实施例30：2-羟基-4-甲氧基-6-甲基苯甲酸甲酯(化合物3')
将5g(27mmol)化合物2溶于100mL甲醇中，加入13.8g(54mmol)I2，加热回流反应4h。蒸出过量甲醇，剩余物加入到100mL饱和Na2S2O3中，乙酸乙酯(100mL×3)萃取。有机层用饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯)，得无色固体2.85g，产率为54％。1H NMR(300MHz,CDCl3)：δ11.77(s,1H),6.30(d,J＝2.6Hz,1H),6.25(d,J＝2.6Hz,1H),3.90(s,3H),3.77(s,3H),2.46(s,3H).13CNMR(75MHz,CDCl3)：δ172.19,165.54,163.91,143.09,111.09,105.18,98.66,55.22,51.77,24.30.
实施例31：2-羟基-3-异戊烯基-4-甲氧基-6-甲基苯甲酸甲酯的合成(化合物C8)
将400mg(2mmol)化合物3'溶于50mL无水甲苯中，加入80mg NaH和异戊烯基溴500mg(2.3mmol)，升温至78℃反应6h。将反应液加入到20mL饱和NaHCO3溶液中，乙醚(50mL×3)萃取，饱和食盐水洗涤，无水Na2SO4干燥，过滤，蒸出溶剂，剩余物硅胶柱层析(环己烷/乙酸乙酯)得白色固体227mg，产率为43％。1H NMR(300MHz,CDCl3)：δ11.80(s,1H),6.28(s,1H),5.43-4.90(m,1H),3.92(s,3H),3.85(s,3H),3.33(d,J＝7.0Hz,2H),2.52(s,3H),1.78(s,3H),1.67(s,3H).13C NMR(75MHz,CDCl3)：δ172.51,161.87,161.09,140.59,131.58,122.46,114.71,106.12,105.69,55.48,51.81,25.84,24.71,21.92,17.80.ESI-MS(m/z):265.3[M+H]+.
实施例32：2-羟基-3-异戊烯基-4-甲氧基-6甲基苯甲酸的合成(化合物D8)
将200mg(0.76mmol)化合物C8加入到乙醇10mL和水4mL的混合溶剂中，加入127mg(2.28mmol)KOH，加热回流反应2h。冷却至室温，滴加10％的盐酸调pH至2，析出大量白色固体，过滤，收集滤饼，粗产物经石油醚/乙酸乙酯重结晶得白色固体127mg，产率为92％。1H NMR(300MHz,Acetone-d6)：δ6.49(s,1H),5.33-5.07(m,1H),3.90(s,3H),3.30(d,J＝7.2Hz,2H),2.59(s,3H),1.75(s,3H),1.63(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.80,162.52,161.31,141.30,130.30,122.68,114.03,106.07,105.07,55.10,24.99,23.75,21.56,16.94.ESI-MS(m/z):251.3[M+H]+；HRMS(ESI):Calcd for[M+H]+C14H19O4,251.12779；found,251.12711.
实施例33：(E)-2,4-二甲氧基-6-(苯乙烯基)苯甲酸甲酯的合成(化合物A9)
以化合物7为原料，制备方法同实施例7，原料用量摩尔比与实施例7相同，得到白色固体，产率为90％。1H NMR(300MHz,CDCl3):δ7.49(d,J＝7.2Hz,2H),7.40-7.24(m,3H),7.14(d,J＝16.1Hz,1H),7.06(d,J＝16.1Hz,1H),6.79(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),3.94(s,3H),3.86(s,3H),3.82(s,3H).13C NMR(75MHz,CDCl3):δ168.52,161.59,158.29,137.56,136.89,131.78,128.74,128.13,126.82,125.43,115.97,101.57,98.05,56.00,55.49,52.35.ESI-MS(m/z):299.3[M+H]+.
实施例34：(E)-2-羟基-4-甲氧基-6-(苯乙烯基)苯甲酸甲酯的合成(化合物B9)
以化合物A2为原料，制备方法同实施例1，原料用量摩尔比与实施例1相同，得白色固体3.6g，产率为95％。1H NMR(300MHz,CDCl3)：δ11.70(s,1H),7.70(d,J＝16.0Hz,1H),7.54-7.46(m,2H),7.43-7.34(m,2H),7.31(m,1H),6.81(d,J＝15.9Hz,1H),6.64(d,J＝2.6,1H),6.45(d,J＝2.6Hz,1H),3.95(s,3H),3.85(s,3H).13C NMR(75MHz,CDCl3)：δ171.69,165.16,164.17,142.88,137.41,130.87,129.86,128.77,127.85,126.68,108.01,103.98,100.21,55.50,52.30.ESI-MS(m/z):591.5[2M+Na]+.
实施例35：(E)-2-羟基-4-甲氧基-6-(苯乙烯基)苯甲酸的合成(化合物E1)
将285mg(1mmol)(E)-2-羟基-4-甲氧基-6-(苯乙烯基)苯甲酸甲酯溶于乙醇15mL和水5mL的混合溶剂中，加入170mg(3mmol)KOH，加热回流反应2h。冷却至室温，用10％的盐酸调pH至2，析出大量白色固体，过滤，收集滤饼，粗产物经硅胶柱层析(石油醚/丙酮)得白色固体238mg，产率为88％。1H NMR(300MHz,Acetone-d6)：δ7.88(d,J＝16.0Hz,1H),7.54-7.48(m,2H),7.23-7.38(m,2H),7.30-7.22(m,1H),6.87(d,J＝16.0Hz,1H),6.68(d,J＝2.4Hz,1H),6.42(d,J＝2.5Hz,1H),3.86(s,3H).13C NMR(75MHz,Acetone-d6)：δ173.01,164.90,164.04,143.04,137.60,130.32,129.52,128.28,127.34,126.33,106.30,104.32,99.77,54.56.HRMS(ESI):Calcd for[M+H]+C16H15O4,271.09649；found,271.09309.
实施例36：(E)-2,4-二甲氧基-6-(4'-甲氧苯乙烯基)苯甲酸甲酯(化合物A10)
以化合物7为原料，制备方法同实施例7，原料用量摩尔比与实施例7相同，得白色固体3.2g，产率为85％。1H NMR(300MHz,CDCl3)：δ7.50-7.38(m,2H),7.03(d,J＝16.1Hz,1H),6.96(d,J＝16.2Hz,1H),6.93-6.86(m,2H),6.77(d,J＝2.1Hz,1H),6.41(d,J＝2.1Hz,1H),3.94(s,3H),3.89(s,3H),3.84(s,3H),3.84(s,3H).13C NMR(75MHz,CDCl3)：δ168.61,161.51,159.66,158.23,137.86,131.29,129.68,128.08,123.22,115.76,114.14,101.29,97.73,56.01,55.49,55.33,52.33.ESI-MS(m/z):329.4[M+H]+.
实施例37：(E)-2-羟基-4-甲氧基-6-(4'-甲氧苯乙烯基)苯甲酸甲酯(化合物B10)
以化合物A10为原料，制备方法同实施例8，原料用量摩尔比与实施例8相同，得到白色固体，产率为90％。得白色固体1.78g，产率为92％。1H NMR(300MHz,CDCl3)：δ11.69(s,1H),7.57(d,J＝15.9Hz,1H),7.43(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),6.77(d,J＝15.9Hz,1H),6.62(d,J＝2.6Hz,1H),6.42(d,J＝2.6Hz,1H),3.94(s,3H),3.85(s,3H),3.84(s,3H).13C NMR(75MHz,CDCl3)：δ171.77,165.13,164.13,159.47,143.16,130.47,130.22,127.91,127.69,114.19,107.66,103.95,99.99,55.47,55.35,52.24.ESI-MS(m/z):337.2[M+Na]+.
实施例38：(E)-2-羟基-4-甲氧基-6-(4'-甲氧基苯乙烯基)苯甲酸的合成(化合物E2)
将315mg(1mmol)(E)-2,4-二甲氧基-6-(4'-甲氧苯乙烯基)苯甲酸甲酯加入到乙醇10mL和水4mL的混合溶剂中，加入168mg(3mmol)KOH，加热回流反应3h。冷却至室温，用10％的盐酸调pH至2，析出大量白色固体E2，过滤，收集滤饼，粗产物经石油醚/丙酮重结晶得白色固体255mg，产率为85％。1H NMR(300MHz,Acetone-d6)：δ12.01(s,1H),7.85(d,J＝16.1Hz,1H),7.53(d,J＝8.7Hz,2H),6.96(m,3H),6.74(d,J＝2.5Hz,1H),6.43(d,J＝2.6Hz,1H),3.90(s,3H),3.83(s,3H).13C NMR(75MHz,Acetone-d6)：δ172.95,165.84,164.39,159.71,143.65,130.53,130.26,128.01,127.34,114.07,106.57,103.52,99.87,55.05,54.70.ESI-MS(m/z):301.3[M+H]+.
实施例39：(E)-2-羟基-4-甲氧基-6-(4'-氟苯乙烯基)苯甲酸E3
将302mg(1mmol)化合物3b加入到乙醇10mL和水4mL的混合溶剂中，加入172mg(3mmol)KOH，加热回流反应2h。冷却至室温，滴加10％的盐酸调pH至2，析出大量白色固体，过滤，收集滤饼，石油醚/丙酮重结晶得白色固体256mg，产率为89％。1H NMR(300MHz,MeOD)：δ7.80(d,J＝16.0Hz,1H),7.60-7.43(m,2H),7.08(t,J＝8.8Hz,2H),6.84(d,J＝16.0Hz,1H),6.65(d,J＝2.5Hz,1H),6.41(d,J＝2.5Hz,1H),3.85(s,3H).13CNMR(75MHz,MeOD)：δ172.93,164.98,164.06,162.41,142.91,134.05,129.53,128.99,128.03,114.99106.35,104.18,99.77,54.53.ESI-MS(m/z):289.3[M+H]+.
实施例40：木豆素结构类似物的抗菌活性测定
测试的化合物包括C系列(C1、C2、C3、C4、C5、C6、C7、C8)、D系列(D1、D2、D3、D4、D5、D6、D7、D8)、E(E1、E2、E3)系列的化合物。
采用肉汤微量二倍稀释法，测定木豆素衍生物体外抑菌作用的最小抑菌浓度(MIC)，具体操作方法如下：(1)在96孔板上每孔加入100μL不同浓度的药液和100μL的菌液，使最终菌液浓度为1～5cfu/ml，以TSB肉汤培养基加菌液作为阴性对照(TSB培养基、菌液各100μL)，以不加菌液的TSB肉汤培养基空白对照(TSB培养基200μL)，将96板密封后置于37℃恒温培养箱中，孵育20h。(2)以阴性对照孔内细菌明显生长为前提条件，通过肉眼观察，以加药后孔内细菌无明显生长的药物最低浓度为该药物的MIC(μg/mL)，实验平行重复三次。结果见表1～3，由表可见，化合物D1、D2、D5对金黄色葡萄球菌具有较强的抗菌活性，MIC值为2～4μg/mL。化合物D1、D2、D5、D6对表皮葡萄球菌的MIC为0.5～8μg/mL，优于木豆素的16μg/mL。化合物D1、D2、D3、D4、D5、D6、D7对枯草芽孢杆菌的抗菌作用较好，MIC为0.5～2μg/mL。化合物D1、D2、D6、D7对各种耐甲氧西林金黄色葡萄球菌均具有较好的抗菌效果，MIC值为0.5～8μg/mL。对MRSA的抗菌药效优于青霉素、诺氟沙星等临床常用药物，对于寻找抗耐药菌的药物具有重要意义。因此，理论和实验研究结果均显示，木豆素作为分子结构完全不同于已有抗菌药物的新化学实体，对于耐药菌具有良好的活性，极有可能作为新化学实体发展为新型抗菌剂。
表1活性实验所用菌株相关信息
| 菌种 | 拉丁文种名 | 培养条件 | 编号 | 菌属 |
| 金黄色葡萄球菌 | Staphylococcus aureus | 营养琼脂培养基37℃,24h | ATCC25923 | G+ |
| 表皮葡萄球菌 | Staphylococcus epidermidis | 营养琼脂培养基37℃,24h | ATCC12228 | G+ |
| 枯草芽孢杆菌 | Bacillus subtilis | 营养琼脂培养基37℃,24h | ATCC6633 | G+ |
| 耐甲氧西林金葡菌 | Methicillin-resistant S.a | 营养琼脂培养基37℃,24h | ATCC43300 | G+ |
| 大肠杆菌 | Escherichia coli | 营养琼脂培养基37℃,24h | ATCC25922 | G- |
| 普通变形球菌 | Proteus vulgaris | 营养琼脂培养基37℃,24h | ATCC49101 | G- |
| 铜绿假单胞菌 | Pesudomonas aeruginosa | 营养琼脂培养基37℃,24h | ATCC27853 | G- |
注：以上供试菌种来源于广东省微生物研究所；G+：革兰氏阳性菌；G-：革兰氏阴性菌.
耐甲氧西林金黄色葡萄球菌MRSA 425055、513045、62202、51033、52056、515992、510019来自广州军区广州总医院，培养条件与耐甲氧西林金黄色葡萄球菌MRSA43300完全相同。
表2木豆素衍生物对普通细菌的最低抑菌浓度(μg/mL)
| 化合物 | S.a | S.e | B.s | MRSA(43300) | E.c | P.v | P.a |
| B1 | ＞128 | 128 | 128 | ＞128 | ＞128 | ＞128 | 128 |
| B2 | ＞128 | 128 | 128 | ＞128 | ＞128 | ＞128 | 128 |
| B3 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| B4 | ＞128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 | ＞128 |
| B5 | 128 | 128 | ＞128 | ＞128 | ＞128 | ＞128 | 128 |
| B6 | 128 | ＞128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 |
| B7 | ＞128 | ＞128 | ＞128 | 128 | 64 | 128 | ＞128 |
| B9 | ＞128 | 128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| B10 | 128 | ＞128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 |
| C1 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C2 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C3 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C4 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C5 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C6 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C7 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C8 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| D1 | 4 | 1 | 0.5 | 1 | 64 | ＞64 | ＞64 |
| D2 | 4 | 2 | 0.5 | 1 | ＞128 | ＞64 | ＞64 |
| D3 | 8 | 4 | 1 | 4 | ＞128 | ＞64 | ＞64 |
| D4 | 16 | 4 | 2 | 2 | 128 | ＞64 | ＞64 |
| D5 | 2 | 8 | 0.5 | 32 | ＞128 | ＞64 | ＞64 |
| D6 | 16 | 0.5 | 2 | 2 | ＞128 | ＞64 | ＞64 |
| D7 | 16 | 8 | 0.5 | 2 | ＞128 | ＞64 | ＞64 |
| D8 | 64 | 32 | 64 | 32 | ＞128 | ＞64 | ＞64 |
| E1 | 64 | 64 | 64 | 64 | ＞128 | ＞128 | ＞128 |
| E2 | 128 | 128 | 128 | 128 | ＞128 | ＞128 | ＞128 |
| E3 | 128 | 64 | 64 | 128 | ＞128 | ＞128 | ＞128 |
| 木豆素 | 16 | 16 | 32 | 16 | ＞128 | ＞64 | ＞64 |
| 青霉素 | 2 | 2 | 2 | 32 | 64 | ＞16 | 16 |
| 诺氟沙星 | 2 | 2 | 2 | 0.5 | 32 | 16 | 16 |
表3木豆素衍生物对耐甲氧西林金黄色葡萄球菌的最低抑菌浓度(MIC)
| 化合物 | 425055 | 513045 | 62202 | 51033 | 52056 | 515992 | 510019 |
| B1 | 128 | 128 | 64 | ＞128 | ＞128 | ＞128 | ＞128 |
| B2 | ＞128 | 128 | 128 | ＞128 | ＞128 | ＞128 | 128 |
| B3 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | 128 | ＞128 |
| B4 | ＞128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 | ＞128 |
| B5 | 128 | 128 | ＞128 | ＞128 | ＞128 | ＞128 | 128 |
| B6 | 128 | ＞128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 |
| B7 | ＞128 | ＞128 | ＞128 | 128 | ＞128 | 64 | ＞128 |
| B9 | ＞128 | 64 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| B10 | 128 | ＞128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 |
| C1 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C2 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C3 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C4 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C5 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C6 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C7 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| C8 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 | ＞128 |
| D1 | 0.5 | 2 | 0.5 | 1 | 2 | 2 | 2 |
| D2 | 2 | 2 | 0.5 | 1 | 0.5 | 1 | 1 |
| D3 | 4 | 8 | 1 | 4 | 2 | 8 | 2 |
| D4 | 4 | 4 | 2 | 0.5 | 2 | 4 | 1 |
| D5 | 0.5 | 0.5 | 8 | 32 | 8 | 8 | 4 |
| D6 | 4 | 0.5 | 4 | 2 | 2 | 4 | 4 |
| D7 | 1 | 8 | 0.5 | 1 | 4 | 1 | 2 |
| D8 | 32 | 32 | 64 | 32 | 16 | 32 | 32 |
| E1 | 64 | 64 | 64 | 64 | 128 | 128 | 128 |
| E2 | 128 | ＞128 | 128 | ＞128 | ＞128 | ＞128 | ＞128 |
| E3 | 128 | 64 | 64 | 128 | ＞128 | 128 | 128 |
| 木豆素 | 16 | 16 | 8 | 16 | 16 | 32 | 32 |
| 青霉素 | 32 | 32 | 32 | 32 | 64 | 32 | 32 |
| 诺氟沙星 | 4 | 4 | 2 | 0.5 | 4 | 4 | 2 |
由实验结果可知，本发明的木豆素类似物对革兰氏阳性菌具有良好的抗菌活性，尤其是对耐甲氧西林金黄色葡萄球菌，优于阳性对照药。这在此类化合物中是第一次被发现。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (6)
1.一种木豆素结构类似物，其特征在于具有式Ⅰ所示结构：
其中，R1为-H或-CH3；
R2为-H、异戊烯基或香叶基；
R3为-CH3或
R4为-H、-F、-Cl、-OCH3、-CF3或-CN，且不限定其在苯环上取代的个数。
2.根据权利要求1所述的木豆素结构类似物，其特征在于具有下述所示结构：
3.根据权利要求1～2任一项所述的木豆素结构类似物在制备抗菌药物中的应用。
4.根据权利要求1～2任一项所述的木豆素结构类似物在制备抗金黄色葡萄球菌药物中的应用。
5.根据权利要求3所述的木豆素结构类似物在制备抗菌药物中的应用，其特征在于：所述的药物指含有所述木豆素结构类似物或其药用盐和溶剂化物中的至少一种。
6.根据权利要求3所述的木豆素结构类似物在制备抗菌药物中的应用，其特征在于：所述的药物可含有一种或多种药学上可接受的载体或赋形剂。
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| CN111039983A (zh) * | 2019-12-19 | 2020-04-21 | 赵洁 | 一种抗菌药物的制备方法及其用途 |
| CN111494364A (zh) * | 2020-06-19 | 2020-08-07 | 中南民族大学 | 异戊烯基取代的苯酚类化合物抗金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌的应用 |
| CN114075107A (zh) * | 2020-08-17 | 2022-02-22 | 暨南大学 | 一类木豆素衍生物及其在制备抗菌药物中的应用 |
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| CN102372627A (zh) * | 2010-08-18 | 2012-03-14 | 中国医学科学院医药生物技术研究所 | 木豆素及其结构类似物的制备方法 |
| CN103172512A (zh) * | 2011-12-23 | 2013-06-26 | 中国医学科学院医药生物技术研究所 | 一组木豆素结构类似化合物、制备方法和应用 |
| CN103992290A (zh) * | 2013-05-14 | 2014-08-20 | 中国医学科学院医药生物技术研究所 | 二芳基乙烯结构类似化合物及其制备方法和应用 |
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| CN103172512A (zh) * | 2011-12-23 | 2013-06-26 | 中国医学科学院医药生物技术研究所 | 一组木豆素结构类似化合物、制备方法和应用 |
| CN103992290A (zh) * | 2013-05-14 | 2014-08-20 | 中国医学科学院医药生物技术研究所 | 二芳基乙烯结构类似化合物及其制备方法和应用 |
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| CN111039983A (zh) * | 2019-12-19 | 2020-04-21 | 赵洁 | 一种抗菌药物的制备方法及其用途 |
| CN111039983B (zh) * | 2019-12-19 | 2022-04-15 | 赵洁 | 一种抗菌药物的制备方法及其用途 |
| CN111494364A (zh) * | 2020-06-19 | 2020-08-07 | 中南民族大学 | 异戊烯基取代的苯酚类化合物抗金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌的应用 |
| CN111494364B (zh) * | 2020-06-19 | 2021-02-12 | 中南民族大学 | 异戊烯基取代的苯酚类化合物抗金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌的应用 |
| CN114075107A (zh) * | 2020-08-17 | 2022-02-22 | 暨南大学 | 一类木豆素衍生物及其在制备抗菌药物中的应用 |
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