CN101948430A - 青藤碱衍生物及其制备方法和应用 - Google Patents
青藤碱衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种在青藤碱A环1位引入卤素、碳碳双键取代基、异噁唑啉杂环取代基的衍生物及其合成方法和应用。本发明青藤碱衍生物是以青藤碱为母体,通过合成技术(包括微流控合成),在青藤碱1位通过Heck反应和1,3-偶极环加成反应生成青藤碱衍生物。所得化合物具有较好的抗炎活性,具有用于关节炎,风湿性关节炎及其抗炎药物的潜力。
Description
技术领域
本发明涉及青藤碱衍生物及其制备方法和应用。
背景技术
青藤碱[(9α,13α,14α)-7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methyl-mophinan-6-one,Sinomenine]是从防己科植物青藤及毛青藤的干燥藤茎中提取的一种异喹啉类生物碱,青藤碱及其衍生物具有镇痛镇静、镇咳局麻、降血压、抗炎作用,为植物中很强的组织胺释放剂,在临床上被应用于治疗风湿性和类风湿性关节炎;动物实验提示在休克和器官损害中有保护作用。其结构式如下:
通过对青藤碱的结构修饰,合成结构新颖、筛选活性更高的衍生物是药物化学目前研究的热点之一。如陈磊等“微生物转化合成羟基化青藤碱及其条件优化”(北京中医药大学学报2008/10);康姚洁等“青藤碱对高糖处理下的血管内皮细胞功能的影响”(第四军医大学学报2009/21);王毅等“青藤碱对人外周血CD4+T淋巴细胞增殖和细胞内Ca2+浓度影响的体外研究”(中华细胞与干细胞移植2009/01);吴敏等“青藤碱与卡铂对宫颈癌Hela细胞增殖的协同抑制研究”(实用妇产科杂志2009/08);褚建波等“青藤碱凝胶剂透皮吸收的研究”(中国现代应用药学2009/08);邓艳平等“盐酸青藤碱缓释组合微丸系统的研究”(中国药科大学学报2009/03)。从目前的研究成果来看,对C环结构改造的比较多,如国内的李玉峰等“从青藤碱制备具有(+)-C-Normorphinan骨架的化合物”(有机化学2009/02),对C环进行了缩环研究;国外的Cantrell,G.L.等“Process for the preparation of 6-hydroxymorphinan compounds from 6-ketomorphinans”(U.S.Pat.Appl.Publ.,2009312552,17 Dec 2009),在青藤碱C环的6位生成了一个羟基;Whittall,J.等“Production of(+)-morphine from(-)-sinomenine”(Brit.UK Pat.Appl.,2392670,10Mar 2004),把青藤碱C环的碳碳双键还原成了碳碳单键;Hitotsuyanagi,Y.等“Syntheses of Antitumor Morphinane Alkaloids,Sinococuline and 6-epi-,7-epi-,and 6-epi-7-epi-Sinococuline,from Sinomenine”(Journal of Organic Chemistry,60(14),4549-58;1995),也报道了青藤碱C环和A环4位羟基的结构修饰。对A环的结构修饰,目前主要都集中在4位羟基上,杨健等“青藤碱衍生物的合成及其镇痛抗炎作用定量构效关系”(武汉大学学报2009/01),以青藤碱为先导化合物,在其A环4位酚羟基进行酰化、醚化合成了七种青藤碱衍生物。对青藤碱D环的结构修饰也有报道,比如17为N原子的烃基化、磺酰化(CN.1785976A;CN.1785977A;CN.1962638A)。对A环1位的结构修饰研究的不多,除了罗娟等(CN.1948291A;有机化学2007/05),对1为进行了大量的胺甲基化修饰外,没见其他系统的研究报道。因此对青藤碱A环1位的结构修饰还有很大的空间,而利用目前热门的微流控合成技术对青藤碱的结构修饰至今更未见报道。
发明内容
发明目的:针对现有技术中存在的不足,本发明的第一个目的是提供一种青藤碱A环衍生物,第二个目的是提供这种青藤碱A环衍生物的制备方法,第三个目的是提供这种青藤碱A环衍生物的应用。
技术方案:为了实现上述发明目的,本发明采用的技术方案如下:
一种青藤碱衍生物,其特征在于,结构如下:
本发明的青藤碱衍生物具有如下结构:
制备A环1位引入卤素取代基的青藤碱衍生物方法为:青藤碱与次氯酸钠溶液反应,生成1氯取代青藤碱;青藤碱与NBS反应,生成1溴取代青藤碱;青藤碱与NIS反应,生成1碘代青藤碱。
制备青藤碱A环1位引入碳碳双键取代基的衍生物方法为:首先以青藤碱为母核,与N-碘代丁二酰亚胺反应,得到1位碘取代的青藤碱衍生物;再在微反应器中,在醋酸钯催化下与丙烯酸酯或甲基丙烯酸甲酯进行Heck反应,生成1位碳碳双键取代的青藤碱衍生物。丙烯酸酯或甲基丙烯酸甲酯特征结构式如下:
其中R1、R2为相同或不同的下列取代基:H或C1~8的烷基,C1~8的烷基为甲基、乙基、正丁基、异丁基、叔丁基、甲氧乙基、正己基、环己基、2-乙基正己基等。
制备青藤碱A环1位引入异噁唑啉杂环取代基的青藤碱衍生物方法为:
1)首先以青藤碱为母核,与N-碘代丁二酰亚胺反应,得到1位碘取代的青藤碱衍生物,再在微反应器中,在醋酸钯催化下与丙烯酸甲酯进行Heck反应,生成1位碳碳双键取代的青藤碱衍生物。
2)在微反应器1中生成1位碳碳双键取代的青藤碱衍生物的同时,在微反应器2中进行芳醛肟和N-氯代丁二酰亚胺的反应,生成氯肟。
3)微反应器1中生成的碳碳双键取代的青藤碱衍生物与微反应器2中生成的氯肟,在微反应器3中,进行1,3-偶极环加成反应,生成1位为异噁唑啉杂环取代基的青藤碱衍生物。芳醛肟由相应的芳醛和盐酸羟氨反应制得,其特征结构式如下:
其中R1~R5为相同或不同的下列取代基:H、甲基的C1~4的烷基、甲氧基的C1~4的烷氧基、氯、溴、碘等。
一种上述的制备方法的专用装置,包括微量注射泵、注射器、T-型混合器、接头、石英毛细管和加热装置;所述的注射器设置在微量注射泵上,T-型混合器通过接头与注射器相通的石英毛细管相连接,所述的加热装置为油浴加热器。
上述的青藤碱衍生物在用于制备治疗关节炎,风湿性关节炎及其抗炎药物中的应用。
有益效果:本发明的青藤碱衍生物是以青藤碱为母体,通过合成技术(包括微流控合成),在青藤碱1位通过Heck反应和1,3-偶极环加成反应生成青藤碱衍生物。所得化合物具有较好的抗炎活性,具有用于关节炎,风湿性关节炎及其抗炎药物的潜力。
附图说明
图1是用于合成青藤碱A环1位引入碳碳双键取代基的青藤碱衍生物的微反应器装置图。
图2是用于合成青藤碱A环1位引入异噁唑啉杂环取代基的青藤碱衍生物的微反应器装置图。
具体实施方式
下面结合具体实施例来对本发明做进一步的解释。
实施例1:1-氯代青藤碱的合成
将化学纯的安替福民溶液稀释到25%(v/v),在搅拌下,于10min中内慢慢滴加50mL到2g青藤碱盐酸盐1的20mL水溶液中,滴加完成后,用盐酸调节pH=9~10,用二氯甲烷萃取(3×20mL),用无水Na2SO4干燥,旋转蒸发,得到粗产品,柱层析纯化(DCM/CH3OH,v/v=15∶1)得到1-氯代青藤碱1,产率:58%。
mp:179~181℃;ESI-MS m/z:364,366[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:6.72(1H,s),5.48(1H,d,J=1.8Hz),4.37(1H,d,J=15.6Hz),3.76(3H,s),3.49(3H,s),3.32(1H,m),3.09(1H,m),3.05(1H,m),2.53(3H,m),2.42(3H,s),1.96(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,152.3,145.3,143.5,127.4,124.0,122.9,114.6,110.0,56.0,55.9,54.8,48.9,46.8,45.4,42.6,40.7,35.5,22.8ppm.
实施例2:1-溴代青藤碱的合成
室温下,将2.2g青藤碱溶于50mL的二氯甲烷中,搅拌下,于5min中内慢慢加入1.25g的NBS,于50℃下继续反应30min,冷却后,加入40mL的Na2S2O3饱和溶液,搅拌5min,分出二氯甲烷层,分别用适量水、饱和食盐水洗涤,用无水Na2SO4干燥,旋转蒸发,得到淡黄色固体1-溴代青藤碱2,产率为93%。
mp:134-136℃;ESI-MS m/z:407,408[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:6.92(1H,s),5.44(1H,d,J=1.8Hz),4.34(1H,d,J=15.6Hz),3.81(3H,s),3.50(3H,s),3.33(1H,m),3.12(1H,m),3.01(1H,d,J=18.9Hz),2.62(1H,m),2.48(5H,m),1.97(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.8,152.8,146.0,144.5,128.9,124.6,114.5,113.6,113.4,57.0,56.5,55.2,49.1,47.3,45.5,42.9,41.1,35.7,26.4ppm.
实施例3:1-碘代青藤碱的合成
在80mL的二氯甲烷中,加入青藤碱3.29g(10mmol),溶解后,加入N-碘代丁二酰亚胺2.25g(10mmol),室温搅拌2小时,加入适量饱和硫代硫酸钠溶液洗涤二氯甲烷溶液,再用饱和食盐水(3×20mL)洗涤二氯甲烷溶液,无水硫酸钠干燥,旋蒸浓缩后,硅胶柱分离,展开剂为:二氯甲烷/甲醇,得1-碘代青藤碱3(4.14g,产率92%)。
产率:92%;mp:106-108℃;ESI-MS m/z:454[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.16(1H,s),6.58(1H,br),5.44(1H,s),4.35(1H,d,J=15.6Hz),3.80(3H,s),3.50(3H,s),3.37(1H,m),3.14(1H,m),2.90(1H,d,J=18.9Hz),2.66(1H,m),2.49(5H,m),2.00(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:194.0,152.6,146.1,145.5,132.3,124.7,119.6,115.0,88.1,57.4,56.4,55.2,49.1,47.2,46.0,43.0,41.5,35.8,32.2ppm.
实施例4:青藤碱A环1位引入碳碳双键取代基的青藤碱衍生物5a-5j的合成
如图1所示,将反应物用混合溶剂DMF/Et3N(5∶1v/v)配制成2mL、0.5M的反应液:1-碘代青藤碱3(455mg,1mmol);Pd(OAc)2(11.2mg,0.05mmol);PPh3(26.2mg,0.1mmol);丙烯酸酯或甲基丙烯酸甲酯(1mmol)。将盛有反应液的注射器置于微量注射泵上,设置流速为8μL/min;石英毛细管微反应器置于油浴中,油浴温度85℃;反应液流出时,用水立即淬灭。待反应完成后,旋掉溶剂和水,加入10mL乙酸乙酯,用饱和食盐水洗涤(3×5mL),无水硫酸钠干燥,浓缩,用核磁鉴定1-碘代青藤碱3转化为1位碳碳双键取代基的青藤碱衍生物的转化率,并用硅胶柱分离,展开剂为:二氯甲烷/甲醇,得到青藤碱衍生物5a-5j。
衍生物5a:转化率:98%;mp:249℃;ESI-MS m/z:412[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.99(1H,d,J=15.6Hz),6.92(1H,s),6.23(1H,d,J=15.6Hz),5.47(1H,d,J=1.8Hz),4.36(1H,d,J=15.6Hz),3.84(3H,s),3.82(3H,s),3.49(3H,s),3.33(1H,m),3.12(1H,d,J=18.9Hz),3.09(1H,m),2.73(1H,dd,J1=18.3Hz,J2=6.0Hz),2.62(1H,m),2.50(1H,d,J=15.6Hz),2.45(3H,s),2.00(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.9,168.0,152.7,147.4,145.6,142.2,131.1,123.5,123.3,116.8,114.8,107.0,56.5,56.2,55.1,51.9,49.3,47.3,45.6,43.1,40.9,35.7,22.3ppm.
衍生物5b:转化率:94%;mp:166℃;ESI-MS m/z:426[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.98(1H,d,J=15.6Hz),6.92(1H,s),6.23(1H,d,J=15.6Hz),5.47(1H,d,J=1.8Hz),4.36(1H,d,J=15.6Hz),4.28(2H,q,J=7.2Hz),3.83(3H,s),3.49(3H,s),3.33(1H,m),3.12(1H,d,J=18.9Hz),3.07(1H,m),2.73(1H,dd,J1=18.3Hz,J2=6.0Hz),2.56(1H,m),2.51(1H,d,J=15.6Hz),2.43(3H,s),1.99(3H,m),1.36(3H,t,J=7.2Hz)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.8,167.4,152.4,147.2,145.4,141.7,131.0,123.3,123.0,116.9,114.7,106.8,60.5,56.2,55.9,54.9,49.1,47.1,45.3,42.8,40.7,35.4,22.0,14.4ppm.
衍生物5c:转化率:92%;mp:130℃;ESI-MS m/z:454[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.99(1H,d,J=15.6Hz),6.93(1H,s),6.23(1H,d,J=15.6Hz),5.48(1H,d,J=1.8Hz),4.37(1H,d,J=15.6Hz),4.23(2H,t,J=6.6Hz),3.84(3H,s),3.50(3H,s),3.32(1H,m),3.13(1H,d,J=18.9Hz),3.07(1H,m),2.72(1H,dd,J1=18.3Hz,J2=6.0Hz),2.58(1H,m),2.51(1H,d,J=15.6Hz),2.44(3H,s),2.00(3H,m),1.72(2H,m),1.48(2H,m),0.99(3H,t,J=7.2Hz)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.9,167.6,152.4,147.2,145.4,141.8,131.1,123.4,123.1,116.9,114.8,106.8,64.5,56.2,56.0,54.9,49.2,47.1,45.5,42.9,40.7,35.6,30.9,22.0,19.3,13.9ppm.
衍生物5d:转化率:90%;mp:165℃;ESI-MS m/z:454[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:8.01(1H,d,J=15.6Hz),6.94(1H,s),6.25(1H,d,J=15.6Hz),5.48(1H,d,J=1.8Hz),4.37(1H,d,J=15.6Hz),4.02(1H,d,J=6.6Hz),3.84(3H,s),3.50(3H,s),3.34(1H,m),3.14(1H,d,J=18.9Hz),3.08(1H,m),2.69(1H,dd,J1=18.3Hz,J2=6.0Hz),2.58(1H,m),2.51(1H,d,J=15.6Hz),2.44(3H,s),2.04(4H,m),1.01(6H,d,J=6.9Hz)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,167.5,152.4,147.3,145.4,141.8,131.0,123.4,123.0,116.7,114.7,106.8,70.6,56.1,55.9,54.9,49.1,47.0,45.3,42.8,40.7,35.4,27.9,22.0,19.2ppm.
衍生物5e:转化率:93%;mp:167℃;ESI-MS m/z:454[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.91(1H,d,J=15.6Hz),6.91(1H,s),6.16(1H,d,J=15.6Hz),5.46(1H,d,J=1.8Hz),4.36(1H,d,J=15.6Hz),3.81(3H,s),3.48(3H,s),3.31(1H,m),3.12(1H,d,J=18.9Hz),3.06(1H,m),2.71(1H,dd,J1=18.3Hz,J2=6.0Hz),2.57(1H,m),2.46(1H,d,J=15.6Hz),2.42(3H,s),1.99(3H,m),1.55(9H,s)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.9,166.9,152.4,147.0,145.3,140.8,130.9,123.2,123.1,118.5,114.7,106.7,80.5,56.2,55.9,54.9,49.1,47.0,45.4,42.9,40.7,35.5,28.3,22.0ppm.
衍生物5f:转化率:93%;mp:135℃;ESI-MS m/z:456[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:8.00(1H,d,J=15.6Hz),6.92(1H,s),6.30(1H,d,J=15.6Hz),5.45(1H,d,J=1.8Hz),4.38(3H,t,J=4.8Hz),4.36(1H,d,J=15.6Hz),3.84(3H,s),3.68(3H,t,J=4.8Hz),3.48(3H,s),3.44(3H,s),3.29(1H,m),3.11(1H,d,J=18.9Hz),3.04(1H,m),2.69(1H,dd,J1=18.3Hz,J2=6.0Hz),2.56(1H,m),2.48(1H,d,J=15.6Hz),2.43(3H,s),1.97(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.8,167.5,152.5,147.2,145.3,142.3,131.3,123.3,123.2,116.6,114.7,106.9,70.7,63.6,59.2,56.3,56.0,54.9,49.2,47.1,45.5,43.0,40.7,35.7,22.0ppm.
衍生物5g:转化率:94%;mp:118℃;ESI-MS m/z:482[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.98(1H,d,J=15.6Hz),6.92(1H,s),6.22(1H,d,J=15.6Hz),5.46(1H,d,J=1.8Hz),4.35(1H,d,J=15.6Hz),4.21(2H,t,J=6.6Hz),3.83(3H,s),3.48(3H,s),3.30(1H,m),3.11(1H,d,J=18.9Hz),3.05(1H,m),2.70(1H,dd,J1=18.3Hz,J2=6.0Hz),2.68(1H,m),2.49(1H,d,J=15.6Hz),2.42(3H,s),1.95(3H,m),1.71(2H,m),1.35(6H,m),0.91(3H,t,J=6.6Hz)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,167.5,152.4,147.1,145.3,141.7,131.0,123.3,123.1,116.8,114.7,106.7,64.7,56.1,55.9,54.8,49.1,47.0,45.4,42.8,40.6,35.5,31.4,28.7,25.6,22.5,21.9,14.0ppm.
衍生物5h:转化率:93%;mp:158℃;ESI-MS m/z:480[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.96(1H,d,J=15.6Hz),6.92(1H,s),6.21(1H,d,J=15.6Hz),5.46(1H,d,J=1.8Hz),4.89(1H,m),4.35(1H,d,J=15.6Hz),3.83(3H,s),3.48(3H,s),3.31(1H,m),3.11(1H,d,J=18.9Hz),3.05(1H,m),2.71(1H,dd,J1=18.3Hz,J2=6.0Hz),2.57(1H,m),2.49(1H,d,J=15.6Hz),2.43(3H,s),1.94(5H,m),1.77(2H,m),1.48(6H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,167.6,152.4,147.3,145.4,141.7,131.0,123.3,123.0,116.8,114.7,106.8,67.0,55.9,54.8,49.1,47.0,45.4,42.8,40.7,38.9,35.5,30.5,29.0,23.9,23.0,22.0,14.1,11.1ppm.
衍生物5i:产率:91%;mp:114℃;ESI-MS m/z:510[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.99(1H,d,J=15.6Hz),6.93(1H,s),6.22(1H,d,J=15.6Hz),5.47(1H,d,J=1.8Hz),4.36(1H,d,J=15.6Hz),4.14(2H,t,J=5.4Hz),3.83(3H,s),3.48(3H,s),3.31(1H,m),3.12(1H,d,J=18.9Hz),3.06(1H,m),2.71(1H,dd,J1=18.3Hz,J2=6.0Hz),2.57(1H,m),2.50(1H,d,J=15.6Hz),2.42(3H,s),1.99(3H,m),1.67(1H,m),1.40(8H,m),0.91(6H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.8,166.9,152.5,147.1,145.4,141.5,131.1,123.4,123.2,117.5,114.8,106.8,72.8,56.2,56.0,54.9,49.2,47.1,46.8,45.5,42.9,40.7,35.6,31.9,31.7,25.5,25.4,24.0,23.8,22.0ppm.
衍生物5j:产率:92%;mp:189℃;ESI-MS m/z:436[M-H]-;1H NMR(300MHz;CDCl3;TMS)δ:7.63(1H,s),6.55(1H,s),5.43(1H,d,J=2.1Hz),4.34(1H,d,J=15.6Hz),3.81(3H,s),3.78(3H,s),3.46(3H,s),3.26(1H,m),3.06(1H,m),2.82(1H,d,J=18.9Hz),2.57(1H,m),2.48(1H,m),2.46(1H,d,J=15.6Hz),2.40(3H,s),2.03(3H,m),1.92(3H,s)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.8,168.9,152.3,144.8,144.5,138.1,129.2,128.1,124.4,122.7,114.5,109.8,56.3,55.9,54.8,52.0,49.0,47.1,45.2,42.7,40.4,35.4,22.4,14.0ppm.
实施例5:青藤碱A环1位引入异噁唑啉杂环取代基的青藤碱衍生物7a-14a、7b-14b的合成
如图2所示:1)将反应物用混合溶剂DMF/Et3N(5∶1v/v)配制成2mL、0.5M的反应液:1-碘代青藤碱3(455mg,1mmol);Pd(OAc)2(11.2mg,0.05mmol);PPh3(26.2mg,0.1mmol);丙烯酸甲酯(1mmol)。将盛有反应液的注射器置于微量注射泵上,设置流速为8μL/min;石英毛细管微反应器1置于油浴中,油浴温度85℃。2)将不同取代基的肟分别配制成1mL、1M的DMF溶液,盛于注射器中;将N-氯代丁二酰亚胺配制成1mL、1M的DMF溶液,盛于注射器中;将盛有反应液的两支注射器置于双通道微量注射泵上,设置流速4μL/min,石英毛细管微反应器2置于空气中,室温。3)微反应器1的反应液与微反应器2的反应液通过一个T-型混合器,进入微反应器3中进行反应,石英毛细管微反应器3置于油浴中,油浴温度70℃。反应液流出时,用水立即淬灭。待反应完成后,旋掉溶剂和水,加入10mL乙酸乙酯,用饱和食盐水洗涤(3×5mL),无水硫酸钠干燥,浓缩,并用硅胶柱将异构体与杂质初步分离,展开剂为:二氯甲烷/甲醇,用核磁鉴定两种异构体的比例后,再用硅胶柱分离异构体,得到青藤碱衍生物7a-14a、7b-14b。
衍生物7,产率:92%;异构体比例:a∶b=39∶61。
衍生物7的异构体7a:mp:151-153℃;ESI-MS m/z:533[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.71(2H,m),7.42(3H,m),6.74(1H,s),6.07(1H,d,J=5.7Hz),5.44(1H,d,J=1.8Hz),4.37(1H,d,J=15.6Hz),4.24(1H,d,J=5.7Hz),3.78(3H,s),3.77(3H,s),3.50(3H,s),3.29(1H,m),3.05(1H,m),2.84(1H,d,J=17.7Hz),2.60(2H,m),2.47(3H,s),2.45(1H,d,J=15.6Hz),1.95(3H,m)ppm;13CNMR(75MHz;CDCl3;TMS)δ:193.7,170.2,153.5,152.6,145.5,144.9,130.7,129.0,128.4,127.1,127.0,126.2,123.2,114.4,106.2,84.6,62.0,56.4,56.2,55.0,53.4,49.3,47.4,45.5,42.8,40.7,35.8,29.8,21.7ppm.
衍生物7的异构体7b:mp:147-149℃;ESI-MS m/z:533[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.66(2H,m),7.41(3H,m),6.76(1H,s),6.17(1H,d,J=6.0Hz),5.48(1H,d,J=2.1Hz),4.35(1H,d,J=15.6Hz),4.08(1H,d,J=6.0Hz),3.78(3H,s),3.76(3H,s),3.55(3H,s),3.32(1H,m),3.08(1H,m),2.97(1H,d,J=18.0Hz),2.60(1H,m),2.48(5H,m),2.06(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.8,170.2,153.6,152.6,145.6,144.9,130.7,129.0,128.3,127.3,127.0,126.3,123.5,114.4,106.1,84.2,61.9,56.5,56.2,55.0,53.4,48.9,47.3,45.2,42.9,40.7,35.4,21.5ppm.
衍生物8,产率:93%;异构体比例:a∶b=37∶63。
衍生物8的异构体8a:mp:160-162℃;ESI-MS m/z:547[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.60(2H,d,J=8.4Hz),7.21(2H,d,J=8.4Hz),6.73(1H,s),6.05(1H,d,J=5.7Hz),5.45(1H,d,J=1.8Hz),4.37(1H,d,J=15.6Hz),4.21(1H,d,J=5.7Hz),3.78(3H,s),3.77(3H,s),3.50(3H,s),3.29(1H,m),3.04(1H,m),2.83(1H,d,J=17.7Hz),2.62(2H,m),2.47(3H,s),2.45(1H,d,J=15.6Hz),2.38(3H,s),1.94(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.6,170.1,153.3,152.4,145.3,144.7,140.8,129.5,127.0,126.7,126.0,125.3,123.0,114.3,106.0,54.2,61.9,56.2,56.0,54.7,53.2,49.1,47.2,45.3,42.6,40.5,35.6,21.4ppm.
衍生物8的异构体8b:mp:153-155℃;ESI-MS m/z:547[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.54(2H,d,J=8.4Hz),7.20(2H,d,J=8.4Hz),6.75(1H,s),6.15(1H,d,J=6.3Hz),5.48(1H,d,J=2.1Hz),4.35(1H,d,J=15.6Hz),4.06(1H,d,J=6.3Hz),3.77(3H,s),3.76(3H,s),3.55(3H,s),3.30(1H,m),3.05(1H,m),2.96(1H,d,J=18.3Hz),2.57(1H,m),2.47(5H,m),2.37(3H,s),2.00(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,170.1,153.3,152.4,145.3,144.7,140.8,129.5,127.1,126.7,126.1,125.2,123.3,114.4,105.8,83.8,61.8,56.2,56.0,54.8,53.2,48.7,47.0,45.1,42.7,40.5,35.2,21.4,21.2ppm.
衍生物9,产率:92%;异构体比例:a∶b=47∶53。
衍生物9的异构体9a:mp:153-155℃;ESI-MS m/z:547[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.58(1H,s),7.45(1H,d,J=7.5Hz),7.28(2H,m),6.74(1H,s),6.06(1H,d,J=5.7Hz),5.44(1H,d,J=1.8Hz),4.38(1H,d,J=15.6Hz),4.23(1H,d,J=5.7Hz),3.78(3H,s),3.77(3H,s),3.50(3H,s),3.38(1H,m),3.14(1H,m),2.88(1H,d,J=18Hz),2.68(2H,m),2.52(3H,s),2.46(1H,d,J=15.6Hz),2.38(3H,s),1.97(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.5,170.2,153.6,152.7,145.6,144.9,138.8,131.5,128.9,128.3,127.5,127.2,125.7,124.1,123.0,114.0,106.4,84.4,62.0,56.6,56.2,55.0,53.4,49.1,47.5,44.9,42.6,40.5,35.4,21.8,21.5ppm.
衍生物9的异构体9b:mp:144-146℃;ESI-MS m/z:547[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.52(1H,s),7.40(1H,d,J=7.5Hz),7.27(2H,m),6.75(1H,s),6.15(1H,d,J=5.7Hz),5.48(1H,d,J=2.1Hz),4.35(1H,d,J=15.9Hz),4.07(1H,d,J=5.7Hz),3.78(3H,s),3.76(3H,s),3.56(3H,s),3.34(1H,m),3.10(1H,m),2.98(1H,d,J=18Hz),2.61(1H,m),2.47(5H,m),2.36(3H,s),2.05(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,170.2,153.7,152.6,145.6,144.9,138.8,131.5,128.9,128.1,127.5,127.3,126.1,124.1,123.4,114.4,106.1,84.0,61.9,56.5,56.2,55.0,53.4,48.8,47.3,45.1,42.8,40.6,35.3,29.8,21.5ppm.
衍生物10,产率:96%;异构体比例:a∶b=34∶66。
衍生物10的异构体10a:mp:158-160℃;ESI-MS m/z:563[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.66(2H,m),6.92(2H,m),6.74(1H,s),6.04(1H,d,J=5.7Hz),5.45(1H,d,J=2.1Hz),4.38(1H,d,J=15.6Hz),4.20(1H,d,J=5.7Hz),3.84(3H,s),3.79(3H,s),3.78(3H,s),3.50(3H,s),3.30(1H,m),3.05(1H,m),2.82(1H,d,J=17.7Hz),2.62(2H,m),2.47(3H,s),2.45(1H,d,J=15.6Hz),1.95(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.5,170.1,161.3,152.8,152.4,145.3,144.6,128.4,127.1,125.9,123.0,120.6,114.2,106.0,84.0,62.0,56.2,56.0,55.3,54.7,53.2,49.1,47.2,45.2,42.6,40.5,35.6,21.4ppm.
衍生物10的异构体10b:mp:150-152℃;ESI-MS m/z:563[M+H]+;1H NMR(300MHz;CDCl3;TMS)δ:7.60(2H,d,J=9Hz),6.91(2H,d,J=9Hz),6.76(1H,s),6.14(1H,d,J=6.3Hz),5.48(1H,d,J=1.8Hz),4.35(1H,d,J=15.6Hz),4.04(1H,d,J=6.3Hz),3.83(3H,s),3.79(3H,s),3.77(3H,s),3.56(3H,s),3.33(1H,m),3.09(1H,m),2.97(1H,d,J=18.3Hz),2.61(1H,m),2.47(5H,s),2.06(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.6,170.1,161.2,152.9,152.3,145.4,144.8,128.3,127.2,125.9,123.3,120.5,114.3,114.2,105.9,83.6,61.9,56.2,55.9,55.3,54.8,53.2,48.7,47.1,44.9,42.6,40.4,35.1,29.6,21.3ppm.
衍生物11,产率:81%;异构体比例:a∶b=28∶72。
衍生物11的异构体11a:mp:157-159℃;ESI-MS m/z:567,569[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.66(2H,m),7.39(2H,m),6.73(1H,s),6.09(1H,d,J=5.7Hz),5.44(1H,d,J=2.1Hz),4.38(1H,d,J=15.6Hz),4.25(1H,d,J=5.7Hz),3.79(6H,s),3.51(4H,m),3.28(1H,m),2.95(1H,m),2.78(2H,m),2.59(3H,s),2.58(1H,d,J=15.6Hz),2.04(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:192.9,169.7,152.6,152.5,145.6,144.8,136.6,129.1,128.1,126.9,126.7,124.8,122.4,112.9,106.4,84.4,61.5,56.8,56.1,54.9,53.4,48.6,47.5,44.0,42.2,40.0,34.5,21.8ppm.
衍生物11的异构体11b:mp:151-153℃;ESI-MS m/z:567,569[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.60(2H,m),7.38(2H,m),6.72(1H,s),6.19(1H,d,J=6.3Hz),5.47(1H,d,J=2.1Hz),4.35(1H,d,J=15.6Hz),4.05(1H,d,J=6.3Hz),3.78(3H,s),3.77(3H,s),3.55(3H,s),3.32(1H,m),3.08(1H,m),2.97(1H,d,J=18Hz),2.60(1H,m),2.46(5H,m),2.01(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.6,169.7,152.5,152.4,145.4,144.8,136.5,129.1,128.0,126.8,126.6,126.0,123.3,114.2,105.8,84.2,61.4,56.2,26.0,54.8,53.3,48.6,47.1,44.9,42.6,40.4,35.1,21.3ppm.
衍生物12,产率:84%;异构体比例:a∶b=43∶57。
衍生物12的异构体12a:mp:152-154℃;ESI-MS m/z:567,569[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.66(2H,m),7.39(2H,m),6.71(1H,s),6.09(1H,d,J=6.0Hz),5.43(1H,s),4.37(1H,d,J=15.6Hz),4.22(1H,d,J=6.0Hz),3.79(3H,s),3.78(3H,s),3.51(3H,s),3.38(1H,m),3.15(1H,m),2.92(1H,d,J=17.7Hz),2.69(2H,m),2.52(3H,s),2.47(1H,d,J=15.6Hz),1.99(3H,m)ppm;13CNMR(75MHz;CDCl3;TMS)δ:193.2,169.6,152.5,145.4,144.8,134.9,130.5,130.1,130.0,126.8,126.7,125.5,124.9,122.8,113.6,106.1,84.6,61.3,56.4,56.1,54.8,53.3,48.8,47.3,44.6,42.4,40.3,35.0,29.6,21.6ppm.
衍生物12的异构体12b:mp:146-148℃;ESI-MS m/z:567,569[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.60(2H,m),7.37(2H,m),6.72(1H,s),6.19(1H,d,J=6.3Hz),5.47(1H,m),4.35(1H,d,J=15.6Hz),4.05(1H,d,J=6.3Hz),3.79(3H,s),3.77(3H,s),3.55(3H,s),3.33(1H,m),3.10(1H,m),2.97(1H,d,J=17.7Hz),2.62(1H,m),2.48(5H,m),2.06(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.6,169.5,152.4,145.5,144.9,134.8,130.4,130.0129.9,126.8,126.7,126.0,124.8,123.5,114.2,105.9,84.3,61.9,56.2,56.0,54.8,53.3,48.6,47.2,47.1,44.8,42.5,40.4,35.0,29.6,21.3ppm.
衍生物13,产率:87%;异构体比例:a∶b=34∶66。
衍生物13的异构体13a:mp:158-160℃;ESI-MS m/z:611,613[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.57(4H,m),6.70(1H,s),6.10(1H,d,J=6.0Hz),5.45(1H,d,J=2.1Hz),4.37(1H,d,J=15.6Hz),4.20(1H,d,J=6.0Hz),3.79(3H,s),3.77(3H,s),3.50(3H,s),3.30(1H,m),3.05(1H,m),2.81(1H,d,J=17.7Hz),2.60(2H,m),2.46(3H,s),2.45(1H,d,J=15.6Hz),1.95(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.6,169.7,152.5,152.4,145.4,144.9,132.0,128.2,127.2,126.5,126.0,124.8,123.1,114.3,105.9,84.6,61.4,56.1,56.0,54.7,53.3,49.1,47.2,45.2,42.6,40.5,35.5,21.5ppm.
衍生物13的异构体13b:mp:153-155℃;ESI-MS m/z:611,613[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.53(4H,m),6.72(1H,s),6.19(1H,d,J=6.3Hz),5.47(1H,d,J=2.1Hz),4.35(1H,d,J=15.6Hz),4.05(1H,d,J=6.3Hz),3.78(3H,s),3.77(3H,s),3.55(3H,s),3.33(1H,m),3.10(1H,m),2.97(1H,d,J=18.3Hz),2.61(1H,m),2.47(5H,m),20.2(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.7,169.6,152.6,152.3,145.6,145.1,132.0,128.2,127.1,126.5,126.2,124.7,123.7,114.5,105.8,84.2,61.3,56.0,55.9,54.8,53.3,48.7,47.0,44.8,42.5,40.5,35.0,29.6,21.3ppm.
衍生物14,产率:86%;异构体比例:a∶b=31∶69。
衍生物14的异构体14a:mp:157-159℃;ESI-MS m/z:611,613[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:ppm;7.91(1H,m),7.59(2H,m),7.29(1H,m),6.69(1H,s),6.10(1H,d,J=6.0Hz),5.44(1H,d,J=1.8Hz),4.37(1H,d,J=15.6Hz),4.20(1H,d,J=6.0Hz),3.80(3H,s),3.78(3H,s),3.51(3H,s),3.32(1H,m),3.08(1H,m),2.83(1H,d,J=17.7Hz),2.63(2H,m),2.48(3H,s),2.46(1H,d,J=15.6Hz),1.96(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.5,169.6,152.4,152.2,145.4,144.8,133.3,130.3,130.2,129.7,126.5,125.9,125.3,123.0,122.9,114.1,105.9,84.7,61.3,56.2,56.0,54.8,53.3,49.0,47.2,45.0,42.5,40.4,35.4,21.5ppm.
衍生物14的异构体14b:mp:149-151℃;ESI-MS m/z:611,613[M+H]+;1HNMR(300MHz;CDCl3;TMS)δ:7.85(1H,m),7.56(2H,m),7.28(1H,m),6.74(1H,s),6.19(1H,d,J=6.0Hz),5.48(1H,d,J=1.8Hz),4.36(1H,d,J=15.6Hz),4.07(1H,d,J=6.0Hz),3.80(3H,s),3.79(3H,s),3.56(4H,m),3.27(1H,m),3.02(1H,d,J=18.3Hz),2.79(1H,m),2.63(1H,m),2.56(3H,s),2.52(1H,d,J=15.6Hz),2.08(3H,m)ppm;13C NMR(75MHz;CDCl3;TMS)δ:193.2,169.5,152.5,152.3,145.6,145.0,133.4,130.3,130.0,129.7,126.8,125.3,125.1,123.0,122.9,113.3,106.1,84.1,61.1,56.4,56.0,54.9,53.4,48.2,47.2,43.9,42.1,40.1,34.4,29.6,21.5 ppm.
实施例6:微反应器与常规反应的比较
将上述部分在微反应器中实施的反应与在常规玻璃容器中的反应进行了比较,从反应速度和产率来看,微反应器反应明显要优于常规反应。反应进行20min后,微反应器反应都能达到90%以上的较为理想的转化率(见下表),而常规反应只有约30-50%的转化率(见下表),远低于理想的转化率。
a产率由1H NMR测定
实施例7:青藤碱衍生物抑制LPS诱导巨噬细胞产生NO活性的测定(10μM)
小鼠单核巨噬细胞RAW264.7用含5%FBS、100U/mL青霉素、100μg/mL链霉素的H-DMEM培养基,在含5%CO2的37℃培养箱中培养。实验时,设置LPS对照组、阴性对照组、阳性药对照组和测试药物组,将细胞计数调整至每毫升4×106个细胞,种于96孔板中,每孔100μL细胞悬液。37℃培养箱中培养2小时后,除开阴性对照组,其余分别加入含有刺激物的培养基100μL。用Griess试剂检测细胞上清中的NO含量实验,培养48小时。
细胞培养上清中的NO含量通过Griess法测定亚硝酸盐的量来间接测定。按照试剂盒说明书操作,具体步骤如下:
1)将冷藏保存的Sulfanilamide溶液和NED溶液恢复至室温;
2)每孔吸取待测细胞培养上清50μL至96孔板中,分别加入50μLSulfanilamide溶液,室温避光10分钟;
3)每孔分别加入50μL NED溶液,室温避光10分钟;
4)30分钟内,用酶标仪检测540nm处的吸光值OD540。
化合物对NO释放的抑制率计算公式为:
抑制率(%)=[LPS对照组(OD540)-测试药物组(OD540)]/[LPS对照组(OD540)-阴性对照组(OD540)]×100
所得化合物活性测试结果如下:大多数化合物表现了较好的抑制作用,具有潜在的用于关节炎,风湿性关节炎及其抗炎作用。
化合物 | 抑制率% | 化合物 | 抑制率 | 化合物 | 抑制率 |
L-NMMA | 40.3±1.3 | 6b | 40.4±1.3 | 11b | 100.0±0.9 |
青藤碱 | 16.3±4.3 | 6c | 99.2±0.8 | 12a | 100.0±0.9 |
1 | 2.5±3.2 | 6d | 99.6±0.3 | 12b | 90.6±0.4 |
2 | 0.0±5.6 | 6e | 81.6±8.7 | 13a | 100.0±0.4 |
3 | 6.5±2.2 | 6f | 34.2±1.1 | 13b | 100.0±1.0 |
4 | 79.3±2.0 | 6g | 100.0±1.0 | 14a | 100.0±0.9 |
5a | 0.0±0.3 | 6h | 100.0±0.5 | 14b | 100.0±0.5 |
5b | 0.0±3.1 | 6i | 100.0±0.7 | 15a | 100.0±0.6 |
5c | 83.3±0.7* | 7a | 0.0±5.3 | 15b | 97.9±0.4 |
5d | 0.0±4.9 | 7b | 0.0±13.8 | 16a | 100.0±0.4 |
5e | 34.5±8.8 | 8a | 65.5±0.8 | 16b | 41.8±0.7 |
5f | 0.0±7.9 | 8b | 0.0±4.1 | 17a | 94.1±4.4 |
5g | 100.0±0.6 | 9a | 47.8±2.7 | 17b | 100.0±0.4 |
5h | 0.0±4.2 | 9b | 0.0±5.1 | 18a | 26.6±2.5 |
5i | 67.0±10.7 | 10a | 0.0±0.7 | 18b | 17.4±4.0 |
5j | 0.0±0.9 | 10b | 0.0±9.0 | ||
6a | 39.9±3.1 | 11a | 0.0±5.4 |
表中数据为抑制率,表示为平均值±标准偏差。化合物浓度为10μM。
Claims (6)
2.一种制备权利要求1所述的青藤碱衍生物的方法,其特征在于,包括:青藤碱与次氯酸钠溶液、NBS或NIS反应,分别生成1氯取代青藤碱、1溴取代青藤碱或1碘代青藤碱。
3.一种制备权利要求1所述的青藤碱衍生物的方法,其特征在于,包括:首先以青藤碱为母核,与N-碘代丁二酰亚胺反应,得到1位碘取代的青藤碱;在醋酸钯催化下与丙烯酸酯或甲基丙烯酸甲酯进行Heck反应,生成1位碳碳双键取代的青藤碱衍生物。
4.一种制备权利要求1所述的青藤碱衍生物的方法,其特征在于,包括以下步骤:
1)首先以青藤碱为母核,与N-碘代丁二酰亚胺反应,得到1位碘取代的青藤碱,再在微反应器中,在醋酸钯催化下与丙烯酸甲酯进行Heck反应,生成1位碳碳双键取代的青藤碱衍生物;
2)生成1位碳碳双键取代的青藤碱衍生物与芳醛肟和N-氯代丁二酰亚胺的反应,生成氯肟;
3)生成的碳碳双键取代的青藤碱衍生物与氯肟,进行1,3-偶极环加成反应,生成1位为异噁唑啉杂环取代基的青藤碱衍生物。;
其中,芳醛肟由相应的芳醛和盐酸羟氨反应制得,其特征结构式如下:
其中R3~R7为相同或不同的下列取代基:H、甲基的C1~4的烷基、甲氧基的C1~4的烷氧基、氯、溴或碘。
5.一种权利要求2或3所述的制备方法的专用装置,其特征在于:包括微量注射泵、注射器、T-型混合器、接头、石英毛细管和加热装置;所述的注射器设置在微量注射泵上,T-型混合器通过接头与注射器相通的石英毛细管相连接,所述的加热装置为油浴加热器。
6.权利要求1所述的青藤碱衍生物在用于制备治疗关节炎,风湿性关节炎及其抗炎药物中的应用。
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