CN108191812B - 鼠尾草酸衍生物以及制备方法和应用 - Google Patents

鼠尾草酸衍生物以及制备方法和应用 Download PDF

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CN108191812B
CN108191812B CN201711329759.4A CN201711329759A CN108191812B CN 108191812 B CN108191812 B CN 108191812B CN 201711329759 A CN201711329759 A CN 201711329759A CN 108191812 B CN108191812 B CN 108191812B
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carnosic acid
chlorobenzylamine
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张荣平
胡炜彦
于浩飞
刘丹丹
梁新新
张兰春
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Kunming Medical University
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Abstract

本发明涉及鼠尾草酸衍生物以及制备方法和应用，属于天然药物化学领域，该方法制备得到的鼠尾草酸衍生物具有神经保护作用效果佳、稳定性好、产率高等优点，在制备治疗神经退行性疾病药物中起着重要作用。同时，该制备方法简单易行、普适性强，衍生物产率均在85%~95%。

Description

鼠尾草酸衍生物以及制备方法和应用
技术领域
本发明涉及一种衍生物，尤其是鼠尾草酸衍生物，还涉及其制备方法和应用，属于天然药物化学领域。
背景技术
神经系统是人体结构和功能最为复杂的系统，起着对生命活动过程进行调控的重要作用。尤其是中枢神经系统，是对各种信号进行整合处理的关键部位。中枢神经系统退行性疾病是慢性进行性中枢神经组织退行性变性而产生的一组疾病的总称，主要包括帕金森病(PD)、阿尔兹海默病(AD)、亨廷顿病(HD)、肌萎缩侧索硬化病(ALS)等。随着社会发展和人口老龄化的出现，中枢神经系统退行性疾病已经成为影响人类健康水平和生活质量的重大问题。因此，寻找和研制安全有效的药物成为神经系统退行性疾病治疗的关键。
鼠尾草酸(Carnosic acid)属于松香烷型三环二萜类化合物，外观为无色至淡黄色粉末晶体，易溶于油脂而不溶于水，主要存在于迷迭香、三叶鼠尾草、南欧丹参等植物中，是这些植物中主要的天然抗氧化成分，具有抗氧化、抗炎、抗菌、抗肿瘤、神经保护等多种生物活性。我们的实验结果表明：鼠尾草酸能够保护小鼠海马神经元免受H2O2或者Aβ损伤。但由于其具有不稳定的邻二酚羟基，在加热、光照及暴露于空气中等条件下都容易发生变化，生成一系列复杂多变的化合物，导致其生物活性降低。
发明内容
为了解决上述技术问题，本发明的第一目的在于提供鼠尾草酸衍生物，第二目的在于提供鼠尾草酸衍生物的制备方法，第三目的在于提供鼠尾草酸衍生物的应用，为鼠尾草酸的开发利用和神经退行性疾病的治疗提供新的选择。
本发明的上述目的是通过以下技术方案实现的：
鼠尾草酸衍生物，其特征在于：该化合物的结构式如式(Ⅰ)、式(Ⅱ)或式(Ⅲ)所示：
Figure BDA0001506396260000011
其中，R1为-H、-OH、-O-(7-氮苯并三氮唑)、甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基。
Figure BDA0001506396260000021
其中，R2为羟基。
Figure BDA0001506396260000022
其中，R3为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基。
本发明涉及的鼠尾草酸衍生物的制备方法，其特征在于：包括如下步骤：
步骤(1)、进行反应(ⅰ)，取式(IV)结构的鼠尾草酸溶于丙酮溶液中，在原甲酸三甲酯作脱水剂，对甲苯磺酸催化下，室温条件下发生缩酮反应，生成式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物；
步骤(2)、进行反应(ⅱ)，取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物在二氯甲烷溶剂中，DIPEA为催化剂，室温条件下与HATU反应，得到式(Ⅰ)R1为-O-(7-氮苯并三氮唑)结构的鼠尾草酸衍生物；
或，
步骤(2)、进行反应(ⅲ)，取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物，在二氯甲烷溶剂中，以HATU为缩合剂，DIPEA为催化剂，室温条件下与伯胺发生缩合反应，得到式(Ⅰ)R1为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基结构的鼠尾草酸衍生物；
或，
步骤(2)、进行反应(iv)，取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物，在无水四氢呋喃溶剂中，回流条件下被锂铝氢还原，得到式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物；
步骤(3)、进行反应(ⅴ)，取式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物在二氯甲烷溶剂中，室温条件下被戴斯-马丁氧化剂氧化，得到式(Ⅰ)R1为-H结构的鼠尾草酸衍生物；
或，
步骤(3)、进行反应(ⅵ)，取式(Ⅰ)结构的鼠尾草酸衍生物在三氟乙酸的水溶液中，室温条件下脱去异丙基保护基团，得到式(Ⅲ)结构的鼠尾草酸衍生物，如下：
Figure BDA0001506396260000031
进一步地，作为其中一个实施例，步骤(1)中，进行反应(ⅰ)，取式(IV)结构的鼠尾草酸80.0-120.0mg溶于4-8ml丙酮溶液中，加入原甲酸三甲酯作脱水剂，对甲苯磺酸催化，氮气保护下室温搅拌5-10h，使用EtOAc/H2O萃取，有机相分别用饱和NaHCO3溶液、饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物。
进一步地，作为其中一个实施例，步骤(2)中，进行反应(ⅱ)，取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物80.0-120.0mg，溶于4-6ml二氯甲烷(DCM)中，加入0.1-0.15ml DIPEA，冰浴搅拌10-20min，加入110.0-120.0mgHATU，室温搅拌0.5-1.2h，使用DCM/H2O萃取，用饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-O-(7-氮苯并三氮唑)结构的鼠尾草酸衍生物。
进一步地，作为其中一个实施例，步骤(2)中，进行反应(ⅲ)，取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物80.0-120.0mg，溶于4-8ml DCM中，加入0.10-0.20ml N,N-二异丙基乙胺(DIPEA)，冰浴搅拌10-20min，加入110.0-120.0mg HATU，室温搅拌1h后加入伯胺，薄层色谱法检测反应进程，DCM/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基结构的鼠尾草酸衍生物。
进一步地，作为其中一个实施例，步骤(2)中，进行反应(iv)，取35.0-45.0mg锂铝氢于二颈瓶中，加入10-20ml无水四氢呋喃，通氮气保护，冰浴下加入溶于无水THF的式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物80.0-120.0mg，回流反应6-10h，冰浴加水淬灭，硅藻土过滤，通过EtOAc/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，减压浓缩，经柱层析纯化，得到式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物。
进一步地，作为其中一个实施例，步骤(3)中，进行反应(ⅴ)，取式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物80-120.0mg，溶于4-8ml DCM中，加入140.0-150.0mg戴斯-马丁氧化剂，室温搅拌1-2h，用DCM/H2O萃取，有机相分别用饱和NaHCO3溶液、饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-H结构的鼠尾草酸衍生物。
进一步地，作为其中一个实施例，步骤(3)中，进行反应(ⅵ)，取式(Ⅰ)结构的鼠尾草酸衍生物80.0-120.0mg，加入TFA/H2O溶液中，室温搅拌0.5-1.5h，冰浴下加饱和NaHCO3溶液调PH中性，用EtOAc/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，减压浓缩，经柱层析纯化，得到式(Ⅲ)结构的鼠尾草酸衍生物。
本发明涉及的鼠尾草酸衍生物在治疗神经系统疾病药物中的应用。
进一步地，所述的治疗神经系统退行性疾病药物为治疗Aβ或者H2O2诱导的神经细胞的氧化损伤的药物。
与现有技术相比，本发明的有益效果如下：
(1)本发明的鼠尾草酸酰胺类衍生物具有更好的稳定性，鼠尾草酸在无水乙醇溶液中，室温条件下，72h降解44％。因此，我们对鼠尾草酸进行结构修饰，将不稳定的邻二酚羟基保护起来，并在20位引入酰胺结构，提高其稳定性及神经保护活性。合成路线的优点：其一，通常邻二酚羟基的保护方法是与酸酐或者酰氯反应生成酯，但是酯在碱性条件下水解脱保护。异丙叉保护鼠尾草酸的邻二酚羟基在碱性条件下稳定，在下一步碱性条件下进行还原或者缩合反应时，不会脱保护。其二，通常酰胺的合成需要进行两步反应：羧酸与二氯亚砜在四氢呋喃溶液中加热回流条件下生成酰氯，酰氯再与胺反应生成酰胺。本发明用HATU缩合剂合成鼠尾草酸酰胺类衍生物，缩短了反应步骤，只需要1步反应；无需加热回流，室温即可，简单易行；普适性强，适用于羧基与各种胺的缩合。
(2)本发明的合成方法简单易行，产率高，均在85％～95％。
(3)本发明合成的鼠尾草酸衍生物，在制备治疗神经系统退行性疾病药物中具有显著效果，保护作用效果佳、稳定性好，尤其是用于治疗H2O2诱导的神经细胞氧化损伤的药物或治疗Aβ诱导的神经细胞氧化损伤的药物。
附图说明
图1为鼠尾草酸的结构式及碳原子编号。
具体实施方式
下面用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。实施例1鼠尾草酸20位还原衍生物的合成
1仪器与材料
1.1仪器BSA124S-CW电子分析天平(德国Sartorius赛多利斯)；R-200旋转蒸发仪(瑞士BUCHI步琦)；SHZ-D(III)循环水式真空泵(巩义市予华仪器有限责任公司)；DLSB-5/25低温冷却液循环泵(巩义市予华仪器有限责任公司)；CMAG HS7加热磁力搅拌器(德国Ika艾卡)；AVANCE-400核磁共振仪、AVANCE-500核磁共振仪(德国Bruker布鲁克)；上海仪电物光WRS-1C熔点仪。
1.2材料鼠尾草酸(纯度95％，西安百川生物科技有限公司)；GF254薄层层析板(青岛海洋化工厂)；柱层层析硅胶(200～300目，青岛海洋化工厂)；化学合成试剂均为分析纯，购于上海泰坦科技股份有限公司；柱层析用溶剂为重蒸的工业级溶剂。
2合成方法
反应(ⅰ)、式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物的合成
取式(IV)结构的鼠尾草酸115.0mg溶于7ml丙酮溶液中，加入原甲酸三甲酯作脱水剂、对甲苯磺酸做催化剂，氮气保护下室温搅拌7h，使用EtOAc/H2O萃取，有机相分别用饱和NaHCO3溶液和饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物。C23H32O4浅黄色固体，产率91.0％，熔点：156-157℃。
1H NMR(400MHz,CDCl3)δ6.42(1H,s),3.29(1H,d,J＝13.4Hz),2.91-2.77(3H,m),2.36(1H,ddd,J＝18.8,12.4,6.0Hz),2.12-2.00(1H,m),1.81(1H,q,J＝6.4Hz),1.62(3H,s),1.54(2H,dd,J＝12.8,2.0Hz),1.46(1H,d,J＝13.2Hz),1.32(3H,s),1.28-1.24(2H,m),1.20(6H,dd,J＝6.9,4.1Hz),0.95(3H,s),0.83(3H,s).
13C NMR(100MHz,CDCl3)δ144.72,142.53,129.98,128.51,120.42,119.06,116.46,53.40,46.71,41.84,34.02,33.91,32.36,30.75,28.32,25.63,25.30,22.21,21.94,19.93,19.91,18.64.
反应(ⅰ)之后进行反应(iv)
取41.0mg锂铝氢(LAH)于二颈瓶中，加入15ml无水四氢呋喃(THF)，氮气保护，冰浴下加入溶于无水THF的式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物100.0mg(0.27mmol)，回流反应8h，冰浴加水淬灭，硅藻土过滤，EtOAc/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，减压浓缩，经柱层析纯化，得到式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物(83.0mg)，C23H34O3白色固体，产率85.9％，熔点：91-92℃，
1H NMR(500MHz,CDCl3)δ6.46(1H,s),4.08(1H,dd,J＝11.0,6.5Hz),3.87(1H,dd,J＝11.0,6.4Hz),3.00-2.78(4H,m),1.81-1.76(2H,m),1.66-1.64(1H,m),1.63(6H,d,J＝4.0Hz),1.57-1.52(3H,m),1.30-1.24(2H,m),1.21(6H,d,J＝7.0Hz),0.95(6H,d,J＝5.6Hz).
13C NMR(125MHz,CDCl3)δ144.57,142.32,130.05,128.28,124.31,119.57,115.91,66.18,51.64,43.47,41.56,33.69,33.54,32.82,30.75,28.40,25.76,25.64,22.31,22.19,22.07,18.91,18.88.
实施例2鼠尾草酸20位氧化衍生物的合成
本实施例中，反应(ⅰ)、反应(iv)之后进行反应(ⅴ)
取式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物80mg，溶于4ml二氯甲烷中，加入140.0mg戴斯-马丁氧化剂(DMP)，室温搅拌1h，用DCM/H2O萃取，有机相分别用饱和NaHCO3溶液、饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-H结构的鼠尾草酸衍生物，产率91.3％，C23H32O3无色油状物，
1H NMR(500MHz,CDCl3)δ9.84(1H,d,J＝1.5Hz),6.48(1H,s),3.34(1H,d,J＝13.4Hz),2.97-2.84(3H,m),2.08-1.99(1H,m),1.96-1.92(1H,m),1.74(1H,dt,J＝13.8,3.6Hz),1.65-1.62(5H,m),1.60-1.57(1H,m),1.55(3H,s),1.46(1H,d,J＝13.2Hz),1.30(1H,dd,J＝13.5,4.1Hz),1.21(6H,d,J＝7.0Hz),0.98(3H,s),0.82(3H,s).
13C NMR(125MHz,CDCl3)δ198.38,146.19,143.10,130.83,129.22,119.18,116.80,115.32,52.93,52.11,41.46,33.92,31.87,31.22,30.30,28.40,25.67,25.62,22.03,21.93,20.92,19.37,18.55.
实施例3鼠尾草酸20位酯化衍生物的合成
本实施例中，反应(ⅰ)之后进行反应(ⅱ)
取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物100.0mg式(Ⅴ)结构的异丙叉鼠尾草酸溶于5ml DCM中，加入0.14ml N,N-二异丙基乙胺(DIPEA)，冰浴搅拌15min，加入112.4mg O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(HATU)，室温搅拌1h，使用DCM/H2O萃取，用饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-O-(7-氮苯并三氮唑)结构的鼠尾草酸衍生物，产率93.0％，C28H34N4O4浅黄色固体，熔点：56-57℃，
1H NMR(400MHz,CDCl3)δ8.60(1H,dd,J＝4.5,1.3Hz),8.34(1H,dd,J＝8.4,1.3Hz),7.35(1H,dd,J＝8.4,4.5Hz),6.50(1H,s),3.68(1H,d,J＝13.8Hz),3.01-2.84(3H,m),2.50(1H,ddd,J＝19.0,12.3,6.1Hz),2.34-2.22(1H,m),2.02(1H,dd,J＝13.5,6.4Hz),1.78-1.74(2H,m),1.72(6H,s),1.47-1.36(3H,m),1.25(6H,d,J＝6.9Hz),1.08(6H,d,J＝12.0Hz).
13C NMR(100MHz,CDCl3)δ170.61,151.30,145.39,143.05,140.95,134.80,129.77,129.42,128.91,120.45,119.37,117.91,117.40,53.98,47.25,41.62,34.25,34.16,32.44,30.58,28.50,26.04,25.88,22.07,21.98,20.66,20.11,19.11.
实施例4鼠尾草酸20位酰胺化衍生物的合成
本实施例中，反应(ⅰ)之后进行反应(ⅲ)
取式(Ⅰ)R1为-OH结构的鼠尾草酸衍生物100.0mg，溶于5ml DCM中，加入0.14ml N,N-二异丙基乙胺(DIPEA)(0.81mmol)，冰浴搅拌15min，加入112.4mg O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(HATU)，室温搅拌1h后加入不同的伯胺，薄层色谱法检测反应进程，DCM/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基结构的酰胺类系列化合物A1～A19。所用伯胺及相应反应时间、分离产率如表1所示。
表1不同伯胺的反应时间及产率
Figure BDA0001506396260000081
化合物A1，C24H35NO3浅黄色固体，熔点：102-103℃，
1H NMR(400MHz,CDCl3)δ6.45(1H,s),6.03(1H,d,J＝4.1Hz),3.11(1H,d,J＝14.36Hz),2.93-2.87(2H,m),2.83-2.78(1H,m),2.71(3H,d,J＝4.7Hz),2.68-2.56(1H,m),1.84(1H,q,J＝6.4Hz),1.66(3H,s),1.54(4H,s),1.45(1H,dd,J＝12.3,2.0Hz),1.38(1H,dd,J＝13.8,3.6Hz),1.31(1H,dd,J＝11.7,3.8Hz),1.25(1H,s),1.20(6H,d,J＝6.7Hz),0.93(6H,d,J＝22.4Hz).
13C NMR(100MHz,CDCl3)δ175.16,144.00,142.49,130.12,128.56,122.53,119.69,116.09,53.67,47.20,41.96,35.04,33.85,32.75,30.84,28.40,26.32,25.73,25.67,22.11,21.97,21.36,20.32,19.30.
化合物A2，C25H37NO3无色油状物，
1H NMR(400MHz,CDCl3)δ6.45(1H,s),5.99(1H,t,J＝5.0Hz),3.30-3.10(3H,m),2.94-2.87(2H,m),2.83-2.75(1H,m),2.64(1H,ddd,J＝18.5,12.4,5.9Hz),2.07-1.95(1H,m),1.86-1.81(1H,m),1.64(3H,s),1.57(3H,s),1.53-1.49(1H,m),1.45(1H,dd,J＝12.5,2.2Hz),1.37(1H,dd,J＝14.1,3.8Hz),1.32-1.25(2H,m),1.19(6H,d,J＝6.9Hz),1.08(3H,t,J＝7.2Hz),0.95(3H,s),0.90(3H,s).
13C NMR(100MHz,CDCl3)δ174.18,143.99,142.47,130.06,128.48,122.53,119.63,116.16,53.68,47.01,41.96,34.93,34.27,33.89,32.75,30.80,28.36,25.85,25.72,22.14,21.95,21.31,20.31,19.21,14.75.
化合物A3，C26H37NO3无色油状物，
1H NMR(400MHz,CDCl3)δ6.46(1H,s),6.10(1H,t,J＝5.2Hz),5.85-5.75(1H,m),5.10-5.03(2H,m),3.93-3.85(1H,m),3.76-3.68(1H,m),3.16(1H,d,J＝14.4Hz),2.94-2.87(2H,m),2.84-2.76(1H,m),2.62(1H,ddd,J＝18.7,12.6,6.1Hz),2.08-1.96(1H,m),1.88-1.83(1H,m),1.64(3H,s),1.57(3H,s),1.50-1.45(2H,m),1.42-1.37(1H,m),1.35-1.27(2H,m),1.20(6H,dd,J＝6.9,0.7Hz),0.96(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ174.27,143.98,142.52,134.82,130.04,128.61,122.43,119.71,116.26,115.65,53.60,47.28,41.93,41.90,35.03,33.89,32.79,30.76,28.38,25.87,25.73,22.11,21.96,21.36,20.35,19.25.
化合物A4，C29H43NO3无色油状物，
1H NMR(400MHz,CDCl3)δ6.45(1H,s),5.86(1H,d,J＝7.9Hz),3.78-3.69(1H,m),3.14(1H,d,J＝14.5Hz),2.94-2.87(2H,m),2.84-2.85(1H,m),2.67(1H,ddd,J＝18.2,12.1,5.7Hz),2.07-1.95(1H,m),1.88-1.76(3H,m),1.61(7H,d,J＝4.2Hz),1.59-1.48(4H,m),1.44(1H,dd,J＝12.5,2.4Hz),1.39-1.26(5H,m),1.20(6H,dd,J＝6.9,1.1Hz),1.12-1.09(2H,m),0.95(1H,s),0.91(1H,s).
13C NMR(100MHz,CDCl3)δ173.11,143.99,142.46,130.03,128.43,122.57,119.57,116.17,53.64,47.62,46.92,42.00,34.83,33.93,32.94,32.76,30.66,28.36,26.10,25.68,25.64,24.75,24.61,22.15,21.97,21.29,20.30,19.16.
化合物A5，C30H39NO3浅黄色固体，熔点：69-70℃，
1H NMR(400MHz,CDCl3)δ7.32-7.05(3H,m),7.20-7.18(2H,m),6.50(1H,s),6.33(1H,t,J＝5.3Hz),4.51(1H,dd,J＝14.9,6.0Hz),4.31(1H,dd,J＝15.0,5.0Hz),3.21(1H,d,J＝14.3Hz),2.99-2.91(2H,m),2.89-2.80(1H,m),2.66(1H,ddd,J＝18.8,12.6,6.2Hz),2.12-2.00(1H,m),1.93-1.88(1H,m),1.62(3H,s),1.54-1.51(2H,m),1.45(3H,s),1.42-1.28(3H,m),1.24(6H,dd,J＝6.9,1.3Hz),0.99(6H,d,J＝13.3Hz).
13C NMR(100MHz,CDCl3)δ174.39,143.98,142.57,138.83,129.97,128.63,128.48×2,127.52×2,127.10,122.40,119.77,116.23,53.52,47.37,43.54,41.94,35.06,33.91,32.81,30.69,28.41,25.62,25.61,22.09,22.03,21.40,20.37,19.29.
化合物A6，C31H41NO3白色粉末，熔点：112-113℃，
1H NMR(400MHz,CDCl3)δ7.10-7.05(4H,m),6.47(1H,s),6.25(1H,t,J＝5.1Hz),4.45(1H,dd,J＝14.8,6.0Hz),4.22(1H,dd,J＝14.8,4.8Hz),3.17(1H,d,J＝14.5Hz),2.95-2.88(2H,m),2.85-2.77(1H,m),2.64(1H,ddd,J＝18.8,12.6,6.1Hz),2.32(3H,s),2.07-1.97(1H,m),1.90-1.85(1H,m),1.59(3H,s),1.55-1.47(3H,m),1.45(3H,s),1.41-1.28(2H,m),1.21(6H,dd,J＝6.9,1.3Hz),0.96(6H,d,J＝12.0Hz).
13C NMR(100MHz,CDCl3)δ174.31,143.99,142.56,136.74,135.74,129.99,129.15×2,128.59,127.54×2,122.42,119.74,116.21,53.56,47.30,43.35,41.95,35.01,33.91,32.80,30.69,28.41,25.62×2,22.09,22.02,21.39,21.03,20.36,19.27.
化合物A7，C30H40N2O3浅黄色粉末，熔点：154-155℃，
1H NMR(400MHz,CDCl3)δ7.04(1H,t,J＝7.7Hz),6.54(2H,dd,J＝7.8,2.2Hz),6.47(1H,s),6.41(1H,s),6.25(1H,t,J＝5.2Hz),4.38(1H,dd,J＝15.0,6.0Hz),4.18(1H,dd,J＝14.9,4.9Hz),3.60(2H,s),3.18(1H,d,J＝14.2Hz),2.97-2.88(2H,m),2.80(3H,s),2.63(1H,ddd,J＝18.8,12.6,6.1Hz),2.07-1.97(1H,m),1.89-1.84(1H,m),1.59(3H,s),1.51(1H,d,J＝2.3Hz),1.46(3H,s),1.41-1.34(1H,m),1.28-1.24(1H,m),1.21(6H,dd,J＝6.9,1.0Hz),0.96(6H,d,J＝10.8Hz).
13C NMR(100MHz,CDCl3)δ174.30,146.59,144.02,142.51,140.02,130.10,129.38,128.59,122.48,119.75,117.47,116.30,114.05,113.77,53.52,47.35,43.47,41.96,38.58,35.06,33.92,32.80,30.68,28.38,25.60,25.58,22.20,21.97,21.45,20.37,19.28.
化合物A8，C31H41NO4浅黄色粉末，熔点：104-105℃，
1H NMR(400MHz,CDCl3)δ7.09(2H,dt,J＝8.7,2.7Hz),6.80(2H,dt,J＝8.6,2.9Hz),6.47(1H,s),6.24(1H,t,J＝5.2Hz),4.40(1H,dd,J＝14.6,5.9Hz),4.21(1H,dd,J＝14.7,5.0Hz),3.78(3H,s),3.16(1H,d,J＝14.3Hz),2.95-2.88(2H,m),2.85-2.76(1H,m),2.64(1H,ddd,J＝18.7,12.6,6.1Hz),2.07-1.95(1H,m),1.89-1.84(1H,m),1.59(3H,s),1.56-1.47(3H,m),1.43(3H,s),1.41-1.27(2H,m),1.22(6H,dd,J＝6.9,1.0Hz),0.95(6H,d,J＝14.2Hz).
13C NMR(100MHz,CDCl3)δ174.26,158.72,143.97,142.54,130.90,129.99,128.84×2,128.58,122.40,119.74,116.19,113.85×2,55.24,53.55,47.29,43.01,41.95,35.02,33.91,32.79,30.68,28.41,25.64,25.61,22.09,22.02,21.41,20.35,19.27.
化合物A9，C30H38FNO3白色粉末，熔点：102-103℃，
1H NMR(400MHz,CDCl3)δ7.13-7.09(2H,m),6.96-6.90(2H,m),6.47(1H,s),6.30(1H,t,J＝5.4Hz),4.41(1H,dd,J＝14.9,6.0Hz),4.25(1H,dd,J＝14.9,5.4Hz),3.17(1H,d,J＝14.2Hz),2.95-2.88(2H,m),2.86-2.77(1H,m),2.59(1H,ddd,J＝18.9,12.7,6.2Hz),2.06-1.94(1H,m),1.90-1.85(1H,m),1.59(3H,s),1.57-1.47(3H,m),1.42(3H,s),1.38-1.27(2H,m),1.21(6H,dd,J＝7.0,1.0Hz),0.97(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ174.46,163.16,160.72,143.96,142.58,134.72,134.69,129.98,129.17,129.09,128.73,122.36,119.84,116.22,115.35,115.14,53.47,47.43,42.77,41.91,35.08,33.91,32.81,30.67,28.44,25.65,25.59,22.10,22.02,21.39,20.37,19.30.
化合物A10，C30H38ClNO3无色油状物，
1H NMR(400MHz,CDCl3)δ7.32-7.29(1H,m),7.26-7.23(1H,m),7.19-7.12(2H,m),6.48(1H,s),6.42(1H,t,J＝5.8Hz),4.56(1H,dd,J＝15.0,6.5Hz),4.33(1H,dd,J＝15.0,5.4Hz),3.19(1H,d,J＝14.2Hz),2.96-2.89(2H,m),2.87-2.78(1H,m),2.53(1H,ddd,J＝19.0,12.8,6.2Hz),2.11-2.00(1H,m),1.90-1.85(1H,m),1.60(3H,s),1.58-1.47(3H,m),1.40(3H,s),1.38-1.26(2H,m),1.22(6H,dd,J＝7.0,1.5Hz),0.95(3H,s),0.84(3H,s).
13C NMR(100MHz,CDCl3)δ174.45,144.04,142.61,136.12,133.46,130.07,129.77,129.23,128.68,128.46,126.82,122.39,119.72,116.23,53.36,47.40,41.82,41.43,34.97,33.82,32.80,30.64,28.43,25.59,25.55,22.06,22.05,21.02,20.22,19.26.
化合物A11，C31H41NO3无色油状物，
1H NMR(400MHz,CDCl3)δ7.29-7.25(2H,m),7.23-7.19(1H,m),7.12-7.10(2H,m),6.45(1H,s),6.01(1H,t,J＝5.4Hz),3.66-3.58(1H,m),3.27-3.19(1H,m),3.10(1H,d,J＝14.4Hz),2.96-2.89(1H,m),2.87-2.75(3H,m),2.73-2.66(1H,m),2.46(1H,ddd,J＝19.3,12.8,6.5Hz),2.08-1.96(1H,m),1.85-1.80(1H,m),1.60(3H,s),1.57-1.50(2H,m),1.46(3H,s),1.43-1.25(3H,m),1.22(6H,dd,J＝6.9,3.0Hz),0.95(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ174.40,143.97,142.50,139.31,129.84,128.60×2,128.52×2,126.28,122.63,119.59,116.17,53.37,47.27,41.85,40.73,35.77,35.00,33.82,32.78,30.66,28.34,25.64,25.60,22.18,21.93,21.22,20.22,19.18.
化合物A12，C29H38N2O3白色固体，熔点：117-118℃，
1H NMR(400MHz,CDCl3)δ8.47(2H,s),7.46(1H,d,J＝7.8Hz),7.16(1H,dd,J＝7.7,4.8Hz),6.47(1H,s),6.38(1H,t,J＝5.6Hz),4.45(1H,dd,J＝15.2,6.0Hz),4.30(1H,dd,J＝15.2,5.6Hz),3.16(1H,d,J＝14.4Hz),2.95-2.76(3H,m),2.56(1H,ddd,J＝18.9,12.7,6.2Hz),2.04-1.93(1H,m),1.89-1.84(1H,m),1.58(3H,s),1.53-1.46(2H,m),1.42(3H,s),1.38-1.23(3H,m),1.19(6H,d,J＝6.9Hz),0.96(3H,s),0.87(3H,s).
13C NMR(100MHz,CDCl3)δ174.72,148.96,148.55,143.89,142.55,135.42,134.52,129.91,128.79,123.40,122.15,119.86,116.27,53.47,47.39,41.81,40.92,34.99,33.88,32.76,30.66,28.37,25.67,25.54,22.10,21.95,21.31,20.34,19.26.
化合物A13，C28H37NO4浅黄色粉末，熔点：79-80℃，
1H NMR(400MHz,CDCl3)δ7.31(1H,d,J＝1.1Hz),6.47(1H,s),6.35(1H,t,J＝5.1Hz),6.28(1H,dd,J＝3.1,1.9Hz),6.11(1H,d,J＝2.8Hz),4.45(1H,dd,J＝15.6,5.8Hz),4.26(1H,dd,J＝15.6,4.8Hz),3.15(1H,d,J＝14.4Hz),2.94-2.87(2H,m),2.84-2.76(1H,m),2.63(1H,ddd,J＝18.6,12.6,6.0Hz),2.05-1.92(1H,m),1.88-1.83(1H,m),1.63(3H,s),1.60-1.49(3H,m),1.47(3H,s),1.41-1.26(2H,m),1.20(6H,d,J＝7.0Hz),0.96(3H,s),0.89(3H,s).
13C NMR(100MHz,CDCl3)δ174.19,151.83,144.02,142.52,141.75,130.02,128.62,122.09,119.69,116.26,110.29,106.93,53.64,47.23,41.92,36.55,34.99,33.87,32.78,30.73,28.39,25.67,25.55,22.07,21.99,21.31,20.26,19.23.
化合物A14，C30H39NO4白色粉末，熔点：202-203℃，
1H NMR(400MHz,CDCl3)δ6.94-6.84(3H,m),6.64(2H,dt,J＝8.5,2.8Hz),6.46(1H,s),6.31(1H,t,J＝5.3Hz),4.34(1H,dd,J＝14.7,5.8Hz),4.17(1H,dd,J＝14.6,5.0Hz),3.17(1H,d,J＝14.4Hz),2.95-2.87(2H,m),2.85-2.77(1H,m),2.60(1H,ddd,J＝18.9,12.7,6.2Hz),2.06-1.95(1H,m),1.90-1.85(1H,m),1.61-1.49(6H,m),1.42(3H,s),1.38-1.25(2H,m),1.20(6H,dd,J＝6.9,3.6Hz),0.97(3H,s),0.92(3H,s).
13C NMR(100MHz,CDCl3)δ174.76,155.53,144.01,142.58,129.92,129.71,128.81×2,128.72,122.14,119.72,116.33,115.48×2,53.57,47.21,43.28,41.89,34.88,33.91,32.72,30.61,28.40,25.61,25.59,22.13,21.97,21.30,20.30,19.25.
化合物A15，C30H38BrNO3白色粉末，熔点：132-133℃，
1H NMR(400MHz,CDCl3)δ7.37(1H,t,J＝2.4Hz),7.35(1H,t,J＝1.8Hz),7.03(1H,s),7.01(1H,s),6.47(1H,s),6.30(1H,t,J＝5.5Hz),4.40(1H,dd,J＝15.1,6.1Hz),4.23(1H,dd,J＝15.1,5.4Hz),3.17(1H,d,J＝14.1Hz),2.95-2.88(2H,m),2.86-2.77(1H,m),2.57(1H,ddd,J＝19.0,12.8,6.3Hz),2.06-1.95(1H,m),1.90-1.85(1H,m),1.59(3H,s),1.57-1.47(3H,m),1.44(3H,s),1.38-1.27(2H,m),1.21(6H,d,J＝6.9Hz),0.97(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ174.54,143.95,142.60,138.03,131.51×2,129.95,129.21×2,128.78,122.32,120.87,119.86,116.25,53.44,47.46,42.85,41.88,35.07,33.91,32.81,30.66,28.44,25.67,25.58,22.11,22.01,21.37,20.36,19.30.
化合物A16，C30H38ClNO3浅黄色固体，熔点：78-79℃，
1H NMR(400MHz,CDCl3)δ7.19-7.14(3H,m),7.04-7.01(1H,m),6.48(1H,s),6.35(3H,t,J＝5.5Hz),4.42(1H,dd,J＝15.2,6.0Hz),4.28(1H,dd,J＝15.2,5.5Hz),3.19(1H,d,J＝14.4Hz),2.96-2.89(2H,m),2.86-2.78(1H,m),2.59(1H,ddd,J＝19.0,12.6,6.2Hz),2.07-1.95(1H,m),1.91-1.86(1H,m),1.60-1.48(6H,m),1.45(3H,s),1.40-1.25(2H,m),1.21(6H,d,J＝6.9Hz),0.98(3H,s),0.93(3H,s).
13C NMR(100MHz,CDCl3)δ174.53,143.92,142.59,141.02,134.28,129.95,129.71,128.78,127.54,127.23,125.57,122.26,119.85,116.27,53.46,47.47,42.92,41.90,35.11,33.90,32.82,30.65,28.40,25.66,25.59,22.14,21.96,21.42,20.36,19.30.
化合物A17，C31H38F3NO3无色油状物，
1H NMR(400MHz,CDCl3)δ7.48(1H,d,J＝7.3Hz),7.45(1H,s),7.38-7.32(2H,m),6.49,(1H,s),6.45(1H,t,J＝5.7Hz),4.49(1H,dd,J＝15.2,6.0Hz),4.36(1H,dd,J＝15.2,5.6Hz),3.19(1H,d,J＝14.4Hz),2.96-2.88(2H,m),2.86-2.78(1H,m),2.59(1H,ddd,J＝18.9,12.7,6.2Hz),2.05-1.94(1H,m),1.91-1.86(1H,m),1.60(3H,s),1.58-1.43(3H,m),1.40(3H,s),1.37-1.24(2H,m),1.21(6H,d,J＝7.0Hz),0.98(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ174.70,143.93,142.62,140.13,130.92,130.04,128.98,128.88,124.25,124.21,123.96,123.92,122.26,119.93,116.27,53.52,47.57,43.04,41.94,35.23,33.94,32.86,30.70,28.44,25.60×2,22.16,21.97,21.48,20.39,19.36.
化合物A18，C30H37Cl2NO3白色固体，熔点：83-84℃，
1H NMR(400MHz,CDCl3)δ7.31,(1H,d,J＝2.0Hz),7.17(1H,d,J＝8.2Hz),7.11(1H,dd,J＝8.2,2.0Hz),6.48(1H,s),6.39(1H,t,J＝5.9Hz),4.49(1H,dd,J＝15.2,6.5Hz),4.27(1H,dd,J＝15.2,5.5Hz),3.18(1H,d,J＝14.2Hz),2.96-2.89(2H,m),2.86-2.77(1H,m),2.47(1H,ddd,J＝19.0,12.8,6.2Hz),2.09-1.97(1H,m),1.90-1.85(1H,m),1.60(3H,s),1.58-1.47(3H,m),1.44(3H,s),1.41-1.26(2H,m),1.22(6H,d,J＝6.9Hz),0.95(3H,s),0.82(3H,s).
13C NMR(100MHz,CDCl3)δ174.65,144.00,142.64,134.83,133.98,133.44,130.86,129.73,128.98,128.81,127.03,122.30,119.81,116.26,53.28,47.44,41.75,40.90,34.95,33.81,32.78,30.61,28.43,25.59,25.55,22.06,22.04,20.98,20.22,19.26.
化合物A19，C30H38ClNO3白色粉末，熔点：127-128℃，
1H NMR(400MHz,CDCl3)δ7.22(1H,t,J＝2.4Hz),7.20(1H,t,J＝1.9Hz),7.09(1H,s),7.06(1H,s),6.48(1H,s),6.31(1H,t,J＝5.5Hz),4.41(1H,dd,J＝15.1,6.0Hz),4.25(1H,dd,J＝15.1,5.4Hz),3.18(1H,d,J＝14.2Hz),2.97-2.88(2H,m),2.86-2.77(1H,m),2.58(1H,ddd,J＝19.0,12.8,6.3Hz),2.07-1.95(1H,m),1.90-1.85(1H,m),1.59(3H,s),1.57-1.47(3H,m),1.44(3H,s),1.39-1.28(2H,m),1.21(6H,d,J＝7.0Hz),0.97(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ174.52,143.94,142.59,137.49,132.80,129.94,128.84×2,128.76,128.54×2,122.32,119.85,116.24,53.43,47.44,42.78,41.88,35.06,33.89,32.80,30.65,28.43,25.66,25.57,22.10,22.00,21.36,20.35,19.29.
实施例5式(Ⅲ)结构的鼠尾草酸衍生物的合成
本实施例中，反应(ⅰ)、反应(ⅲ)之后进行反应(ⅵ)
脱去异丙叉保护基的反应：
分别取100.0mg式(Ⅰ)结构的的酰胺类鼠尾草酸衍生物A1～A19，加入TFA/H2O(体积比9/1)溶液中，室温搅拌1h，冰浴下加饱和NaHCO3溶液调PH 7，EtOAc/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，减压浓缩，经柱层析(PE/EtOAc)纯化，得到相应的式(Ⅲ)结构的鼠尾草酸衍生物：化合物B1～B19。
化合物B1，C21H31NO3黄色固体，熔点：120-121℃，
1H NMR(400MHz,CDCl3)δ9.21(1H,s),6.49(1H,s),5.96(2H,d,J＝4.0Hz),3.46(1H,dt,J＝13.6,2.9Hz),3.26-3.15(1H,m),2.91-2.88(2H,m),2.77(3H,d,J＝4.8Hz),2.18-2.14(1H,m),1.76-1.50(6H,m),1.34(1H,dd,J＝13.1,4.2Hz),1.21(6H,dd,J＝6.9,2.6Hz),1.03(3H,s),0.93(3H,s).
13C NMR(100MHz,CDCl3)δ178.00,142.90,141.87,133.09,126.59,123.85,118.22,53.04,49.40,41.99,35.57,34.41,33.05,31.57,27.10,26.66,22.90,22.50,22.17,21.03,20.33.
化合物B2，C22H33NO3浅黄色固体，熔点：139-140℃，
1H NMR(400MHz,CDCl3)δ9.42(1H,s),6.49(1H,s),5.97-5.94(2H,m),3.49-3.34(2H,m),3.26-3.11(2H,m),2.91-2.88(2H,m),2.18-2.13(1H,m),1.76-1.50(5H,m),1.33(1H,td,J＝13.0,4.2Hz),1.21(6H,dd,J＝6.9,3.2Hz),1.15(1H,dd,J＝13.0,3.7Hz),1.10(3H,t,J＝10.1Hz),1.04(3H,s),0.98(3H,s).
13C NMR(100MHz,CDCl3)δ177.18,142.93,141.90,132.97,126.58,123.97,118.19,53.09,49.56,42.04,35.63,35.14,34.49,33.12,31.66,27.09,23.31,22.51,22.16,21.02,20.36,13.91.
化合物B3，C23H33NO3浅黄色油状物，
1H NMR(400MHz,CDCl3)δ8.94(1H,s),6.50(1H,s),6.01-5.94(2H,m),5.81-5.72(1H,m),5.09-4.98(2H,m),3.88-3.83(2H,m),3.45(1H,dt,J＝13.7,3.0Hz),3.25-3.15(1H,m),2.91-2.88(2H,m),2.17-2.12(1H,m),2.04(1H,s),1.76-1.50(6H,m),1.21(6H,dd,J＝7.0,1.5Hz),1.03(3H,s),0.95(3H,s).
13C NMR(100MHz,CDCl3)δ177.22,142.85,141.77,133.13,133.11,126.71,124.03,118.34,117.30,53.08,49.51,42.59,41.95,35.48,34.45,33.00,31.51,27.08,23.07,22.48,22.18,20.95,20.32.
化合物B4，C26H39NO3黄色粉末，熔点：139-140℃，
1H NMR(400MHz,CDCl3)δ9.53(1H,s),6.48(1H,s),5.96(1H,s),5.86(1H,d,J＝7.4Hz),3.79-3.70(1H,m),3.46(1H,d,J＝13.7Hz),3.25-3.15(1H,m),2.90-2.87(2H,m),2.16-2.11(1H,m),2.00-1.97(1H,m),1.74-1.64(6H,m),1.62-1.53(4H,m),1.37-1.28(3H,m),1.21(6H,dd,J＝6.9,2.2Hz),1.17-1.11(3H,m),1.03(3H,s),1.00(3H,s).
13C NMR(100MHz,CDCl3)δ176.29,142.92,141.86,132.85,126.56,124.23,118.19,53.08,49.76,49.25,42.04,35.59,34.47,33.17,32.29,32.22,31.69,27.07,25.45,24.71,24.53,23.54,22.53,22.15,20.99,20.35.
化合物B5，C27H35NO3黄色固体，熔点：53-54℃，
1H NMR(400MHz,CDCl3)δ8.76(1H,s),7.25-7.23(3H,m),7.05-7.02(2H,m),6.52(1H,s),6.16(1H,t,J＝4.9Hz),5.89(1H,s),4.47(1H,dd,J＝14.8,5.9Hz),4.36(1H,dd,J＝14.8,7.0Hz),3.48(1H,dt,J＝13.6,2.8Hz),3.28-3.17(1H,m),2.90-2.86(2H,m),2.14-2.09(1H,m),1.81-1.72(2H,m),1.66-1.49(4H,m),1.35(1H,dd,J＝13.2,4.2Hz),1.23(6H,dd,J＝7.0,3.1Hz),1.00(3H,s),0.87(3H,s).
13C NMR(100MHz,CDCl3)δ177.26,142.74,141.95,137.22,133.13,128.69×2,127.59×2,127.55,126.62,123.98,118.57,53.09,49.55,44.23,41.98,35.42,34.48,32.89,31.41,27.15,22.93,22.44,22.33,20.99,20.33.
化合物B6，C28H37NO3黄色粉末，熔点：140-141℃，
1H NMR(400MHz,CDCl3)δ8.91(1H,s),7.07(1H,s),7.05(1H,s),6.96(1H,s),6.94(1H,s),6.51(1H,s),6.13(1H,t,J＝4.9Hz),5.94(1H,s),4.41(1H,dd,J＝14.6,5.6Hz),4.33(1H,dd,J＝14.6,5.0Hz),3.50-3.47(1H,m),3.28-3.18(1H,m),2.89-2.86(2H,m),2.31(3H,s),2.15-2.05(1H,m),1.83-1.71(2H,m),1.65-1.56(2H,m),1.54-1.49(1H,m),1.33(1H,td,J＝13.2,4.2Hz),1.24(6H,dd,J＝6.9,3.6Hz),1.21-1.18(1H,m),1.00(3H,s),0.88(3H,s).
13C NMR(100MHz,CDCl3)δ177.15,142.78,141.93,137.27,134.05,133.08,129.36×2,127.63×2,126.63,123.98,118.49,53.09,49.55,44.05,41.99,35.45,34.46,32.92,31.44,27.13,23.01,22.45,22.29,21.05,20.96,20.34.
化合物B7，C27H36N2O3黄色粉末，熔点：80-81℃，
1H NMR(400MHz,CDCl3)δ7.01(1H,t,J＝7.7Hz),6.53-6.50(2H,m),6.44(1H,d,J＝7.8Hz),6.14-6.11(2H,m),4.53(1H,dd,J＝15.0,6.6Hz),4.15(1H,dd,J＝14.8,4.6Hz),3.47(1H,td,J＝13.7,3.0Hz),3.25-3.18(1H,m),2.90-2.87(2H,m),2.14-2.10(1H,m),1.90-1.75(2H,m),1.72-1.58(2H,m),1.53(1H,dt,J＝13.2,3.1Hz),1.37-1.26(2H,m),1.22(6H,d,J＝7.0Hz),1.01(3H,s),0.91(3H,s).
13C NMR(100MHz,CDCl3)δ177.20,146.56,143.02,141.53,138.70,133.44,129.46,127.14,124.24,118.60,117.40,114.06,113.65,53.09,49.39,43.65,41.91,35.26,34.45,32.82,31.36,27.10,22.68,22.62,22.19,20.87,20.29.
化合物B8，C28H37NO4黄色粉末，熔点：130-131℃，
1H NMR(400MHz,CDCl3)δ8.95(1H,s),7.00-6.97(2H,m),6.80-6.76(2H,m),6.51(1H,s),6.11(1H,t,J＝5.0Hz),5.94(1H,s),4.39-4.29(2H,m),3.77(3H,s),3.50-3.46(1H,m),3.28-3.17(1H,m),2.89-2.85(2H,m),2.12-2.08(1H,m),1.81-1.70(2H,m),1.64-1.55(2H,m),1.53-1.50(1H,m),1.32(1H,td,J＝13.2,4.2Hz),1.23(6H,dd,J＝6.9,3.7Hz),1.21-1.17(1H,m),1.00(3H,s),0.86(3H,s).
13C NMR(100MHz,CDCl3)δ177.07,159.00,142.79,141.93,133.06,129.14,129.02×2,126.64,123.97,118.47,114.03×2,55.20,53.07,49.55,43.75,41.98,35.45,34.46,32.92,31.45,27.13,23.04,22.44,22.29,20.95,20.34.
化合物B9，C27H34FNO3黄色粉末，熔点：144-145℃，
1H NMR(400MHz,CDCl3)δ8.63(1H,s),7.02-6.99(2H,m),6.95-6.90(2H,m),6.52(1H,s),6.14(1H,t,J＝5.2Hz),5.87(1H,s),4.44-4.30(2H,m),3.45(1H,dt,J＝13.7,3.0Hz),3.27-3.16(1H,m),2.90-2.86(2H,m),2.14-2.10(1H,m),1.82-1.72(2H,m),1.64-1.58(2H,m),1.53-1.48(1H,m),1.36-1.26(2H,m),1.23(6H,dd,J＝6.9,3.0Hz),1.00(3H,s),0.84(3H,s).
13C NMR(100MHz,CDCl3)δ177.26,163.35,160.90,142.69,141.86,133.19,133.10,133.06,129.35,129.27,126.67,123.91,118.59,115.62,115.40,53.05,49.50,43.45,41.91,35.34,34.46,32.85,31.36,27.14,22.87,22.43,22.31,20.97,20.30.
化合物B10，C27H34ClNO3黄色固体，熔点：166-167℃，
1H NMR(400MHz,CDCl3)δ8.38(1H,s),7.20-7.10(3H,m),6.52(1H,s),6.40(1H,t,J＝5.8Hz),5.78(1H,s),4.54-4.44(2H,m),3.41(1H,dt,J＝13.7,2.6Hz),3.25-3.15(1H,m),2.91-2.89(2H,m),2.18-2.13(1H,m),1.76-1.63(3H,m),1.60-1.54(2H,m),1.46(1H,dt,J＝13.2,3.0Hz),1.31(1H,dd,J＝13.2,4.3Hz),1.23(6H,dd,J＝6.9,5.6Hz),1.19-1.15(1H,m),0.98(3H,s),0.74(3H,s).
13C NMR(100MHz,CDCl3)δ177.39,142.56,141.88,134.65,133.46,133.08,130.28,129.30,129.01,127.01,126.54,123.82,118.69,53.07,49.51,42.01,41.97,35.26,34.45,32.79,31.28,27.14,22.43,22.34,22.26,20.90,20.26.
化合物B11，C28H37NO3黄色油状物，
1H NMR(400MHz,CDCl3)δ9.14(1H,s),7.23-7.18(3H,m),6.88-6.86(2H,m),6.52(1H,s),5.96(1H,s),5.89(1H,t,J＝5.0Hz),3.81-3.73(1H,m),3.45(1H,dt,J＝13.6,2.9Hz),3.30-3.21(2H,m),2.88-2.72(3H,m),2.68-2.61(1H,m),2.00-1.95(1H,m),1.69-1.64(2H,m),1.61-1.54(1H,m),1.49-1.44(1H,m),1.30-1.28(1H,m),1.24(6H,dd,J＝9.2,6.9Hz),1.20-1.15(1H,m),0.94(3H,s),0.73(3H,s).
13C NMR(100MHz,CDCl3)δ177.30,142.78,141.88,138.40,133.03,128.66×2,128.63×2,126.63,126.55,123.90,118.37,52.96,49.49,41.99,41.10,35.40,34.68,34.34,32.90,31.39,27.09,22.71,22.55,22.25,20.74,20.32.
化合物B12，C26H34N2O3浅黄色粉末，熔点：86-87℃，
1H NMR(400MHz,CDCl3)δ8.39-8.35(2H,m),7.39-7.37(1H,m),7.14(1H,dd,J＝7.8,4.9Hz),6.50(1H,s),6.26(1H,t,5.8Hz),4.48(1H,dd,J＝15.2,6.4Hz),4.30(1H,dd,J＝15.3,5.4Hz),3.51-3.47(1H,m),3.27-3.16(1H,m),2.87-2.85(2H,m),2.04-1.82(3H,m),1.67(1H,dd,J＝12.9,1.8Hz),1.60-1.54(2H,m),1.32-1.21(4H,m),1.19(3H,s),1.17(3H,s),0.98(3H,s),0.84(3H,s).
13C NMR(100MHz,CDCl3)δ177.17,148.45,147.95,143.65,140.70,135.69,134.51,134.06,128.13,125.03,123.51,118.32,53.11,49.01,41.34,41.31,34.96,34.14,32.68,31.44,27.02,22.72,22.42,22.06,20.28,20.18.
化合物B13，C25H33NO4黄色固体，熔点：119-120℃，
1H NMR(400MHz,CDCl3)δ8.86(1H,s),7.31(1H,d,J＝1.3Hz),6.51(1H,s),6.28(1H,dd,J＝3.1,1.9Hz),6.24(1H,t,J＝9.6Hz),6.10(1H,d,J＝3.2Hz),5.89(1H,s),4.55(1H,dd,J＝15.5,5.8Hz),4.26(1H,dd,J＝15.5,4.8Hz),3.47(1H,dt,J＝13.7,3.0Hz),3.26-3.15(1H,m),2.90-2.87(2H,m),2.16-2.11(1H,m),1.75-1.60(4H,m),1.52-1.47(1H,m),1.33(1H,dd,J＝13.2,4.2Hz)1.26(1H,s),1.22(6H,dd,J＝6.9,2.0Hz),1.00(3H,s),0.83(3H,s).
13C NMR(100MHz,CDCl3)δ177.13,150.21,142.77,142.22,141.89,133.12,126.72,123.83,118.47,110.42,107.72,53.10,49.55,41.98,37.03,35.48,34.39,32.98,31.50,27.13,22.53,22.44,22.24,20.91,20.31.
化合物B14，C27H35NO4黄色油状物，
1H NMR(400MHz,CDCl3)δ8.54(1H,s),6.90(1H,s),6.88(1H,s),6.69(1H,s),6.67(1H,s),6.50(1H,s),6.14(1H,t,J＝5.2Hz),5.92(2H,s),4.36-4.25(2H,m),3.49-3.45(1H,m),3.25-3.15(1H,m),2.88-2.85(2H,m),2.06(1H,s),1.84-1.74(2H,m),1.68-1.57(2H,m),1.54-1.50(1H,m),1.35-1.26(2H,m),1.22(6H,dd,J＝6.9,1.2Hz),0.99(3H,s),0.86(3H,s).
13C NMR(100MHz,CDCl3)δ177.19,155.30,142.87,141.52,133.30,129.11,128.99,127.09,124.26,118.50,115.54,53.14,49.38,43.78,41.82,35.29,34.39,32.85,31.42,27.10,22.79,22.50,22.31,20.76,20.28.
化合物B15，C27H34BrNO3黄色油状物，
1H NMR(400MHz,CDCl3)δ8.43(1H,s),7.36-7.33(2H,m),6.90(1H,s),6.88(1H,s),6.52(1H,s),6.15(1H,t,J＝5.4Hz),5.86(1H,s),4.42(1H,dd,J＝15.0,6.1Hz),4.28(1H,dd,J＝15.0,5.2Hz),3.45(1H,dt,J＝13.8,3.0Hz),3.27-3.16(1H,m),2.90-2.87(2H,m),2.16-2.10(1H,m),1.84-1.49(6H,m),1.34(1H,dd,J＝13.2,4.2Hz),1.23(6H,dd,J＝6.9,3.9Hz),1.00(3H,s),0.85(3H,s).
13C NMR(100MHz,CDCl3)δ177.34,142.68,141.77,136.41,133.27,131.72×2,129.25×2,126.74,123.95,121.39,118.63,53.05,49.46,43.48,41.86,35.28,34.44,32.81,31.33,27.15,22.79,22.45,22.31,20.94,20.28.
化合物B16，C27H34ClNO3浅黄色固体，熔点：90-91℃，
1H NMR(400MHz,CDCl3)δ8.31(1H,s),7.21-7.13(2H,m),7.03(1H,s),6.87(1H,d,J＝7.4Hz),6.52(1H,s),6.18(1H,t,J＝5.4Hz),5.81(1H,s),4.47(1H,dd,J＝15.1,6.2Hz),4.29(1H,dd,J＝15.1,5.2Hz),3.46(1H,dt,J＝13.8,3.2Hz),3.26-3.15(1H,m),2.91-2.88(2H,m),2.16-2.11(1H,m),1.83-1.50(6H,m),1.37-1.29(1H,m),1.22(6H,dd,J＝6.9,3.0Hz),1.01(3H,s),0.87(3H,s).
13C NMR(100MHz,CDCl3)δ177.39,142.67,141.67,139.50,134.45,133.34,129.87,127.64,126.80,125.47,123.97,118.64,53.06,49.40,43.45,41.83,35.26,34.43,32.79,31.31,27.14,22.68,22.50,22.24,20.92,20.27.
化合物B17，C28H34F3NO3浅黄色粉末，熔点：89-90℃，
1H NMR(400MHz,CDCl3)δ8.22(1H,s),7.48(1H,d,J＝7.8Hz),7.37-7.32(2H,m),7.17(1H,d,J＝7.7Hz),6.52(1H,s),6.24(1H,t,J＝5.4Hz),5.76(1H,s),4.53(1H,dd,J＝15.2,6.2Hz),4.40(1H,dd,J＝15.2,5.4Hz),3.46(1H,dt,J＝13.8,3.0Hz),3.25-3.14(1H,m),2.91-2.88(2H,m),2.16-2.11(1H,m),1.89-1.50(6H,m),1.34(1H,dd,J＝13.2,4.2Hz),1.23(3H,d,J＝1.9Hz),1.21(3H,d,J＝1.8Hz),1.00(3H,s),0.85(3H,s).
13C NMR(100MHz,CDCl3)δ177.47,142.66,141.56,138.61,133.34,130.73,129.09,126.90,124.34,124.30,124.29,124.25,123.98,118.62,53.07,49.38,43.56,41.77,35.25,34.40,32.77,31.30,27.14,22.62,22.48,22.21,20.88,20.25.
化合物B18，C27H33Cl2NO3黄色粉末，熔点：151-152℃，
1H NMR(400MHz,CDCl3)δ8.09(1H,s),7.28(1H,d,J＝2.0Hz),7.11-7.02(2H,m),6.52(1H,s),6.34(1H,t,J＝5.9Hz),5.73(1H,s),4.50-4.35(2H,m),3.38(1H,dt,J＝13.8,3.1Hz),3.25-3.15(1H,m),2.91-2.88(2H,m),2.18-2.13(1H,m),1.81-1.45(6H,m),1.32(1H,dd,J＝13.2,4.2Hz),1.23(6H,t,J＝7.2Hz)0.99(3H,s),0.76(3H,s).
13C NMR(100MHz,CDCl3)δ177.53,142.47,141.78,134.03,134.01,133.37,133.22,131.07,129.10,127.22,126.60,123.76,118.77,53.04,49.45,41.88,41.45,35.14,34.44,32.72,31.21,27.16,22.45,22.31,22.22,20.89,20.22.
化合物B19，C27H34ClNO3黄褐色粉末，熔点：149-150℃，
1H NMR(400MHz,CDCl3)δ8.45(1H,s),7.21-7.18(2H,m),6.96(1H,s),6.94(1H,s),6.52(1H,s),6.15(1H,t,J＝5.4Hz),5.87(1H,s),4.43(1H,dd,J＝14.9,6.1Hz),4.30(1H,dd,J＝14.9,5.2Hz),3.45(1H,dt,J＝13.7,3.1Hz),3.27-3.16(1H,m),2.90-2.87(2H,m),2.14-2.10(1H,m),1.80-1.73(2H,m),1.65-1.58(2H,m),1.54-1.49(1H,m),1.26(2H,s),1.23(6H,dd,J＝6.9,3.7Hz),1.00(3H,s),0.85(3H,s).
13C NMR(100MHz,CDCl3)δ177.33,142.68,141.78,135.89,133.31,133.26,128.91×2,128.76×2,126.74,123.97,118.63,53.05,49.46,43.44,41.86,35.28,34.44,32.81,31.33,29.68,27.15,22.79,22.44,22.31,20.93,20.28.
实施例6鼠尾草酸衍生物对H2O2损伤小鼠海马神经细胞的保护作用
1、仪器与材料
C57孕鼠(购于昆明医科大学实验动物中心)；神经元培养基(Neurobasalmedium)、DMEM培养基、胰蛋白酶(Typsine)、磷酸盐缓冲液(PBS)、胎牛血清(FBS)、B27、CCK-8试剂盒，L-多聚赖氨酸(PDL)等均购自Invitrogen公司。H2O2购自Sigma公司。
2、原代小鼠海马神经细胞的培养
将C57孕鼠脱臼处死，无菌操作取出胎鼠的海马，剪碎，0.125％Typsine 37℃消化15min，用含10％FBS的DMEM终止消化后，75μm筛网滤过，滤液1000r/min离心5min，弃上清。再次加Neurobasal medium混悬，1000r/min离心5min，弃上清。加Neurobasal medium混悬，测细胞密度，调整细胞密度为5×105个/mL，接种于用PDL(0.01％solution)包被过的96孔板。培养至72h后加入终浓度为2.5mg/L阿糖胞苷纯化神经元。培养7天后用于实验。
3、CCK-8检测神经细胞活力
小鼠原代海马神经元于培养6天后，分别加入溶于DMSO的鼠尾草酸及其衍生物(5μM,50μM)预处理30min，加入终浓度50μM的H2O2损伤神经元后继续培养(相同体积的DMSO作为溶剂空白对照组)。6h后于倒置显微镜下观察神经元形态，加入CCK-8试剂，继续培养2h后，测定450nm处吸光度。
各组细胞活力＝(各组吸光度/溶剂空白对照组吸光度)×100％
所有数据以
Figure BDA0001506396260000203
表示，采用单因素方差分析比较数据，P＜0.05为差异有统计学意义，统计软件使用SPSS 22.0。
4、鼠尾草酸及其衍生物对H2O2损伤小鼠海马神经细胞的保护作用实验
取鼠尾草酸及实施例3、6、7的衍生物对H2O2损伤小鼠海马神经细胞的作用进行实验，结果如表2所示，其中，化合物1为式(Ⅳ)结构的鼠尾草酸，化合物2为式(Ⅴ)结构的异丙叉鼠尾草酸，化合物3为式(Ⅵ)结构的羟基化的异丙叉鼠尾草酸，化合物4为式(Ⅰ)结构的鼠尾草酸衍生物，化合物5为式(Ⅶ)结构的鼠尾草酸衍生物。
表2鼠尾草酸及其衍生物对H2O2损伤小鼠海马神经细胞的保护作用
Figure BDA0001506396260000201
Figure BDA0001506396260000202
Figure BDA0001506396260000211
*P＜0.05,compared with the H2O2-induced group.
结果显示，多种鼠尾草酸衍生物具有较好的神经保护活性，尤其是A系列酰胺类衍生物。其中，化合物5、A6、A10、A11、A18(50μM)对H2O2损伤小鼠海马神经细胞的保护作用比鼠尾草酸更好。但是，B1～B19活性不理想，可能是因为脱去保护基团后，化合物不稳定，邻二酚羟基易氧化失活。这些鼠尾草酸衍生物具有成为制备治疗神经系统疾病药物的潜力。

Claims (10)

1.鼠尾草酸衍生物，其特征在于：该化合物的结构式如式(Ⅰ)、式(Ⅱ)、式(Ⅲ)或式(IV)所示：
Figure FDA0002755183800000011
其中，R1为-H、-O-(7-氮苯并三氮唑)、甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基；
Figure FDA0002755183800000012
其中，R2为羟基；
Figure FDA0002755183800000013
其中，R3为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基；
Figure FDA0002755183800000014
2.权利要求1所述的鼠尾草酸衍生物的制备方法，其特征在于：包括如下步骤：
步骤(1)、进行反应(ⅰ)，取式(V)结构的鼠尾草酸溶于丙酮溶液中，在原甲酸三甲酯作脱水剂，对甲苯磺酸催化下，室温条件下发生缩酮反应，生成式(IV)结构的衍生物；
步骤(2)、进行反应(ⅱ)，式(IV)结构的衍生物在二氯甲烷溶剂中，DIPEA为催化剂，室温条件下与HATU反应，得到式(Ⅰ)R1为-O-(7-氮苯并三氮唑)结构的鼠尾草酸衍生物；
或，
步骤(2)、进行反应(ⅲ)，取式(IV)结构的衍生物，在二氯甲烷溶剂中，以HATU为缩合剂，DIPEA为催化剂，室温条件下与伯胺发生缩合反应，得到式(Ⅰ)R1为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基结构的鼠尾草酸衍生物；
或，
步骤(2)、进行反应(iv)，取式(IV)结构的鼠尾草酸衍生物，在无水四氢呋喃溶剂中，回流条件下被锂铝氢还原，得到式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物；
步骤(3)、进行反应(ⅴ)，取式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物在二氯甲烷溶剂中，室温条件下被戴斯-马丁氧化剂氧化，得到式(IV)结构的鼠尾草酸衍生物；
或，
步骤(3)、进行反应(ⅵ)，取式(Ⅰ)结构的鼠尾草酸衍生物在三氟乙酸的水溶液中，室温条件下脱去异丙基保护基团，得到式(Ⅲ)结构的鼠尾草酸衍生物，如下：
Figure FDA0002755183800000021
其中，R1为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基；
R3为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基。
3.权利要求2所述的鼠尾草酸衍生物的制备方法，其特征在于：步骤(1)中，进行反应(ⅰ)，取式(V)结构的鼠尾草酸80.0-120.0mg溶于4-8ml丙酮溶液中，加入原甲酸三甲酯作脱水剂，对甲苯磺酸催化，氮气保护下室温搅拌5-10h，使用EtOAc/H2O萃取，有机相分别用饱和NaHCO3溶液、饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(IV)结构的鼠尾草酸衍生物。
4.权利要求2所述的鼠尾草酸衍生物的制备方法，其特征在于：步骤(2)中，进行反应(ⅱ)，取式(IV)结构的鼠尾草酸衍生物80.0-120.0mg，溶于4-6ml二氯甲烷(DCM)中，加入0.1-0.15ml DIPEA，冰浴搅拌10-20min，加入110.0-120.0mg HATU，室温搅拌0.5-1.2h，使用DCM/H2O萃取，用饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为-O-(7-氮苯并三氮唑)结构的鼠尾草酸衍生物。
5.权利要求2所述的鼠尾草酸衍生物的制备方法，其特征在于：步骤(2)中，进行反应(ⅲ)，取式(IV)结构的鼠尾草酸衍生物80.0-120.0mg，溶于4-8ml DCM中，加入0.10-0.20mlN,N-二异丙基乙胺(DIPEA)，冰浴搅拌10-20min，加入110.0-120.0mg HATU，室温搅拌1h后加入伯胺，薄层色谱法检测反应进程，DCM/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(Ⅰ)R1为甲胺基、乙胺基、烯丙基胺基、环己胺基、苯甲胺基、4-甲基苄胺基、3-氨基苄胺基、4-甲氧基苄胺基、对氟苄胺基、邻氯苯甲胺基、2-苯乙胺基、3-吡啶甲胺基、2-呋喃甲胺基、4-羟基苄胺基、4-溴苄胺基、3-氯苄胺基、3-(三氟甲基)苯甲胺基、2,4-二氯苯甲胺基或对氯苄胺基结构的鼠尾草酸衍生物。
6.权利要求2所述的鼠尾草酸衍生物的制备方法，其特征在于：步骤(2)中，进行反应(iv)，取35.0-45.0mg锂铝氢于二颈瓶中，加入10-20ml无水四氢呋喃，通氮气保护，冰浴下加入溶于无水THF的式(IV)结构的鼠尾草酸衍生物80.0-120.0mg，回流反应6-10h，冰浴加水淬灭，硅藻土过滤，通过EtOAc/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，减压浓缩，经柱层析纯化，得到式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物。
7.权利要求2所述的鼠尾草酸衍生物的制备方法，其特征在于：步骤(3)中，进行反应(ⅴ)，取式(Ⅱ)R2为-OH结构的鼠尾草酸衍生物80-120.0mg，溶于4-8ml DCM中，加入140.0-150.0mg戴斯-马丁氧化剂，室温搅拌1-2h，用DCM/H2O萃取，有机相分别用饱和NaHCO3溶液、饱和NaCl溶液洗涤，无水Na2SO4干燥，过滤，减压浓缩，经柱层析纯化，得到式(IV)结构的鼠尾草酸衍生物。
8.权利要求2所述的鼠尾草酸衍生物的制备方法，其特征在于：步骤(3)中，进行反应(ⅵ)，取式(Ⅰ)结构的鼠尾草酸衍生物80.0-120.0mg，加入TFA/H2O溶液中，室温搅拌0.5-1.5h，冰浴下加饱和NaHCO3溶液调PH中性，用EtOAc/H2O萃取，有机相用饱和NaCl溶液洗涤，无水Na2SO4干燥，减压浓缩，经柱层析纯化，得到式(Ⅲ)结构的鼠尾草酸衍生物。
9.权利要求1-8之一的鼠尾草酸衍生物在制备治疗神经系统疾病药物中的应用。
10.根据权利要求9所述的应用，其特征在于：所述的治疗神经系统疾病药物为治疗Aβ或者H2O2诱导的神经细胞的氧化损伤的药物。
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