CN106008653A - 甘草次酸酰腙类衍生物及其制备方法和用途 - Google Patents
甘草次酸酰腙类衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种甘草次酸酰腙类衍生物及其制备方法和用途。所述的甘草次酸酰腙类衍生物，具有式(Ⅰ)的结构，其中R为氢、卤素、C1～C3烷基或甲氧基。所述的制备方法包括：酸催化下，式(Ⅱ)所示的甘草次酸与乙醇进行反应，得式(Ⅲ)所示的甘草次酸乙酯；有机溶剂中，甘草次酸乙酯与水合肼反应，得式(Ⅳ)所示的甘草次酸酰肼；有机溶剂中，所述的甘草次酸酰肼与苯甲醛或取代苯甲醛反应，得所述的甘草次酸酰腙类化合物。本发明还公开了所述的甘草次酸酰腙类衍生物在制备药物中的应用。本发明的甘草次酸酰腙类衍生物对细菌具有明显的抑制作用，可以用于制备抗菌药物。
Description
技术领域
本发明涉及化学合成，尤其涉及一类新型甘草次酸酰腙类衍生物及制备方法与作为抗菌药物的用途
背景技术
甘草是一种常见的中草药，它广泛分布在我国的西北、西南和东北，共有八个品种。其有效成分是甘草酸及甘草酸盐类物质，而甘草次酸是甘草酸经胃酸水解或经肝中β-葡萄糖醛酸酶分解形成的活性成分之一，是一种齐墩果烷型五环三萜化合物，具有抗炎，抗溃疡，抗病毒，抗肿瘤，抗肝毒素以及调节免疫功能等广泛的生理活性。甘草酸的药理作用实质上是甘草次酸的效用。
酰腙类化合物是由酰肼与醛或酮缩合而成的一类特殊的Schiff碱类化合物，比普通的Sichiff碱化合物稳定。对甘草次酸的结构进行修饰，增强其抗菌活性，是很有意义的课题。
发明内容
发明目的：本发明的目的是提供一类具有抗菌效果的甘草次酸酰腙类衍生物，本发明的另一个目的是提供其制备方法和用途。
技术方案：一种甘草次酸酰腙类衍生物，它具有如下通式：
式(Ⅰ)中，R为氢、卤素、C1～C3烷基或甲氧基。
进一步的，式(Ⅰ)中，R为氢、卤素、甲基或甲氧基。
进一步的，所述的卤素为氟或氯。
本发明还提供了一种所述甘草次酸酰腙类衍生物的制备方法，包括以下步骤：
(1)酸催化下，式(Ⅱ)所示的甘草次酸与乙醇进行反应，得式(Ⅲ)所示的甘草次酸乙酯；
(2)有机溶剂中，甘草次酸乙酯与水合肼反应，得式(Ⅳ)所示的甘草次酸酰肼；
(3)有机溶剂中，所述的甘草次酸酰肼与苯甲醛或取代苯甲醛反应，得所述的甘草次酸酰腙类化合物；
本发明化合物设计是利用甘草次酸的羧基这一活性基团，通过一系列的反应，生成甘草次酸酰肼，甘草次酸酰肼再与苯甲醛或取代苯甲醛反应生成抗菌活性活性更好的甘草次酸酰腙。
步骤(1)中，反应时间为5～7h，反应温度为70～80℃，酸为浓硫酸或稀盐酸。
具体的，步骤(1)可以为：于乙醇中加入甘草次酸，搅拌溶解，缓慢滴入浓硫酸，回流反应，TLC跟踪；反应结束后，减压蒸馏除去乙醇，加入乙酸乙酯，用水溶液洗涤后除去硫酸，无水硫酸钠干燥，得白色固体，即甘草次酸乙酯。
步骤(2)中，反应时间为18～20h，反应温度为80～90℃。有机溶剂为乙醇或甲醇。
具体的，步骤(2)可以为：用乙醇溶解甘草次酸乙酯，然后加入水合肼回流反应，TLC跟踪；反应结束后，蒸馏除去乙醇，冷却析出白色固体，水溶液洗涤，再用乙醇洗涤，然后在乙醇中重结晶得白色针状固体，过滤，干燥，得甘草次酸酰肼。
步骤(3)中，反应时间为6～8h，反应温度为20～30℃。有机溶剂为乙醇或者甲醇。
具体的，步骤(3)可以为：将所述的甘草次酸酰肼和等物质的量的取代苯甲醛加入到乙醇中反应，析出固体，乙醇洗涤，过滤，干燥，得到甘草次酸酰腙类化合物。
本发明还提供了所述甘草次酸酰腙类衍生物在制备药物中的应用。
本发明还提供了一种药物，包括所述的甘草次酸酰腙类衍生物。
以有效量的甘草次酸酰腙类衍生物为活性成分，添加药学上可接受的载体，可以制备成相应的药物。
所述的药物为抗细菌药物。细菌可以为革兰氏阴性菌或革兰氏阳性菌，具体为枯草芽孢杆菌、金黄色葡萄球菌、粪肠球菌、铜绿假单胞菌、大肠杆菌、阴沟肠杆菌等。
与现有技术相比，本发明的有益效果包括：
实验结果表明，本发明的新型甘草次酸酰腙类衍生物对细菌具有明显的抑制作用，因此本发明甘草次酸类衍生物可以用于制备抗菌药物。
具体实施方式
以下将结合实施例更详细的解释本发明，本发明的实施例仅用于说明本发明的技术方案，本发明的范围并不受这些实施例的任何限制
实施例1苯甲醛甘草次酸酰腙(化合物1)的制备
化合物1结构为：
步骤1：于100mL乙醇中加入10g甘草次酸，搅拌溶解，缓慢滴入10mL浓硫酸，78℃回流，TLC跟踪反应，反应5小时。反应结束后，减压蒸馏除去乙醇，加入乙酸乙酯，用水洗涤3次除去硫酸，无水硫酸钠干燥，旋干，得甘草次酸乙酯。
步骤2：用30mL乙醇溶解10克甘草次酸乙酯，然后加入水合肼(浓度为85％的水合肼水溶液)50mL，90℃回流，TLC跟踪反应，反应18小时。反应结束后，减压蒸馏除去乙醇，冷却至室温，大量白色固体析出，水洗涤3次，乙醇洗涤3次，在乙醇中重结晶得白色针状固体，过滤，干燥，得甘草次酸酰肼。
步骤3：将步骤2中得到的甘草次酸酰肼1mmol和等物质的量的苯甲醛加入到10mL乙醇中溶解，常温(一般为25℃)下反应6小时，析出固体，乙醇洗涤3次，过滤，干燥，得到目标化合物，白色粉末，产率95％。
m p:208-209℃.1H NMR(DMSO,300MHz),11.25(s,1H,NH),8.36(s,1H,CH),7.97-7.95(d,J＝6.06Hz,1H,ArH),7.75-7.74(d,J＝1.23Hz,1H,ArH),7.44-7.43(m,3H,ArH),5.77(s,1H,CH),4.91(s,1H,OH),3.34(m,1H,CH),2.01(m,3H,CH),1.85-1.92(m,8H,CH2),1.55-1.67(m,8H,CH2),1.29(s,3H),1.10(s,3H)，1.05(s,3H)，0.93(m,2H,CH2),0.88(s,3H,CH3)，0.85(s,3H,CH3)，0.66(s,3H,CH3)，0.67(s,3H,CH3),MS(ESI):573.8(C37H53N2O3,[M+H]+).Anal.Calcd for(C37H52N2O3:C,77.58；H,9.15；O,8.38 Found:C,77.50；H,9.08；O,8.29
实施例2：对甲基苯甲醛甘草次酸酰腙(化合物2)的制备
化合物2结构为：
制备方法同实例1，以对甲基苯甲醛代替苯甲醛，得到目标化合物，白色粉末，产率93％。
m p:219-220℃.1H NMR(DMSO,300MHz),11.25(s,1H,NH),8.36(s,1H,CH),7.97-7.95(d,J＝6.06Hz,1H,ArH),7.75-7.74(d,J＝1.23Hz,1H,ArH),7.44-7.43(m,2H,ArH),5.77(s,1H,CH),4.91(s,1H,OH),3.34(m,1H,CH),2.36(s,1H,CH3)2.01(m,3H,CH),1.85-1.92(m,8H,CH2),1.55-1.67(m,8H,CH2),1.29(s,3H),1.10(s,3H)，1.05(s,3H)，0.93(m,2H,CH2),0.88(s,3H,CH3)，0.85(s,3H,CH3)，0.66(s,3H,CH3)，0.67(s,3H,CH3)，MS(ESI):587.8(C38H55N2O3,[M+H]+).Anal.Calcd for(C38H54N2O3:C,77.77；H,9.28；O,8.18 Found:C,77.80；H,9.31；O,8.28
实施例3对甲氧基苯甲醛甘草次酸酰腙(化合物3)的制备
化合物3结构为：
制备方法同实施例1，以对甲氧基苯甲醛代替苯甲醛，得到目标化合物，白色粉末，产率90％。
m p:231-232℃.1H NMR(DMSO,300MHz),11.25(s,1H,NH),8.36(s,1H,CH),7.97-7.95(d,J＝6.06Hz,1H,ArH),7.75-7.74(d,J＝1.23Hz,1H,ArH),7.44-7.43(m,2H,ArH),5.77(s,1H,CH),4.91(s,1H,OH),3.83(s,3H,OCH3),3.34(m,1H,CH),2.01(m,3H,CH),1.85-1.92(m,8H,CH2),1.55-1.67(m,8H,CH2),1.29(s,3H),1.10(s,3H)，1.05(s,3H)，0.93(m,2H,CH2),0.88(s,3H,CH3)，0.85(s,3H,CH3)，0.66(s,3H,CH3)，0.67(s,3H,CH3)，MS(ESI):603.4(C38H55N2O4,[M+H]+).Anal.Calcdfor(C38H54N2O4:C,75.71；H,9.03；O,10.62 Found:C,75.65；H,9.12；O,10.50
实施例4对氯苯甲醛甘草次酸酰腙(化合物4)的制备
化合物4结构为：
制备方法同实施例1，以对氯苯甲醛代替苯甲醛，得到目标化合物，白色粉末，产率91％。
m p:212-213℃.1H NMR(DMSO,300MHz),11.25(s,1H,NH),8.36(s,1H,CH),7.97-7.95(d,J＝6.06Hz,1H,ArH),7.75-7.74(d,J＝1.23Hz,1H,ArH),7.44-7.43(m,2H,ArH),5.77(s,1H,CH),4.91(s,1H,OH),3.34(m,1H,CH),2.01(m,3H,CH),1.85-1.92(m,8H,CH2),1.55-1.67(m,8H,CH2),1.29(s,3H),1.10(s,3H)，1.05(s,3H)，0.93(m,2H,CH2),0.88(s,3H,CH3)，0.85(s,3H,CH3)，0.66(s,3H,CH3)，0.67(s,3H,CH3)，MS(ESI):607.4(C37H52ClN2O3,[M+H]+).Anal.Calcd for(C37H51ClN2O3,C,73.18；H,8.47；O,7.90 Found:C,73.12；H,8.45；O,7.85
实施例5对氟苯甲醛甘草次酸酰腙(化合物5)的制备
化合物5结构为：
制备方法同实施例1，以对氟苯甲醛代替苯甲醛，得到目标化合物，白色粉末，产率94％。
m p:221-222℃.1H NMR(DMSO,300MHz)11.25(s,1H,NH),8.36(s,1H,CH),7.97-7.95(d,J＝6.06Hz,1H,ArH),7.75-7.74(d,J＝1.23Hz,1H,ArH),7.44-7.43(m,2H,ArH),5.77(s,1H,CH),4.91(s,1H,OH),3.83(s,3H,OCH3),3.34(m,1H,CH),2.01(m,3H,CH),1.85-1.92(m,8H,CH2),1.55-1.67(m,8H,CH2),1.29(s,3H),1.10(s,3H)，1.05(s,3H)，0.93(m,2H,CH2),0.88(s,3H,CH3)，0.85(s,3H,CH3)，0.66(s,3H,CH3)，0.67(s,3H,CH3)，MS(ESI):607.4(C37H52FN2O3,[M+H]+).Anal.Calcd for(C37H51FN2O3,C,73.18；H,8.47；O,7.90 Found:C,73.22；H,8.46；O,7.93
实施例6
甘草次酸酰腙类衍生物对枯草芽孢杆菌(B.subtilis)，金黄色葡萄球菌(S.aureus)，粪肠球菌(S.faecalis)，铜绿假单胞菌(P.aeruginosa)，大肠杆菌(E.coli)和阴沟肠杆菌(E.cloacae)的作用
方法：MTT法。取培养的枯草芽孢杆菌(B.subtilis)，金黄色葡萄球菌(S.aureus),粪肠球菌(S.faecalis)，铜绿假单胞菌(P.aeruginosa)，大肠杆菌(E.coli)和阴沟肠杆菌(E.cloacae)的菌株，分别稀释成2×104个/ml，分装于96孔板(0.2ml/孔)。设青霉素和卡那霉素为参比对照组，DMSO为空白对照组及5个不同浓度的受测化合物每孔10μl，各组设3个平行孔，置37℃恒温培养箱中培养24h，打入MTT液(2mg/ml)5μl/孔，再培养4h，取出培养板，加入SDS100μl/孔，再培养12h，在570nm波长下，用美国生产的BioRad550型酶标仪测出OD值，按下列公式计算出细菌生长抑制率(最小半数抑制浓度，MICs)
生长抑制率＝(1-用药组平均OD值/对照组平均OD值)×100％
MICs越小，此化合物的抗菌性越好，结果见表1
表1 五种甘草次酸酰腙类衍生物的抑菌活性测试结果
结果表明：甘草次酸酰腙类衍生物对枯草芽孢杆菌(B.subtilis)，金黄色葡萄球菌(S.aureus)，粪肠球菌(S.faecalis)，铜绿假单胞菌(P.aeruginosa),大肠杆菌(E.coli)和阴沟肠杆菌(E.cloacae)都有不同程度的抑制作用，其抗菌效果均优于甘草次酸。
Claims (10)
1.一种甘草次酸酰腙类衍生物，其特征在于，它具有如下通式：
式(Ⅰ)中，R为氢、卤素、C1～C3烷基或甲氧基。
2.根据权利要求1所述的甘草次酸酰腙类衍生物，其特征在于，R为氢、卤素、甲基或甲氧基。
3.根据权利要求1所述的甘草次酸酰腙类衍生物，其特征在于，所述的卤素为氟或氯。
4.根据权利要求1所述的甘草次酸酰腙类衍生物的制备方法，其特征在于，包括：
(1)酸催化下，式(Ⅱ)所示的甘草次酸与乙醇进行反应，得式(Ⅲ)所示的甘草次酸乙酯；
(2)有机溶剂中，甘草次酸乙酯与水合肼反应，得式(Ⅳ)所示的甘草次酸酰肼；
(3)有机溶剂中，所述的甘草次酸酰肼与苯甲醛或取代苯甲醛反应，得所述的甘草次酸酰腙类化合物；
5.根据权利要求4所述的制备方法，其特征在于，步骤(1)中，反应时间为5～7h，反应温度为70～80℃；酸为浓硫酸或稀盐酸。
6.根据权利要求4所述的制备方法，其特征在于，步骤(2)中，反应时间为18～20h，反应温度为80～90℃；有机溶剂为乙醇或甲醇。
7.根据权利要求4所述的制备方法，其特征在于，步骤(3)中，反应时间为6～8h，反应温度为20～30℃；有机溶剂为乙醇或甲醇。
8.根据权利要求1～3任一项所述的甘草次酸酰腙类衍生物在制备药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的药物为抗细菌药物。
10.一种药物，其特征在于，包括所述的甘草次酸酰腙类衍生物。
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