CN112824383B - 联苄类化合物及其制备方法和用途 - Google Patents
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明属于医药技术领域,涉及联苄类化合物及其制备方法和用途,具体涉及3个联苄类化合物及其盐、异构体及其制备方法和在制备预防或治疗神经退行性疾病药物领域中的应用,所述化合物的通式如下:
Description
技术领域
本发明属于医药技术领域,具体涉及白及中新的联苄类化合物及其制备方法和应用。
背景技术
白及(Bletilla striata)又称连及草、白根、白芨等。主要分布在贵州、四川、云南、湖南、湖北、安徽等省。
白及作为珍稀名贵中药材,其味苦、甘、涩、性凉,归肺、胃、肝经,主治咯血、吐血、外伤出血、疮疡肿毒、皮肤皲裂。现代药理活性研究表明白及具有明显的抗肿瘤、抗氧化、抗菌、促进伤口愈合等作用,其化学成分主要为联苄类、菲类、二氢菲类、联菲类、萜类、多糖类等。
发明内容
本发明的目的在于提供一系列联苄类化合物及其制备方法和新的医药用途。
本发明提供了联苄类化合物及其盐、异构体,其具有如下结构:
R1为氢、C1-C4烷基或葡萄糖基;R2为氢、羟基、C1-C4烷氧基或吡咯烷酮环。
进一步地,R1为氢、甲基或葡萄糖基;R2为氢、羟基、甲氧基或吡咯烷酮环。
本发明具体公开了如下3个具体化合物:
本发明还提供了所述联苄类化合物1-3的制备方法,该方法包括如下步骤:
(1)白及(Bletilla striata)的干燥块茎用70%~95%乙醇提取,回收提取液得粗提物;
(2)步骤(1)所得粗提物经水溶解后,用有机溶剂萃取,用石油醚、二氯甲烷、乙酸乙酯、正丁醇,以水相和有机相的体积比1:1依次萃取,得到不同极性的萃取物;
(3)上述步骤(2)中所得萃取物经硅胶柱色谱法分离,以石油醚和乙酸乙酯混合溶剂100:1~1:1、石油醚和丙酮混合溶剂100:1~1:1、氯仿和丙酮混合溶剂100:1~100:10、二氯甲烷和丙酮混合溶剂100:1~100:10、氯仿和甲醇混合溶剂100:1~100:10、二氯甲烷和甲醇混合溶剂100:1~100:10梯度洗脱;
(4)上述步骤(3)中所得100:1~100:25流分经ODS柱色谱分离,以甲醇和水混合溶剂,或以乙腈和水混合溶剂为流动相梯度洗脱;
(5)上述步骤(4)中所得甲醇和水3:7~9:1、乙腈和水1:9~7:3洗脱物经制备型HPLC-UV进一步分离,以甲醇和水混合溶剂4:6~9:1,或以乙腈和水3:7~7:3混合溶剂为流动相梯度洗脱,得到联苄类化合物1和2的消旋混合物及化合物3;
(6)上述步骤(5)所得到的联苄类化合物的消旋混合物经HPLC手性拆分得到的化合物1和2,溶剂为正己烷和无水乙醇混合溶剂,其体积比例为70:30~95:5。
本发明提供的所述联苄类化合物1-3的制备方法,步骤(1)中所述提取方法为加热回流提取或加热超声提取1~3次,所用溶剂为70%~95%的乙醇,优选75%~95%乙醇。药材:溶剂的重量体积比为1:5~1:20g/mL,优选1:10~1:15。
本发明提供的所述联苄类化合物1-3的制备方法,步骤(2)中所述的有机溶剂萃取法,采用水溶解粗提物,按照水相和有机相的体积比1:1,分别使用石油醚、二氯甲烷、乙酸乙酯和正丁醇依次萃取3-5次,优选5次,减压回收以上有机溶剂。
本发明提供的所述联苄类化合物1-3的制备方法,步骤(3)中所述洗脱溶剂石油醚和乙酸乙酯混合溶剂、石油醚和丙酮混合溶剂的体积比例为100:1~1:1,优选100:4~10:1;二氯甲烷和丙酮混合溶剂、氯仿和丙酮混合溶剂、二氯甲烷和甲醇混合溶剂、或氯仿和甲醇的混合溶剂的体积比例为100:1~100:10,优选100:1~100:6。
本发明提供的所述联苄类化合物1-3的制备方法,步骤(4)中所述甲醇和水混合溶剂的体积比例为3:7~9:1,优选6:4~8:2;乙腈和水混合溶剂的体积比例为1:9~7:3,优选4:6~1:1。
本发明提供的所述联苄类化合物1-3的制备方法,步骤(5)所述的甲醇和水混合溶剂、乙腈和水混合溶剂,其中甲醇和水混合溶剂的体积比例为:4:6~9:1,优选6:4~8:2;乙腈和水混合溶剂的体积比例为3:7~7:3,优选4:6~1:1。
本发明提供的所述联苄类化合物1-3的制备方法,步骤(6)所述的手性色谱柱拆分溶剂为正己烷和无水乙醇混合溶剂,其体积比例为70:30~95:5,优选75:25~80:20。
本发明以LPS诱导BV2小胶质细胞过度活化模型,对制备得到的联苄类化合物1-3的抗神经炎症活性进行了评价。结果显示,化合物1、2和3能够抑制LPS诱导的过度活化的BV2小胶质细胞NO的释放,表现出中等强度的抗神经炎症活性。因此,本发明中制备的联苄类化合物可在开发治疗神经退行性疾病药物方面应用。
本发明首次提供了以白及为原料,制备、鉴定3个联苄类化合物的方法,并系统评价了其神经保护方面的活性,阐明了其在开发和治疗神经退行性疾病药物方面的应用。
具体实施方式
下面的实施例将对本发明予以进一步的说明,但并不因此限制本发明。
实施例1
(1)白及块茎500g用75%乙醇提取1次(用量为10L),减压回收提取液得粗提物;
(2)上述步骤(1)所得75%乙醇粗提物用水溶解,经石油醚、二氯甲烷、乙酸乙酯、正丁醇依次萃取,每个有机溶剂萃取3次,每次水相和有机相的体积比1:1,得到不同极性部位的萃取物;
(3)步骤(2)中石油醚萃取物,经硅胶柱色谱分离,依次以石油醚和乙酸乙酯混合溶剂100:1,100:3,100:8,100:10洗脱;
(4)上述步骤(3)中所得的石油醚:乙酸乙酯100:4~100:8流分经ODS色谱,用30:70,50:50,70:30,90:10甲醇-水的混合溶剂梯度洗脱;
(5)上述步骤(4)中所得甲醇-水(50:50~90:10)流分经HPLC-UV色谱分离制备,210nm检测,流速为4mL/min,流动相为甲醇:水=75:25,得到联苄1和2的消旋混合物(tR=40min)(收率为0.00011%)。化合物1和2的消旋混合物再经手性柱色谱分离,以正己烷:乙醇(75:25)为流动相洗脱得到新的化合物1(9.958min),2(11.304min)(收率各为0.00005%)。
(6)上述步骤(4)中所得甲醇-水(50:50~90:10)流分经HPLC-UV色谱分离,210nm检测,流速为4mL/min,以60:40甲醇-水的混合溶剂为流动相,得到联苄3(tR=35min)(收率为0.00010%)。
根据化合物1-3的理化性质和波谱数据鉴定了其结构。
化合物1的结构鉴定数据如下:
紫色粉末(甲醇)。-30.4(c 1.0,MeOH),HR-ESI-MS给出准分子离子峰[M+H]+m/z:328.1539(calcd.328.1543for C19H22NO4),提示其分子式为C19H21NO4。1H NMR(600MHz,CD3OD):δH 7.06(1H,t,J=7.8Hz,H-5'),6.60(1H,m,H-4'),6.58(1H,m,H-6'),6.62(1H,m,H-2')为一组间位取代苯环的氢信号,6.33(1H,d,J=2.4Hz,H-4),6.23(1H,d,J=2.4Hz,H-6)为苯环上间位偶合的氢信号;δH 2.74-2.89(4H,m,H-α,α')为联苄类化合物亚甲基特征氢信号;δH3.75(3H,s,3-OCH3)为一个甲氧基氢信号,5.03(1H,dd,J=9.0,5.0Hz,H-5”),2.39(1H,m,H-3”a),2.50(1H,m,H-3”b),2.06(1H,m,H-4”a),2.32(1H,m,H-4”b)为5个脂肪族氢信号,包含两组亚甲基氢信号,为一组吡咯烷酮氢信号。13C NMR(150MHz,CD3OD)谱中给出19个碳信号:δC 143.3(C-1),120.0(C-2),161.4(C-3),99.2(C-4),159.0(C-5),109.7(C-6),144.3(C-1'),120.9(C-2'),158.5(C-3'),114.0(C-4'),130.4(C-5'),116.4(C-6')为12个sp2杂化碳信号;δC 55.9(3-OCH3),39.7(C-α'),36.7(C-α)为脂肪碳信号;181.5(C-2”),32.2(C-3”),27.4(C-4”),53.4(C-5”)组成一个五元氮杂环-吡咯烷酮。
利用HSQC将所有的氢碳信号进行归属,并通过HMBC谱将取代基的位置进一步确定。在HMBC谱中,δH5.03(H-5”)与δC 143.3(C-1),161.4(C-3)远程相关,提示吡咯烷酮连接在C-2位,δH 3.75(3-OCH3)与161.4(C-3)的远程相关提示甲氧基连接在C-3位,因此确定了该化合物的结构。经检索为一未见文献报道的新化合物,命名为dusuanlansin E1。
表1化合物1和2的NMR数据归属
化合物2的结构鉴定数据如下:
紫色粉末(甲醇)。-30.4(c 1.0,MeOH),HR-ESI-MS给出准分子离子峰[M+H]+m/z:328.1539(calcd.328.1543for C19H22NO4),提示其分子式为C19H21NO4。
由于化合物1和2是通过手性柱拆分得到的一对对映异构体,它们的氢碳谱数据是完全一致的(见表1),不同的地方表现在CD谱图上,其中化合物1在195-220nm处为+cotton效应;而化合物2在该波长处为-cotton效应;经检索为一未见文献报道的新化合物,命名为dusuanlansin E2。
化合物3的结构鉴定数据如下:
深黄色粉末(甲醇)。HR-ESI-MS给出准分子离子峰[M-H]-m/z:405.1534(calcd.405.1555for C21H25O8),提示其分子式为C21H26O8,1H NMR(600MHz,DMSO-d6):δH7.17(1H,t,J=7.8Hz,H-5'),6.84(1H,m,H-6'),6.89(1H,m,H-4'),6.83(1H,m,H-2'),6.13(1H,m,H-4),6.21(2H,m,H-2,6)为苯环上的氢信号;4.80(d,J=7.2Hz,H-1”)为糖端基氢信号,δH 2.81-2.88(4H,m,H-α,α')为联苄类化合物亚甲基特征氢信号;δH 3.65(3H,s,5-OCH3)一个甲氧基氢信号。13C NMR(150MHz,DMSO-d6)谱中给出21个碳信号:δC 143.4(C-1),108.2(C-2),160.3(C-3,5),98.9(C-4),104.3(C-6),143.1(C-1'),113.5(C-2'),157.5(C-3'),116.3(C-4'),129.0(C-5'),121.8(C-6')为12个sp2杂化碳信号;100.4(C-1”),73.3(C-2”),76.7(C-3”),69.7(C-4”),77.0(C-5”),60.7(C-6”)为葡萄糖碳信号,δC 54.7(5-OCH3),36.7(C-α'),37.2(C-α)为脂肪碳信号。
表2化合物3的NMR数据归属
根据HSQC谱将氢碳信号一一归属,并结合HMBC谱确定取代基及糖片段的连接位置。4.80(H-1”)与157.5(C-3')的远程相关表明葡萄糖连接在C-3'位,以及3.65(5-OCH3)与160.3(C-5)的相关表明甲氧基连接在C-5位;经检索为一未见文献报道的新化合物,命名为3-hydroxy-5-methoxybibenzyl-3'-O-β-D-glucopyranoside。
实施例2
(1)白及1000g用95%乙醇加热回流提取3次(用量:10L),减压回收提取液得粗提物;
(2)步骤(1)所得乙醇提取物经有机溶剂萃取,依次用石油醚、二氯甲烷、乙酸乙酯、正丁醇以水相和有机相的体积比1:1进行萃取,得到不同极性部位的萃取物;
(3)步骤(2)中石油醚萃取物,经硅胶柱色谱分离,依次以石油醚和乙酸乙酯混合溶剂100:2,100:4,100:8,100:10洗脱;
(4)上述步骤(3)中所得的石油醚:乙酸乙酯100:4~100:7流分经ODS色谱,用30:70,60:40,70:30,90:10甲醇-水的混合溶剂梯度洗脱;
(5)上述步骤(4)中所得甲醇-水(70:30~90:10)流分经HPLC-UV色谱分离制备,210nm检测,流速为4mL/min,流动相为甲醇:水=65:35,得到联苄1和2的消旋混合物(tR=40min)(收率为0.00011%)。化合物1和2的消旋混合物再经手性柱色谱分离,以正己烷:乙醇(75:25)为流动相洗脱得到新的1(9.958min),2(11.304min)(收率各为0.00005%)。
(6)上述步骤(4)中所得甲醇-水(60:40~50:50)流分经HPLC-UV色谱分离,210nm检测,流速为4mL/min,以60:40甲醇-水的混合溶剂为流动相,得到联苄3(tR=35min)(收率为0.00011%)。
联苄类1-3的结构鉴定方法见实施例1。
实施例3
(1)白及800g用85%乙醇加热回流提取3次(用量:9.6L),减压回收提取液得粗提物;
(2)步骤(1)所得乙醇提取物经有机溶剂萃取,依次用石油醚、二氯甲烷、乙酸乙酯、正丁醇以水相和有机相的体积比1:1进行萃取,分别萃取4次,得到不同极性部位的萃取物;
(3)步骤(2)中石油醚萃取物,经硅胶柱色谱分离,依次以二氯甲烷和丙酮混合溶剂100:1,100:3,100:5,100:7洗脱;
(4)上述步骤(3)中所得的二氯甲烷:丙酮100:5~100:7流分经ODS色谱,用30:70,60:40,70:30,90:10甲醇-水的混合溶剂梯度洗脱;
(5)上述步骤(4)中所得甲醇-水(70:30~90:10)流分经HPLC-UV色谱分离制备,210nm检测,流速为4mL/min,流动相为甲醇:水=65:35,得到联苄1和2的消旋混合物(tR=36min)(收率为0.00011%)。化合物1和2的消旋混合物再经手性柱色谱分离,以正己烷:乙醇(75:25)为流动相洗脱得到新的1(9.058min),2(11.104min)(收率各为0.00005%)。
(6)上述步骤(4)中所得甲醇-水(60:40~50:50)流分经HPLC-UV色谱分离,210nm检测,流速为4mL/min,以55:45甲醇-水的混合溶剂为流动相,得到联苄3(tR=36min)(收率为0.00011%)。
联苄类1-3的结构鉴定方法见实施例1。
实施例4
(1)白及1200g用95%乙醇加热回流提取2次(用量:18L),减压回收提取液得粗提物;
(2)步骤(1)所得乙醇提取物经有机溶剂萃取,依次用石油醚、二氯甲烷、乙酸乙酯、正丁醇以水相和有机相的体积比1:1进行萃取,分别萃取3次,得到不同极性部位的萃取物;
(3)步骤(2)中石油醚萃取物,经硅胶柱色谱分离,依次以二氯甲烷和甲醇混合溶剂100:1,100:3,100:5,100:8洗脱;
(4)上述步骤(3)中所得的二氯甲烷:甲醇100:3~100:5流分经ODS色谱,用30:70,50:50,90:10甲醇-水的混合溶剂梯度洗脱;
(5)上述步骤(4)中所得甲醇-水(90:10)流分经HPLC-UV色谱分离制备,210nm检测,流速为4mL/min,流动相为乙腈:水=45:55,得到联苄1和2的消旋混合物(tR=46min)(收率为0.00010%)。化合物1和2的消旋混合物再经手性柱色谱分离,以正己烷:乙醇(77:23)为流动相洗脱得到新的1(9.008min),2(11.100min)(收率各为0.00005%)。
(6)上述步骤(4)中所得甲醇-水(50:50)流分经HPLC-UV色谱分离,210nm检测,流速为4mL/min,以53:47甲醇-水的混合溶剂为流动相,得到联苄3(tR=36min)(收率为0.00013%)。
联苄类1-3的结构鉴定方法见实施例1。
实施例5
(1)白及600g用80%乙醇加热回流提取3次(用量:10L),减压回收提取液得粗提物;
(2)步骤(1)所得乙醇提取物经有机溶剂萃取,依次用石油醚、二氯甲烷、乙酸乙酯、正丁醇以水相和有机相的体积比1:1进行萃取,分别萃取3次,得到不同极性部位的萃取物;
(3)步骤(2)中石油醚萃取物,经硅胶柱色谱分离,依次以氯仿和丙酮混合溶剂100:1,100:3,100:5,100:6洗脱;
(4)上述步骤(3)中所得的氯仿:丙酮100:5~100:6流分经ODS色谱,用30:70,45:55,60:40,65:35乙腈-水的混合溶剂梯度洗脱;
(5)上述步骤(4)中所得乙腈-水(45:55)流分经HPLC-UV色谱分离制备,210nm检测,流速为4mL/min,流动相为甲醇:水=66:34,得到联苄1和2的消旋混合物(tR=34min)(收率为0.00011%)。化合物1和2的消旋混合物再经手性柱色谱分离,以正己烷:乙醇(78:22)为流动相洗脱得到新的1(9.058min),2(11.104min)(收率各为0.00005%)。
(6)上述步骤(4)中所得乙腈-水(30:70)流分经HPLC-UV色谱分离,210nm检测,流速为4mL/min,以55:45甲醇-水的混合溶剂为流动相,得到联苄3(tR=33min)(收率为0.00013%)。
联苄类1-3的结构鉴定方法见实施例1。
实施例6
(1)白及300g用90%乙醇加热回流提取3次(用量:3L),减压回收提取液得粗提物;
(2)步骤(1)所得乙醇提取物经有机溶剂萃取,依次用石油醚、二氯甲烷、乙酸乙酯、正丁醇以水相和有机相的体积比1:1进行萃取,分别萃取3次,得到不同极性部位的萃取物;
(3)步骤(2)中石油醚萃取物,经硅胶柱色谱分离,依次以氯仿和甲醇混合溶剂100:1,100:3,100:5,100:7洗脱;
(4)上述步骤(3)中所得的氯仿:甲醇100:3~100:5流分经ODS色谱,用20:80,30:70,50:50,60:40,乙腈-水的混合溶剂梯度洗脱;
(5)上述步骤(4)中所得乙腈-水(50:50)流分经HPLC-UV色谱分离制备,210nm检测,流速为4mL/min,流动相为甲醇:水=65:35,得到联苄1和2的消旋混合物(tR=36min)(收率为0.00011%)。化合物1和2的消旋混合物再经手性柱色谱分离,以正己烷:乙醇(75:25)为流动相洗脱得到新的1(9.058min),2(11.104min)(收率各为0.00005%)。
(6)上述步骤(4)中所得乙腈-水(20:80)流分经HPLC-UV色谱分离,210nm检测,流速为4mL/min,以30:70乙腈-水的混合溶剂为流动相,得到联苄3(tR=36min)(收率为0.00014%)。
联苄类1-3的结构鉴定方法见实施例1。
实施例7实施例1-6中制备得到的新联苄类1-3的抗神经炎症活性测试
(1)实验原理:小胶质细胞活化介导的慢性炎症反应是神经退行性疾病的发生、发展过程中的重要环节,抑制小胶质细胞的激活可能成为药物发现的一个新的靶点。LPS激活小胶质细胞释放NO、促炎症细胞因子和活性氧等。本实验通过建立体外LPS激活BV2小胶质细胞异常活化的筛选模型,以激活小胶质细胞释放NO为指标,评价新联苄类1-3抗炎活性。
(2)实验方法:
①小鼠小胶质细胞系BV2的培养
细胞培养和模型建立中使用的所有玻璃器皿及金属器械(培养瓶,移液管,溶液瓶等),均经过121℃高压灭菌30min,以彻底去除污染的LPS。以DMEM培养基作为基础配制成内含10%胎牛血清及50μM 2-巯基乙醇的细胞培养液。小胶质细胞以约4×105cells/ml的浓度在5%CO2,37℃培养瓶中传代培养,至第三天贴壁细胞约占培养瓶底面积50-60%,以胰酶消化贴壁细胞,传代至另一培养瓶。以-80℃超低温冰箱冻存复苏后的BV2作为第一代,选择第3-8代BV2细胞进行实验。
②药物配制方法
测试化合物均为粉末状,用DMSO溶解。配成母液,浓度为50mM,储存于-20℃。临用时用DMEM培养液将其进行稀释,依次稀释为100μM、30μM、10μM、3μM、1μM。DMSO终浓度<1‰。
③Griess法检测化合物对LPS激活小胶质细胞的抑制作用
取对数生长期的BV2小胶质细胞,用含5%胎牛血清的新鲜DMEM培养基将细胞密度调至3×105cells/ml,接种于96孔板内,100μl/well,于37℃,5%CO2的培养箱内培养。细胞贴壁培养24h后换成无血清的新鲜培养液,同时进行加药处理。每种化合物设剂量1、3、10、30、100μM与LPS共同作用。同时设空白对照。各给药组中LPS终浓度为100ng/ml。细胞加药后继续培养24h后,收集上清液,Griess比色法检测上清液中NO2-含量。
④MTT法检测化合物对小胶质细胞细胞成活率的影响
取对数生长期培养的BV2小胶质细胞,用含5%胎牛血清的新鲜DMEM培养基将细胞密度调至3×105cells/ml,接种于96孔板内,100μl/well,于37℃,5%CO2的培养箱内培养。细胞贴壁培养24h后换成新鲜培养液,同时进行加药处理。每种化合物设剂量1、3、10、30、100μM与LPS共同作用。同时设空白对照。各给药组中LPS终浓度为100ng/ml。细胞加药后继续培养24h,然后向细胞液中加入MTT溶液,10μl/well,将细胞与0.25mg/ml MTT于37℃下共同孵育3h,吸除培养液,然后加入100μl的DMSO溶液,测定其光密度OD值。数据处理,利用酶标仪相应软件进行数据处理,计算每一种样品6个孔OD值的平均值,利用平均值按如下公式计算细胞成活率(cell viability,CV%)。
细胞成活率%=样品组OD值的平均值/空白对照组OD值的平均值×100%
⑤统计方法
全部资料采用SPSS(13.0)统计软件包进行检验分析。结果用平均值±标准误表示,评价整体性差异,组间均数采用One-Way ANOVA分析法进行方差齐性分析,并结合Dunnett’s test分析方法进行组间比较。多样本方差齐性检验采用Levene检验,当p>0.05,方差是齐的,采用Dunnett’s双侧T检验多组间均数的差异,当p<0.05,方差不齐,采用Dunnett T3检验多组间均数的差异。
⑥IC50的计算方法
将各剂量和抑制率等参数用非线性回归拟合计算IC50。
(3)实验结果:见表3
表3联苄类1-3抑制小胶质细胞活化作用实验结果
显著性:*P<0.05,**P<0.01,***P<0.001与LPS诱导组相比;###P<0.001与对照组相比。
结果可知,实施例1-6中制备得到的新联苄类化合物1(100μM)、2(100μM)及3(30μM,100μM)能够显著的抑制LPS诱导的过度活化的BV2小胶质细胞NO的释放。
Claims (2)
1.联苄类化合物及其药学上可接受的盐的制备方法,其特征在于:该方法包括如下步骤:
(1)植物白及(Bletilla striata)用乙醇溶剂提取,回收提取液得粗提物;
(2)步骤(1)所得粗提物经水溶解,有机溶剂萃取,得到不同极性的萃取物;
(3)上述步骤(2)中所得乙酸乙酯萃取物经硅胶柱色谱法分离,以石油醚和乙酸乙酯混合溶剂、石油醚和丙酮混合溶剂、氯仿和丙酮混合溶剂、二氯甲烷和丙酮混合溶剂、氯仿和甲醇混合溶剂、二氯甲烷和甲醇混合溶剂梯度洗脱;
(4)上述步骤(3)中所得100: 1~100: 25流分经ODS柱色谱分离,以甲醇和水混合溶剂,或以乙腈和水混合溶剂为流动相梯度洗脱;
(5)上述步骤(4)中所得甲醇和水、乙腈和水洗脱物经制备型HPLC-UV进一步分离,以甲醇和水混合溶剂,或以乙腈和水混合溶剂为流动相梯度洗脱,得到联苄类化合物1和2的消旋混合物及化合物3;
(6)上述步骤(5)所得到的联苄类化合物的消旋混合物经HPLC手性拆分得到的化合物1和2;
步骤(3)中所述洗脱溶剂石油醚和乙酸乙酯混合溶剂、石油醚和丙酮混合溶剂的体积比例均为100:1~1:1,二氯甲烷和丙酮混合溶剂、氯仿和丙酮混合溶剂、二氯甲烷和甲醇混合溶剂、或氯仿和甲醇的混合溶剂的体积比例为100:1~100:10;
步骤(4)中所述甲醇和水混合溶剂的体积比例为3: 7~9: 1,乙腈和水混合溶剂的体积比例为1:9~7:3;
步骤(5)所述的甲醇和水混合溶剂、乙腈和水混合溶剂,其中甲醇和水混合溶剂的体积比例为:4:6~9:1,乙腈和水混合溶剂的体积比例为3:7~7:3;
步骤(6)所述的手性色谱柱拆分溶剂为正己烷和无水乙醇混合溶剂,其体积比例为70:30~95: 5;
。
2.按照权利要求1所述的制备方法,其特征在于:步骤(1)中所述的提取方法为加热回流乙醇提取或加热超声提取1~3次,乙醇的体积浓度为70%~95%的乙醇,白及:乙醇的重量体积比为1: 5~1: 20 g/mL;步骤(2)中所述的有机溶剂萃取法,按照水相和有机相的体积比1:1,分别使用石油醚、二氯甲烷、乙酸乙酯和正丁醇依次萃取3-5次,减压回收以上有机溶剂。
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