CN108484428B - 一种枸杞中的酰胺类化合物及酰胺类化合物组分及其制备方法 - Google Patents
一种枸杞中的酰胺类化合物及酰胺类化合物组分及其制备方法 Download PDFInfo
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Abstract
本发明公开了枸杞中一类酰胺类化合物及酰胺类化合物组分及其制备方法,本发明中所述的一类酰胺类化合物及酰胺类化合物组分,具有良好的药理活性和广泛的应用,适宜作为标准品及药物开发用;其中所述的制备方法具有较高的收率,成本低、耗时短,操作简便,且所得产品纯度高。
Description
技术领域
本发明涉及一种枸杞中的酰胺类化合物及酰胺类化合物组分及其制备方法。
背景技术
枸杞是一种耐干旱、耐盐碱的多年生灌木经济作物,为茄科枸杞属,在地球上约80多种,中国有7个种3个变种,主要分布于我国北部地区。我国是世界主要的枸杞原产国,同时也是世界上最大的枸杞消费国,年需求量达到7万吨左右。在中国,枸杞果实中药称枸杞子,始载于《神农本草经》,并列为上品,具有滋补肝肾、益精明目的作用。根皮中药称地骨皮,具有凉血除湿,清肺降火的功效。枸杞化学成分包括生物碱类、酰胺类、黄酮类、萜类等化合物,枸杞具有神经保护、抗阿尔茨海默病(Alzheimer's disease,AD)、抗氧化、抗肿瘤、抗炎、肝保护等。
我国对临床治疗AD的111个中药方剂进行了统计,筛选出了使用频次位列前20的药材,枸杞子就位列其中。苏国辉院士课题组近年来对枸杞子进行了深入研究,发现枸杞子提取物具有显著的抗AD活性[1]。酰胺类化合物具有抗β-淀粉样蛋白(Aβ)活性,Aβ是AD的致病物质,Aβ在脑内过度产生和沉积,引起神经元突触功能障碍、Tau蛋白过度磷酸化和继发炎性反应,导致神经元变性死亡,最终产生痴呆。因此,对枸杞中酰胺类化合物及酰胺类化合物组分及其制备方法研究,将具有较大的研究意义。故本发明以枸杞为主要研究对象,进行酰胺类化合物及酰胺类化合物组分的发现及其制备方法研究。
[1]周正群.枸杞子抗阿尔茨海默病活性成分研究[D].广州,暨南大学,2016.
发明内容
本发明的目的是提供一类酰胺类化合物及酰胺类化合物组分及其制备方法。
为了满足上述目的,本发明采用的技术方案为:
一种枸杞中的酰胺类化合物及酰胺类化合物组分,所述酰胺类化合物的结构式如下:
其中R1选自以下基团:
其中R2选自以下基团:
其中基团R3、R4、R5、R6和R7各自独立的选自以下基团:
其中基团R8和R9各自独立的选自以下基团:
其中基团R10选自以下基团:
其中基团R11选自以下基团:
其中基团R12和R13各自独立的选自以下基团:
优选的,一类酰胺类化合物及酰胺类化合物组分的制备方法,其具体步骤如下:
1)将枸杞粉碎,用提取溶剂进行提取,所述枸杞和提取溶剂的质量比为1:3-20,得提取液,提取液加压浓缩至无有机溶剂,得到总浸膏A;
2)将总浸膏A溶于水,再利用D101大孔吸附树脂柱层析,或者利用石油醚、乙酸乙酯、正丁醇分别萃取,得到不同的浸膏组分;利用D101大孔吸附树脂柱层析,得到的五个不同的浸膏组分B(水)、C(30%)、D(60%)、E(80%)、F(100%);利用石油醚、乙酸乙酯和正丁醇分别萃取,得到四个不同的浸膏组分G(石油醚相)、H(乙酸乙酯相)、I(正丁醇相)和J(水相);
3)对浸膏组分(简称为N)进行硅胶柱层析或MCI柱层析或sephadex LH-20柱层析或反相ODS柱层析,用石油醚-丙酮、二氯甲烷-丙酮、二氯甲烷-甲醇、氯仿-丙酮、氯仿-甲醇、甲醇-水或乙醇-水为洗脱剂洗脱,等份收集洗脱液,每份洗脱液采用薄板层析色谱(TLC)定性检测,合并含相同成分的洗脱液,得到3-20个不同的浸膏组分N-3~N-20;
4)对浸膏N-1~N-20进行制备HPLC分离纯化,得到单体化合物,通过多种波谱学技术,确定单体化合物的结构。
优选的,所述步骤1)中的提取溶剂为水、甲醇/水的混合溶液或者乙醇/水混合溶液,所述甲醇的体积百分数为0-100%,所述乙醇的体积百分数为0-100%。
优选的,所述步骤1)中的提取方法有室温冷浸提取、加热回流提取、渗漏提取或超声提取。
优选的,所述步骤2)中的利用D101大孔吸附树脂柱层析,所用实验条件为用乙醇/水混合溶液或甲醇/水混合溶液为洗脱溶剂梯度洗脱,梯度洗脱溶剂体积比为水、30%、60%、80%、100%,不同体积比的洗脱溶剂洗脱体积为2-7倍柱体积,分别将不同体积比的洗脱液浓缩,得到五个浸膏组分。
优选的,所述步骤2)中利用石油醚、乙酸乙酯、正丁醇分别萃取,所用实验方法为总浸膏A溶于水后,用等体积的石油醚萃取三次,合并石油醚萃取液,浓缩,得到石油醚相,用同样的方法分别进行乙酸乙酯和正丁醇萃取,得到乙酸乙酯相和正丁醇相,萃取完之后所得水相浓缩得到水相。
优选的,所述提取方法室温冷浸提取每次需要将枸杞在提取溶剂中浸泡3-10天,浸提次数为1-4次;所述提取方法加热回流提取的加热温度为50-100℃,每次提取0.5-3.0小时,提取次数为1-4次;所述提取方法渗漏提取需要将枸杞在提取溶剂中浸泡6-24h,再置于渗漏装备;所述提取方法超声提取的提取温度为30-60℃,频率为20-50Hz,功率为70-1000W,每次提取0.5-2.0小时,提取次数为1-4次。
优选的,所述步骤3)中硅胶柱层析或MCI柱层析或sephadexLH-20柱层析或反相ODS柱层析所用洗脱剂石油醚-丙酮中石油醚与丙酮的体积比为30:1~1:3;二氯甲烷-丙酮中氯仿与丙酮的体积比为30:1~1:3;二氯甲烷-甲醇中氯仿与甲醇的体积比为30:1~1:3;氯仿-丙酮中氯仿与丙酮的体积比为30:1~1:3;氯仿-甲醇中氯仿与甲醇的体积比为30:1~1:3;甲醇-水中水与甲醇的体积比为30:1~1:3;乙醇-水中水与乙醇的体积比为30:1~1:3。
优选的,所述步骤4)中多种波谱学技术包括核磁共振谱(NMR谱)、质谱、高分辨质谱、红外(IR谱)、紫外光谱(UV谱)X-ray单晶衍射谱。
优选的,所述步骤4)中制备HPLC分离所用色谱柱为半制备Benetnach C18柱(Hanban Sci&Tech,10.0×250mm,10μm),流动相为甲醇-水,甲醇与水的洗脱比例为1:20~1:1,流速为1~5mL/min,进样体积:1-100μL,检测器:紫外检测器,检测波长:208nm和254nm。
本发明的有益效果为:
1、枸杞子提取物具有显著的抗阿尔茨海默病(AD)活性,枸杞中发现一类酰胺类化合物,该类化合物及该类化合物的组分具有抗β-淀粉样蛋白(Aβ)活性,具有治疗AD的作用。酰胺类化合物及酰胺类化合物组分的发现及其制备方法的研究,为AD的治疗提供了一种研究思路,为AD治疗药物的研制提供了物质基础。
2、半制备HPLC分离纯化样品,制备单体化合物,获得高纯度(99%以上)的化合物,确定了酰胺类化合物组分的化合物类型和结构,为新药研发提供了物质基础和标准物质。
具体实施方式
实施例1:酰胺类化合物组分制备方法及组分中活性成分1和2的分离鉴定方法,化学式如下:
1)将枸杞粉碎,用70%的乙醇/水混合溶液在室温条件下冷浸提取3次,每次7天,合并提取液,提取液减压浓缩至无乙醇味,得总浸膏A;
2)将总浸膏A溶于水后,进行D101大孔吸附树脂柱层析,用甲醇/水混合溶液为洗脱溶剂梯度洗脱,洗脱溶剂体积比为水、30%、60%、80%、100%,不同体积比的洗脱溶剂洗脱体积均为3倍柱体积,分别将不同体积比的洗脱液浓缩,得到五个不同的浸膏组分B(水)、C(30%)、D(60%)、E(80%)、F(100%);
3)对浸膏组分D进行硅胶柱层析,用二氯甲烷-甲醇为洗脱剂梯度洗脱,二氯甲烷与甲醇的体积比为30:1~1:1,等份收集洗脱液,每份洗脱液采用TLC定性检测,合并含相同成分的洗脱液,得到5个不同的浸膏组分D-1~D-5;
4)对浸膏D-2进行MCI柱层析,水-甲醇为洗脱剂梯度洗脱,水和甲醇的体积比为7:3~1:1,点板子合并相同点得到2个组分,编号为D-2-1~D-2-2;
5)对浸膏D-2-1进行制备HPLC分离纯化,D-2-1(45mg)经制备HPLC(45%甲醇-水,Benetnach C18柱)分离纯化,得到2个峰:D-2-1-1~D-2-1-2,D-2-1-1经半制备HPLC(48%甲醇-水,Benetnach C18柱)纯化,得到化合物1;D-2-1-2经半制备HPLC(56%甲醇-水,Benetnach C18柱)纯化,得到化合物2。经核磁共振波谱解析确定化合物1和2的结构,数据如下:
化合物1:分子式:C17H17NO3;分子量283;1H NMR(MeOD,400M)δppm:7.36(2H,d,8.4Hz),7.00(2H,d,8.4Hz),6.68(4H,m),6.60(d,12.4Hz),5.79(d,12.4Hz),3.38(2H,t,7.2Hz),2.68(2H,t,7.2Hz).
化合物2:分子式:C17H17NO3;分子量283;1H NMR(DMSO,400M)δppm:8.02(br s),7.38(2H,d,8.4Hz),7.30(d,15.6Hz),7.01(2H,d,8.4Hz),6.78(2H,d,8.4Hz),6.67(2H,d,8.4Hz),6.39(d,15.6Hz),3.33(2H,dd,7.2Hz),2.64(2H,t,7.2Hz).
实施例2:酰胺类化合物组分制备方法及组分中活性成分3、4、5和6的分离鉴定方法,化学式如下:
1)将枸杞粉碎,用75%的甲醇/水混合溶液加热回流提取3次,每次加热温度为80℃,提取2.0小时,合并提取液,减压浓缩至无甲醇味,得总浸膏A;
2)将总浸膏A溶于水后,进行D101大孔吸附树脂柱层析,用甲醇/水混合溶液为洗脱溶剂梯度洗脱,洗脱溶剂体积比为水、30%、60%、80%、100%,不同体积比的洗脱溶剂洗脱体积均为3倍柱体积,分别将不同体积比的洗脱液浓缩,得到五个不同的浸膏组分B(水)、C(30%)、D(60%)、E(80%)、F(100%);
3)对浸膏组分C进行硅胶柱层析,用氯仿-甲醇为洗脱剂梯度洗脱,氯仿与甲醇的体积比为10:1~0:1,等份收集洗脱液,每份洗脱液采用TLC定性检测,合并含相同成分的洗脱液,得到六个不同的浸膏组分C-1~C-6;
4)对浸膏C-3进行sephadex LH-20柱层析,水-甲醇为洗脱剂梯度洗脱,水和甲醇的体积比为8:2~1:2,点板子合并相同点得到4个组分,编号为C-3-1~C-3-4;
5)对浸膏C-3-3进行制备HPLC分离纯化,C-3-3(100mg)经半制备HPLC分离(45%甲醇-水,Benetnach C18柱)分离,得到三个组份:C-3-3-1~C-3-3-3,C-3-3-1经半制备HPLC(40%甲醇-水,Benetnach C18柱)纯化,得到化合物3;C-3-3-2经半制备HPLC(40%甲醇-水,Benetnach C18柱)纯化,得到化合物4和5;C-3-3-3经半制备HPLC(40%甲醇-水,Benetnach C18柱)纯化,得到化合物6。经核磁共振波谱解析确定化合物3、4、5和6的结构,数据如下:
化合物3:分子式:C18H19NO2;分子量281;1H NMR(CDCl3,400M)δppm:7.62(d,15.6Hz),7.49(2H,m),7.35(3H,m),7.14(2H,d,8.0Hz),6.87(2H,d,8.0Hz),6.34(d,15.6Hz),5.63(br s),3.80(3H,s),3.63(2H,dd,6.4Hz),2.83(2H,t,6.4Hz).
化合物4:分子式:C18H19NO;分子量265;1H NMR(CDCl3,400M)δppm:7.61(d,15.6Hz),7.48(2H,m),7.35(3H,m),7.14(2H,d,8.0Hz),7.11(2H,d,8.0Hz),6.30(d,15.6Hz),5.58(br s),3.80(3H,s),3.65(2H,dd,6.8Hz),2.85(2H,t,6.8Hz),2.34(3H,s).
化合物5:分子式:C17H17NO;分子量251;1H NMR(CDCl3,400M)δppm:7.62(d,15.6Hz),7.48(2H,m),7.35(5H,m),7.24(3H,m),6.32(d,15.6Hz),5.65(br s),3.67(2H,dd,6.8Hz),2.90(2H,t,6.8Hz).
化合物6:分子式:C19H21NO3;分子量311;1H NMR(CDCl3,400M)δppm:7.62(d,15.6Hz),7.48(2H,m),7.36(3H,m),6.83(d,8.0Hz),6.76(d,8.0Hz),6.75(s),6.32(d,15.6Hz),5.64(br s),3.87(6H,s),3.65(2H,dd,6.8Hz),2.84(2H,t,6.8Hz).
实施例3:酰胺类化合物组分制备方法及组分中活性成分9、10、11和12的分离鉴定方法,化学式如下:
1)将枸杞粉碎,用甲醇超声提取,提取温度为50℃,频率为40Hz,功率为500W,提1.0小时,枸杞与提取溶剂的质量比为1:8,提取3次,合并提取液,再进行浓缩,干燥,得到提取物A;
2)将总浸膏A溶于水后,利用石油醚、乙酸乙酯、正丁醇分别萃取,首先,将总浸膏A溶于水后,用等体积的石油醚萃取三次,合并石油醚萃取液,浓缩,得到石油醚相(G);水相用等体积的乙酸乙酯萃取三次,合并乙酸乙酯萃取液,浓缩,得到乙酸乙酯相(H);萃取后的水相继续用等体积的正丁醇萃取三次,合并正丁醇萃取液,浓缩,得到正丁醇相(I),水相浓缩得到水相(J);
3)对浸膏组分I进行硅胶柱层析,用氯仿-丙酮为洗脱剂梯度洗脱,氯仿与丙酮的体积比为15:1~0:1,等份收集洗脱液,每份洗脱液采用TLC定性检测,合并含相同成分的洗脱液,得到六个不同的浸膏组分I-1~I-6;
4)对浸膏I-4进行制备HPLC分离纯化,I-4(86mg)经半制备HPLC分离(50%甲醇-水,Benetnach C18柱)分离,得到三个组份:I-4-1~I-4-3,I-4-1经半制备HPLC(46%甲醇-水,Benetnach C18柱)纯化,得到化合物9和10;I-4-2经半制备HPLC(40%甲醇-水,Benetnach C18柱)纯化,得到化合物11和12。经核磁共振波谱解析确定化合物9、10、11和12的结构,数据如下:
化合物9:分子式:C19H21NO3;分子量311;1H NMR(CDCl3,400MHz)δppm:7.57(d,15.2Hz),7.43(2H,d,8.0Hz),7.14(2H,d,8.0Hz),6.87(4H,m),6.18(d,15.2Hz),5.55(brs),3.82(3H,s),3.80(3H,s),3.62(2H,dd,6.8Hz),2.83(2H,t,6.8Hz)。
化合物10:分子式:C19H21NO2;分子量295;1H NMR(CDCl3,400MHz)δppm:7.57(d,15.6Hz),7.43(2H,d,8.0Hz),7.14(2H,d,8.0Hz),7.11(2H,d,8.0Hz),6.88(2H,d,8.0Hz),6.18(d,15.6Hz),5.58(br s),3.82(3H,s),3.63(2H,dd,6.8Hz),2.84(2H,t,6.8Hz),2.33(3H,s)。
化合物11:分子式:C18H19NO2;分子量281;1H NMR(CDCl3,400MHz)δppm:7.58(d,15.6Hz),7.43(2H,d,8.0Hz),7.33(2H,d,8.0Hz),7.23(3H,m),6.88(2H,d,8.0Hz),6.20(d,15.6Hz),5.62(br s),3.82(3H,s),3.66(2H,dd,6.8Hz),2.89(2H,t,6.8Hz)。
化合物12:分子式:C20H23NO4;分子量341;1H NMR(CDCl3,400MHz)δppm:7.58(d,15.6Hz),7.43(2H,d,8.0Hz),6.88(2H,d,8.0Hz),6.83(d,8.0Hz),6.76(d,8.0Hz),6.75(s),6.19(d,15.6Hz),5.57(br s),3.87(6H,s),3.83(3H,s),3.64(2H,dd,6.8Hz),2.84(2H,t,6.8Hz)。
实施例4:酰胺类化合物组分制备方法及组分中活性成分15和16的分离鉴定方法,化学式如下:
1)将枸杞粉碎,用50%的乙醇/水为提取溶剂进行渗漏提取,将枸杞在提取溶剂中浸泡20h,枸杞与提取溶剂的质量比为1:15,合并提取液,再进行浓缩,干燥,得到提取物A;
2)将总浸膏A溶于水后,利用石油醚、乙酸乙酯、正丁醇分别萃取,首先,将总浸膏A溶于水后,用等体积的石油醚萃取三次,合并石油醚萃取液,浓缩,得到石油醚相(G);水相用等体积的乙酸乙酯萃取三次,合并乙酸乙酯萃取液,浓缩,得到乙酸乙酯相(H);萃取后的水相继续用等体积的正丁醇萃取三次,合并正丁醇萃取液,浓缩,得到正丁醇相(I),水相浓缩得到水相(J);
3)对浸膏组分I进行硅胶柱层析,用氯仿-甲醇为洗脱剂梯度洗脱,氯仿与甲醇的体积比为15:1~0:1,等份收集洗脱液,每份洗脱液采用TLC定性检测,合并含相同成分的洗脱液,得到六个不同的浸膏组分I-1~I-6;
4)对浸膏I-5进行MCI柱层析,水-甲醇为洗脱剂梯度洗脱,水和甲醇的体积比为5:1~1:1,点板子合并相同点得到4个组分,编号为I-5-1~I-5-4;
5)对浸膏I-5-3进行制备HPLC分离纯化,I-5-3(110mg)经半制备HPLC分离(55%甲醇-水,Benetnach C18柱)分离,得到两个组份:I-5-3-1~I-5-3-2,I-5-3-1经半制备HPLC(58%甲醇-水,Benetnach C18柱)纯化,得到化合物15;I-5-3-2经半制备HPLC(48%甲醇-水,Benetnach C18柱)纯化,得到化合物16。经核磁共振波谱解析确定化合物15和16的结构,数据如下:
化合物15:分子式:C18H18N2O4;分子量326;1H NMR(CDCl3,400MHz)δppm:8.22(2H,d,8Hz),7.66(d,15.2Hz),7.62(2H,d,8.0Hz),7.14(2H,d,8.0Hz),6.87(2H,d,8.0Hz)),6.43(d,15.2Hz),5.66(br s),3.80(3H,s),3.65(2H,dd,6.8Hz),2.84(2H,t,6.8Hz)。
化合物16:分子式:C18H18N2O3;分子量310;1H NMR(CDCl3,400MHz)δppm:8.22(2H,d,8Hz),7.66(d,15.6Hz),7.63(2H,m),7.15(2H,d,8.0Hz),7.12(2H,d,8.0Hz)),6.42(d,15.6Hz),5.63(br s),3.67(2H,dd,6.8Hz),2.86(2H,t,6.8Hz),2.34(3H,s)。
实施例5:酰胺类化合物组分制备方法及组分中活性成分21和22的分离鉴定方法,化学式如下:
1)将枸杞粉碎,用70%的甲醇/水室温加热回流提取3次,每次加热温度为80℃,提取2.0小时,合并提取液,减压浓缩至无甲醇味,得总浸膏A;
2)将总浸膏A溶于水后,进行D101大孔吸附树脂柱层析,用甲醇/水为洗脱溶剂梯度洗脱,洗脱溶剂体积比为水、30%、60%、80%、100%,不同体积比的洗脱溶剂洗脱体积均为3倍柱体积,分别将不同体积比的洗脱液浓缩,得到五个不同的浸膏组分B(水)、C(30%)、D(60%)、E(80%)、F(100%);
3)对浸膏组分C进行硅胶柱层析,用氯仿-甲醇为洗脱剂梯度洗脱,氯仿与甲醇的体积比为10:1、5:1、3:1、2:1、1:1、0:1,等份收集洗脱液,每份洗脱液采用TLC定性检测,合并含相同成分的洗脱液,得到六个不同的浸膏组分C-1~C-6;
4)对浸膏C-6进行反相ODS柱层析,水-甲醇为洗脱剂梯度洗脱,水和甲醇的体积比为7:3~1:1,点板子合并相同点得到4个组分,编号为C-6-1~C-6-4;
5)对浸膏C-6-2进行制备HPLC分离纯化,C-6-2(55mg)经半制备HPLC分离(45%甲醇-水,Benetnach C18柱)分离,得到三个组份:C-6-2-1~C-6-2-3,C-6-2-1经半制备HPLC(45%甲醇-水,Benetnach C18柱)纯化,得到化合物21;C-6-2-2经半制备HPLC(40%甲醇-水,Benetnach C18柱)纯化,得到化合物22。经核磁共振波谱解析确定化合物21和22的结构,数据如下:
化合物21:分子式:C19H21NO4;分子量327;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.14(2H,d,8.0Hz),7.04(d,8.0Hz),6.97(s),6.89(d,8.0Hz),6.87(2H,d,8.0Hz),6.17(d,15.6Hz),5.55(brs),3.91(3H,s),3.80(3H,s),3.62(2H,dd,6.8Hz),2.83(2H,t,6.8Hz)。
化合物22:分子式:C19H21NO3;分子量311;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.13(2H,d,8.0Hz),7.11(2H,d,8.0Hz),7.03(d,8.0Hz),6.96(s),6.89(d,8.0Hz),6.18(d,15.6Hz),5.62(br s),3.89(3H,s),3.64(2H,dd,6.8Hz),2.84(2H,t,6.8Hz),2.33(3H,s)。
参照实施例1~实施例5的酰胺类化合物组分制备方法及组分中活性成分的分离鉴定方法,化合物7、8、13、14、17-20和23-40的结构化学式如下:
经核磁共振波谱解析确定化合物7、8、13、14、17-20和23-40的结构,数据如下:
化合物7:分子式:C18H19NO2;分子量281;1H NMR(CDCl3,400MHz)δppm:7.62(d,15.6Hz),7.48(2H,m),7.36(3H,m),7.23(d,8.0Hz),6.81(3H,m),6.32(d,15.6Hz),5.67(brs),3.80(3H,s),3.67(2H,dd,6.8Hz),2.87(2H,t,6.8Hz).
化合物8:分子式:C17H16N2O3;分子量296;1H NMR(CDCl3,400MHz)δppm:8.11(2H,d,8.0Hz),7.57(d,15.6Hz),7.43(2H,m),7.30(5H,m),6.27(d,15.6Hz),5.63(br s),3.63(2H,dd,6.8Hz),2.96(2H,t,6.8Hz).
化合物13:分子式:C19H21NO3;分子量311;1H NMR(CDCl3,400MHz)δppm:7.57(d,15.6Hz),7.43(2H,d,8.0Hz),7.23(d,8.0Hz),6.88(2H,d,8.0Hz),6.80(3H,m),6.19(d,15.6Hz),5.59(br s),3.82(3H,s),3.80(3H,s),3.65(2H,dd,6.8),2.86(2H,t,6.8).
化合物14:分子式:C18H18N2O4;分子量326;1H NMR(CDCl3,400MHz)δppm:8.18(2H,d,8.0Hz),7.60(d,15.6Hz),7.44(2H,d,8.0Hz),7.40(2H,d,8.0Hz),6.89(2H,d,8.0Hz),6.21(d,15.6Hz),5.58(br s),3.83(3H,s),3.70(2H,m),3.02(2H,m).
化合物17:分子式:C17H16N2O3;分子量296;1H NMR(CDCl3,400MHz)δppm:8.22(2H,d,8Hz),7.67(d,15.6Hz),7.63(2H,m),7.33(2H,d,8.0Hz),7.23(3H,m),6.43(d,15.6Hz),5.64(br s),3.69(2H,dd,6.8Hz),2.91(2H,t,6.8Hz).
化合物18:分子式:C19H20N2O5;分子量356;1H NMR(CDCl3,400MHz)δppm:8.23(2H,d,8Hz),7.67(d,15.6Hz),7.63(2H,d,15.6Hz),6.84(d,8.0Hz),6.76(d,8.0Hz),6.75(s),6.43(d,15.6Hz),5.66(br s),3.88(6H,s),3.67(2H,dd,6.8Hz),2.86(2H,t,6.8Hz).
化合物19:分子式:C18H18N2O4;分子量326;1H NMR(CDCl3,400MHz)δppm:8.23(2H,d,8Hz),7.67(d,15.6Hz),7.63(2H,d,15.6Hz),7.23(m),6.80(3H,m),6.43(d,15.6Hz),5.65(br s),3.81(3H,s),3.69(2H,dd,6.8Hz),2.88(2H,t,6.8Hz).
化合物20:分子式:C17H15N3O5;分子量341;1H NMR(CDCl3,400MHz)δppm:8.23(2H,d,8.0Hz),8.19(2H,d,8.0Hz),7.69(d,15.6Hz),7.63(2H,d,8.0Hz),7.40(2H,d,8.0Hz),6.44(d,15.6Hz),5.69(br s),3.72(2H,dd,6.8Hz),3.04(2H,q,6.8Hz).
化合物23:分子式:C18H19NO3;分子量297;1H NMR(CDCl3,400MHz)δppm:7.54(d,15.6Hz),7.32(2H,d,8.0Hz),7.24(3H,m),7.04(d,8.0Hz),6.97(s),6.89(d,8.0Hz),6.18(d,15.6Hz),5.62(br s),3.90(3H,s),3.66(2H,dd,6.8Hz),2.89(2H,t,6.8Hz).
化合物24:分子式:C19H21NO4;分子量327;1H NMR(CDCl3,400MHz)δppm:7.54(d,15.6Hz),7.03(d,8.0Hz),6.96(s),6.89(d,8.0Hz),6.82(d,8.0Hz)),6.76(d,8.0Hz),6.74(s),6.19(d,15.6Hz),5.71(br s),3.89(3H,s),3.86(3H,s),3.85(3H,s),3.63(2H,dd,6.8Hz),2.83(2H,t,6.8Hz).
化合物25:分子式:C18H18N2O5;分子量342;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.23(t,8.0Hz),7.02(d,8.0Hz),6.96(s),6.89(d,8.0Hz),6.81(d,8.0Hz),6.79(d,8.0Hz)),6.77(s),6.19(d,15.6Hz),5.74(br s),3.88(3H,s),3.79(3H,s),3.65(2H,dd,6.8Hz),2.86(2H,t,6.8Hz).
化合物26:分子式:C18H18N2O5;分子量342;1H NMR(CDCl3,400MHz)δppm:8.18(2H,d,8.0Hz),7.56(d,15.6Hz),7.40(2H,d,8.0Hz),7.06(d,8.0Hz),6.98(s),6.90(d,8.0Hz),6.18(d,15.6Hz),5.587(br s),3.92(3H,s),3.69(2H,dd,6.8Hz),3.02(2H,t,6.8Hz).
化合物27:分子式:C18H19NO4;分子量313;1H NMR(DMSO,400MHz)δppm:9.34(s),9.10(s),7.22(d,15.6Hz),7.14(2H,d,8.0Hz),6.93(s),6.86(2H,d,8.0Hz),6.83(d,8.0Hz),6.74(d,8.0Hz),6.31(d,15.6Hz),3.71(3H,s),3.34(2H,dd,6.8Hz),2.69(2H,t,6.8Hz).
化合物28:分子式:C18H19NO3;分子量297;1H NMR(DMSO,400MHz)δppm:9.34(s),9.11(s),7.23(d,15.6Hz),7.10(4H,m),6.93(s),6.83(2H,d,8.0Hz),6.74(d,8.0Hz),6.31(d,15.6Hz),3.36(2H,dd,6.8Hz),2.71(2H,t,6.8Hz),3.26(3H,s).
化合物29:分子式:C17H17NO3;分子量283;1H NMR(DMSO,400MHz)δppm:9.34(s),9.11(s),7.30(2H,m),7.22(4H,m),6.93(s),6.83(d,8.0Hz),6.74(d,8.0Hz),6.31(d,15.6Hz),3.39(2H,dd,6.8Hz),2.77(2H,t,6.8Hz).
化合物30:分子式:C19H21NO5;分子量343;1H NMR(DMSO,400MHz)δppm:9.34(s),9.10(s),7.22(d,15.6Hz),6.93(s),6.86(d,8.0Hz),6.81(2H,m),6.73(2H,m),6.32(d,15.6Hz),3.73(3H,s),3.71(3H,s),3.36(2H,dd,6.8Hz),2.69(2H,t,6.8Hz).
化合物31:分子式:C18H19NO4;分子量313;1H NMR(DMSO,400MHz)δppm:9.34(s),9.10(s),7.22(d,15.6Hz),7.20(t,8.0Hz),6.93(s),6.79(4H,m),6.73(2H,d,8.0Hz),6.31(d,15.6Hz),3.73(3H,s),3.39(2H,dd,6.8Hz),2.74(2H,t,6.8Hz).
化合物32:分子式:C17H16N2O5;分子量328;1H NMR(DMSO,400MHz)δppm:9.35(s),9.10(s),8.17(2H,d,8.0Hz),7.52(2H,d,8.0Hz),7.22(d,15.6Hz),6.92(s),6.82(d,8.0Hz),6.73(d,8.0Hz),6.28(d,15.6Hz),3.46(2H,dd,6.8Hz),2.92(2H,t,6.8Hz).
化合物33:分子式:C19H19NO4;分子量325;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.14(2H,d,8.0Hz),6.98(s),6.97(d,8.0Hz),6.86(2H,d,8.0Hz),6.79(d,8.0Hz),6.14(d,15.6Hz),5.98(2H,s),5.56(br s),3.80(3H,s),3.62(2H,dd,6.8Hz),2.82(2H,t,6.8Hz).
化合物34:分子式:C19H19NO3;分子量309;1H NMR(CDCl3,400MHz)δppm:7.52(d,15.6Hz),7.14(2H,d,8.0Hz),7.11(2H,d,8.0Hz),6.98(s),6.97(d,8.0Hz),6.79(d,8.0Hz),6.13(d,15.6Hz),5.99(2H,s),5.51(br s),3.64(2H,dd,6.8Hz),2.84(2H,t,6.8Hz),2.34(3H,s).
化合物35:分子式:C18H17NO3;分子量295;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.33(t,8.0Hz),7.32(d,8.0Hz),7.24(3H,m),6.98(s),6.97(d,8.0Hz),6.79(d,8.0Hz),6.13(d,15.6Hz),5.99(2H,s),5.52(br s),3.66(2H,dd,6.8Hz),2.89(2H,t,6.8Hz).
化合物36:分子式:C20H21NO5;分子量355;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.33(t,8.0Hz),7.32(d,8.0Hz),7.24(3H,m),6.98(s),6.97(d,8.0Hz),6.79(d,8.0Hz),6.13(d,15.6Hz),5.99(2H,s),5.52(br s),3.66(2H,dd,6.8Hz),2.89(2H,t,6.8Hz).
化合物37:分子式:C19H19NO4;分子量325;1H NMR(CDCl3,400MHz)δppm:7.53(d,15.6Hz),7.23(d,8.0Hz),6.98(s),6.97(d,8.0Hz),6.80(4H,m),6.14(d,15.6Hz),5.99(2H,s),5.55(br s),3.80(3H,s),3.66(2H,dd,6.8Hz),2.86(2H,t,6.8Hz).
化合物38:分子式:C18H16N2O5;分子量340;1H NMR(CDCl3,400MHz)δppm:8.18(2H,d,8.0Hz),7.55(d,15.6Hz),7.39(2H,d,8.0Hz),6.98(s),6.97(d,8.0Hz),6.80(d,8.0Hz),6.15(d,15.6Hz),5.99(2H,s),5.58(br s),3.68(2H,dd,6.8Hz),3.02(2H,t,6.8Hz).
化合物39:分子式:C34H39N3O9;分子量633;1H NMR(CD3OD,400MHz)δppm:6.78(s),7.31(s),6.45(d,1.8Hz),6.57(d,8.1Hz),6.38(dd,8.1,1.8Hz),4.79(s),3.66(s),6.81(d,8.2Hz,),6.63(d,8.2Hz),6.63(d,8.2Hz),6.81(d,8.2Hz),2.52(2H,t,6.1Hz),3.22(2H,m),3.14(2H,m),1.48(2H,brs),1.48(2H,brs),3.20(2H,m),1.90(3H,s,N-COCH3),3.54(3H,s,3-OCH3),3.91(3H,s,5-OCH3)。
化合物40:分子式:C36H36N2O8;分子量624;1H NMR(CD3OD,400MHz)δppm:7.49(d,15.6Hz),7.24(d,2.0Hz),7.02(dd,8.0,2.0Hz),6.85(2H,d,8.4Hz),6.73(2H,d,8.4Hz),6.72(d,8.0Hz),6.53(d,15.6Hz),3.92(3H,s),3.48(br t,6.8Hz),2.66(br t,6.8Hz)。
Claims (10)
1.一种枸杞中的酰胺类化合物的制备方法,其特征在于制备方法包括以下步骤:
1)将枸杞粉碎,用提取溶剂进行提取,所述枸杞和提取溶剂的质量比为1:3-20,得提取液,提取液加压浓缩至无有机溶剂,得到总浸膏A;
2)将总浸膏A溶于水,再利用D101大孔吸附树脂柱层析,或者利用石油醚、乙酸乙酯、正丁醇分别萃取,得到不同的浸膏组分;利用D101大孔吸附树脂柱层析,得到五个不同的浸膏组分;利用石油醚、乙酸乙酯和正丁醇分别萃取,得到四个不同的浸膏组分;
3)对浸膏组分进行硅胶柱层析或MCI柱层析或sephadex LH-20柱层析或反相ODS柱层析,用石油醚-丙酮、二氯甲烷-丙酮、二氯甲烷-甲醇、氯仿-丙酮、氯仿-甲醇、甲醇-水或乙醇-水为洗脱剂洗脱,等份收集洗脱液,每份洗脱液采用薄板层析色谱定性检测,合并含相同成分的洗脱液,得到3-20个不同的浸膏组分N-1~N-20;
4)对浸膏N-1~N-20进行制备HPLC分离纯化,得到单体化合物,通过多种波谱学技术,确定单体化合物的结构如下:
2.根据权利要求1所述的制备方法,其特征在于:上述化合物具有抗AD活性。
3.根据权利要求1所述的制备方法,其特征在于:所述步骤1)中的提取溶剂为水、甲醇/水的混合溶液或者乙醇/水混合溶液,所述甲醇的体积百分数为0-100%,所述乙醇的体积百分数为0-100%。
4.根据权利要求1所述的制备方法,其特征在于:所述步骤1)中的提取方法有室温冷浸提取、加热回流提取、渗漏提取或超声提取。
5.根据权利要求1所述的制备方法,其特征在于:所述步骤2)中的利用D101大孔吸附树脂柱层析,所用实验条件为用乙醇/水混合溶液或甲醇/水混合溶液为洗脱溶剂梯度洗脱,梯度洗脱溶剂体积比为水、30%、60%、80%、100%,不同体积比的洗脱溶剂洗脱体积为2-7倍柱体积,分别将不同体积比的洗脱液浓缩,得到五个浸膏组分。
6.根据权利要求1所述的制备方法,其特征在于:所述步骤2)中利用石油醚、乙酸乙酯、正丁醇分别萃取,所用实验方法为总浸膏A溶于水后,用等体积的石油醚萃取三次,合并石油醚萃取液,浓缩,得到石油醚相,用同样的方法分别进行乙酸乙酯和正丁醇萃取,得到乙酸乙酯相和正丁醇相,萃取完之后所得水相浓缩得到水相。
7.根据权利要求4所述的制备方法,其特征在于:所述提取方法室温冷浸提取每次需要将枸杞在提取溶剂中浸泡3-10天,浸提次数为1-4次;所述提取方法加热回流提取的加热温度为50-100℃,每次提取0.5-3.0小时,提取次数为1-4次;所述提取方法渗漏提取需要将枸杞在提取溶剂中浸泡6-24h,再置于渗漏装备;所述提取方法超声提取的提取温度为30-60℃,频率为20-50Hz,功率为70-1000W,每次提取0.5-2.0小时,提取次数为1-4次。
8.根据权利要求1所述的制备方法,其特征在于:所述步骤3)中硅胶柱层析或MCI柱层析或sephadex LH-20柱层析或反相ODS柱层析所用洗脱剂石油醚-丙酮中石油醚与丙酮的体积比为30:1~1:3;二氯甲烷-丙酮中二氯甲烷与丙酮的体积比为30:1~1:3;二氯甲烷-甲醇中二氯甲烷与甲醇的体积比为30:1~1:3;氯仿-丙酮中氯仿与丙酮的体积比为30:1~1:3;氯仿-甲醇中氯仿与甲醇的体积比为30:1~1:3;甲醇-水中水与甲醇的体积比为30:1~1:3;乙醇-水中水与乙醇的体积比为30:1~1:3。
9.根据权利要求1所述的制备方法,其特征在于:所述步骤4)中多种波谱学技术选自核磁共振谱、质谱、高分辨质谱、红外、紫外光谱或X-ray单晶衍射谱。
10.根据权利要求1所述的制备方法,其特征在于:所述步骤4)中制备HPLC分离所用色谱柱为半制备Benetnach C18柱,流动相为甲醇-水,甲醇与水的洗脱比例为1:20~1:1,流速为1~5mL/min,进样体积:1-100μL,检测器:紫外检测器,检测波长:208nm和254nm。
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