CN102649790B - (13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物以及它们的制备、抗植物病毒活性 - Google Patents
(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物以及它们的制备、抗植物病毒活性 Download PDFInfo
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Abstract
本发明涉及(13aS,14S)-14-氨基菲并吲哚里西啶生物碱(I)以及它们的制备、抗植物病毒活性。通式(I)具有很好的抗植物病毒活性,能很好地抑制烟草花叶病毒。通式(I)式中取代基R1-R4具体所指代的内容见说明书。
Description
技术领域
本发明涉及(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物以及它们的制备、抗植物病毒活性。
背景技术
WO03070166公开了菲并吲哚里西啶和菲并喹喏里西啶衍生物的制备方法和它们在医药上的应用,CN200610129555.1公开了菲并吲哚里西啶和菲并喹喏里西啶衍生物及其盐在农药上的应用,CN10134848.3公开了菲并吲哚里西啶衍生物的制备。
发明内容
本发明的目的是提供(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)以及它们的制备、抗植物病毒活性。本发明提供了一种简洁高效的制备(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)的方法。(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)发现具有很好的抗植物病毒活性。
本发明的(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物是具有如下通式(I)所示结构的化合物:
通式(I)
本发明的(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)的制备如下:首先根据我们自己的方法(Z.W.Wang,Z.Li,K.L.Wang,Q.M.Wang Eur.J.Org.Chem.2010,292-299.Z.W.Wang,Q.M.Wang Tetrahedron Lett.2010,51,1377-1379.)方便地制备出取代的双溴菲,双溴菲与L-脯氨酰胺经过氮烷基化反应可方便地制备出L-取代菲甲基脯氨酰胺,再经三氟乙酐脱水得到L-取代菲甲基脯氨腈,脯氨腈经Parham环化硼氢化钠还原得到取代的(13aS,14S)-14-氨基菲并吲哚里西啶,再经衍生化得相应的 (13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)。
方程式1
上述通式和方程式中,
R1和R2分别代表氢、一个至四个卤素原子、一个至四个1-6碳烷氧基、一个至四个羟基、一个至四个酯基、一个至二个OCH2O、一个至二个OCH2CH2O;
R3和R4分别代表氢、1-6碳烷基、1-6碳烷基羰基、1-6碳烷氧基羰基、1-6碳烷胺基羰基、1-6碳烷胺基硫羰基、5-15碳糖取代基。
本发明提供的(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)具有很好的抗植物病毒活性,能很好地抑制烟草花叶病毒(TMV)。
具体实施方式
下述的实施例和生测试验结果可用来进一步说明本发明,但不意味着限制本发明。
实施例1:(13aS,14S)-14-乙酰胺基-7-脱甲氧基娃儿藤碱(6)的合成(见方程式2)
方程式2
S-1-(2,3,6-三甲氧基-10-溴-9-菲甲基)吡咯-2-甲酰胺的合成
250mL的单口瓶中加入2,3,6-三甲氧基-10-溴-9-溴甲基菲(10.64mmol),(S)-吡咯-2-甲酰胺(12.77mmol),无水碳酸钾(15.96mmol),DMF(150mL),加热回流8小时,脱溶,剩余物加饱和食盐水洗涤得白色固体产品S-1-(2,3,6-三甲氧基-10-溴-9-菲甲基)吡咯-2-甲酰胺(4.53g),收率90%,熔点192-194℃,比旋光度[α]20 D+10°(c=1.0,CHCl3); 1H NMR(400MHz,DMSO-d6):δ=8.52(d,J=9.2Hz,1H),8.12(s,1H),8.08(d,J=2.4Hz,1H),7.77(s,1H),7.26(dd,J=2.4,9.2Hz,1H),6.97(d,J=2.5Hz,1H),6.86(d,J=2.8Hz,1H),4.49(d,J=12.6Hz,1H),4.37(d,J=12.6Hz,1H),4.07(s,3H),4.01(s,3H),3.96(s,3H),3.23-3.27(m,1H),2.91(t,J=9.0Hz,1H),2.61-2.68(m,1H),2.05-2.13(m,1H),1.53-1.82(m,3H);13C NMR(100MHz,CDCl3):δ=175.5,158.0,149.8,149.5,130.6,130.4,128.0,125.2,125.0,124.9,121.4,116.1,109.1,104.4,66.3,56.1,55.5,55.4,53.0,29.7,23.2;HRMS(ESI)calcd for C23H26BrN2O4(M+H)+473.1071,found 473.1070。
S-1-(2,3,6-三甲氧基-10-溴-9-菲甲基)吡咯-2-甲腈的合成
250mL的四口瓶中加入无水二氯甲烷(180mL),S-1-(2,3,6-三甲氧基-10-溴-9-菲甲基)吡咯-2-甲酰胺(9.94mmol),三乙胺(21.87mmol),氮气保护,0℃下慢慢滴加三氟乙酐(10.93mmol)的二氯甲烷溶液(10mL),自然升至室温反应10h。分别用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸镁干燥,脱溶,过柱子(二氯甲烷/甲醇50∶1)得白色固体产品S-1-(2,3,6-三甲氧基-10-溴-9-菲甲基)吡咯-2-甲腈(3.62g),收率80%,熔点156-158℃,比旋光度[α]20 D-0.2°(c=1.0,CHCl3);1H NMR(400MHz,CDCl3):δ=8.26(d,J=9.1Hz,1H),7.88(d,J=2.0Hz,1H),7.85(s,1H),7.26(s,1H),4.67(d,J=12.9Hz,1H),4.55(d,J=13.0Hz,1H),4.12(s,3H),4.09(s,3H),4.02(s,3H),3.85(t,J=2.7Hz,1H),2.86(t,J=6.7Hz,2H),2.14-2.23(m,2H),1.78-1.96(m,2H),1.56-1.58(m,1H);13C NMR(100MHz,CDCl3):δ=158.2,150.0,149.6,130.8,129.8,127.6,126.0,125.6,125.2,122.7,119.2,115.5,109.9,104.5,103.3,56.1,56.0,55.5,54.2,53.7,50.4,30.0,22.2;IR(KBr,cm-1):3493,3452,1636,1618,1509,1466,1420,1367,1300,1262,1233,1204,1164,1088,1072,990,831,784;HRMS(ESI)calcd for C22H23BrNO3(M-HCN+H)+428.0856,found428.0848。
(13aS,14S)-14-氨基-7-脱甲氧基娃儿藤碱(3)的合成
500mL的四口瓶中加入S-1-(2,3,6-三甲氧基-10-溴-9-菲甲基)吡咯-2-甲腈(5.15mmol),TMEDA(12.36mmol),无水四氢呋喃(200mL),氮气保护,-78℃下滴加nBuLi的正己烷溶液(11.33mmol),控温-78℃下反应5h,加入甲醇(25mL),硼氢化钠(25.75mmol),控温-40℃下反应1h,自然升至室温反应12h,加水(50mL)淬灭反应,反应物分别用乙酸乙酯(30mL),二氯甲烷(2×30mL)萃取,合并有机相,无水硫酸镁干燥,脱溶,过柱子(二氯甲烷/甲醇40∶1)得浅黄色固体产品3(1.58g),收率81%,熔点139-141℃,比旋光度[α]20 D-4°(c=1.0,CHCl3);1H NMR(400MHz,CDCl3):δ= 7.71(s,2H),7.57(d,J=9.0Hz,1H),7.38(s,1H),7.09(dd,J=1.9,9.0Hz,1H),4.32(d,J=15.3Hz,1H),4.28(s,1H),4.03(s,3H),4.02(s,3H),3.96(s,3H),3.41(d,J=15.1Hz,1H),3.23-3.42(m,3H),2.37-2.42(m,1H),2.24-2.33(m,1H),1.98-2.06(m,1H),1.79-1.88(m,3H);13C NMR(100MHz,CDCl3):δ=157.8,149.7,148.3,130.5,129.2,126.8,125.9,124.6,123.9,123.3,115.0,104.4,103.8,63.8,56.0,56.0,55.4,55.3,54.0,47.2,29.7,24.8,22.3;IR(KBr,cm-1):3527,3488,3458,3384,2956,2925,1619,1514,1469,1306,1257,1233,1204,1128,1091,1040,983,865,776,605,529;HRMS(ESI)calcd for C23H23NO3(M-NH3+H)+362.1751,found 362.1747。
(13aS,14S)-14-乙酰胺基-7-脱甲氧基娃儿藤碱(6)的合成
100mL的四口瓶中加入胺3(0.53mmol),三乙胺(1.27mmol),二氯甲烷(50mL),氮气保护,0℃下滴加乙酰氯(0.64mmol)的二氯甲烷溶液(10mL),自然升至室温反应3h,反应物分别用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸镁干燥,脱溶,过柱子得白色固体产品6(0.15g),收率67%,熔点179-181℃,比旋光度[α]20 D 1°(c=1.0,CHCl3);1H NMR(400MHz,CDCl3):δ=7.84(s,2H),7.75(d,J=9.0Hz,1H),7.69(s,1H),7.17(dd,J=1.7,10.7Hz,1H),6.40(d,J=9.8Hz,1H),5.68(d,J=9.3Hz,1H),4.65(d,J=15.2Hz,1H),4.08(s,3H),4.04(s,3H),3.99(s,3H),3.63(d,J=15.1Hz,1H),3.36-3.43(m,1H),2.62-2.91(m,2H),2.38-2.45(m,1H),2.01(s,3H),1.88-1.96(m,2H),1.72-1.81(m,1H);13C NMR(100MHz,CDCl3):δ=169.7,158.1,149.9,148.7,131.0,127.9,126.7,126.3,124.6,123.7,123.2,115.0,105.1,104.5,103.6,63.7,56.4,56.0,55.5,55.1,54.0,45.9,25.1,23.2,22.1;IR(KBr,cm-1):3568,3356,3321,3255,2960,2928,1751,1656,1617,1518,1471,1425,1287,1262,1205,1170,1145,1093,1042,981,931,868,777,668,618,526;HRMS(ESI)calcd for C25H29N2O4(M+H)+421.2122,found 421.2116。
实施例2:(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)的化学结构式和物理常数,见表1:
表1.(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)的化学结构式和物理常数
实施例3:抗烟草花叶病毒活性的测定,测定程序如下:
离体半叶枯斑法(Half-leafnecrosis):取新鲜具有典型TMV病毒症状的三生烟叶,加入磷酸缓冲溶液(0.01M,pH 7.2),在研钵中研碎,在撒有金刚砂的珊西烟叶上接种,并用清水快速冲洗。接种1.5-2小时后,将接种叶片沿主脉剪成两个相等半叶,一半叶片用待测样品的DMF溶液浸叶处理,另一半浸于清水中作对照,72小时后,统计半叶枯斑数。
活体保护作用筛选方法:选长势一致的5-6叶期心叶烟,用毛笔轻轻在左半叶分别涂施一定浓度的试样和对照样,右半叶片涂施溶媒作对照,24小时后,汁液摩擦接种病毒于处理叶片,每处理3株(共计9片叶片),重复3次,72h后调查心叶烟枯斑数,计算病斑抑制率。
活体钝化作用筛选方法:选长势一致的5-6叶期心叶烟,将一定浓度的试样和对照样分别与病毒汁液1∶1(v/v)混合钝化0.5h,摩擦接种于处理左半叶片,病毒液汁与溶媒1∶1(v/v)混合摩擦接种于右半叶,每处理3株(共计9片叶片),重复3次,72h后调查心叶烟枯斑数,计算病斑抑制率。
活体治疗作用筛选方法:选长势一致的5-6叶期心叶烟,先用病毒汁液摩擦接种于处理叶片,一定时间后分别涂施一定浓度的试样和对照样在左半叶,右半叶以溶媒为对照,每处理3株(共计9片叶片),重复3次,72h后调查心叶烟枯斑数,计算病斑抑制率。
抑制率(%)=[(对照枯斑数-处理枯斑数)/对照枯斑数]×100%
表2为部分化合物的测试结果。
表2部分(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物(I)的抗TMV活性测试结果:
从表中可见,所有化合物均表现出不错的抗抗烟草花叶病毒(TMV)活性,部分化合物在100μg/ml浓度下具有优于宁南霉素或与其相当的抑制活性,化合物3,4,7,8和9在100μg/ml浓度下的抗抗烟草花叶病毒活性明显优于商品化品种病毒唑与商品化品种宁南霉素的活性相当,化合物2和6在100μg/ml浓度下的抗抗烟草花叶病毒活性明显优于商品化品种宁南霉素。
Claims (1)
1.一种制备(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物的方法,其特征在于包括如下方程式1所示的下述步骤:首先双溴菲与L-脯氨酰胺经过氮烷基化反应可方便地制备出L-取代菲甲基脯氨酰胺,再经三氟乙酐脱水得到L-取代菲甲基脯氨腈,脯氨腈经Parham环化硼氢化钠还原得到取代的(13aS,14S)-14-氨基菲并吲哚里西啶,再经衍生化得相应的(13aS,14S)-14-氨基菲并吲哚里西啶生物碱衍生物,
式中,R1和R2分别代表氢、一个至四个卤素原子、一个至四个1-6碳烷氧基、一个至四个羟基、一个至四个酯基、一个至二个OCH2O、一个至二个OCH2CH2O,R3和R4分别代表氢、1-6碳烷基、1-6碳烷基羰基、1-6碳烷氧基羰基、1-6碳烷胺基羰基。
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