CN108912135A - 一种新型岩白菜素硫辛酸酯及其合成方法及抗氧化用途 - Google Patents
一种新型岩白菜素硫辛酸酯及其合成方法及抗氧化用途 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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Abstract
一种新型岩白菜素硫辛酸酯及其合成方法及抗氧化用途,该化合物以岩白菜素和硫辛酸为原料在催化剂作用下于有机溶剂中反应,反应结束后减压浓缩除去溶剂,加入水与氯仿洗涤,取下层有机相干燥浓缩即得该岩白菜素硫辛酸酯。该反应过程采用氮气保护,反应步骤少,原料利用率高且污染小,适用于工业化生产。经抗氧化实验测试,该化合物具有显著的抗氧化活性。目前该岩白菜素硫辛酸酯及其抗氧化活性尚无相关报道,在食品、保健品、药品领域具有较重要的研究应用价值。
Description
技术领域
本发明涉及食品化学领域,具体涉及一种新型岩白菜素硫辛酸酯及其合成方法及抗氧化用途。
背景技术
岩白菜素是一种二氢异香豆素衍生物,是虎耳草科的主要生物活性成分,1880年,Garrean从虎尔草科植物中提取分离出了岩白菜素,但是直到1958年才完成其结构测定。大量研究已经证实岩白菜素具有多种生物活性,包括抗癌,抗肝毒性,抗氧化,抗心律失常,抗HIV和神经保护特性等。此外,有研究表明岩白菜素对2,4-DNPH和酒精中毒引起的组织损伤具有抗氧化修复作用,与此同时对消除血液和代谢过程中氧化剂的副作用也有一定的作用,Takahashi等人(Takahashi H,Kosaka M,Watanabe Y,et al.Synthesis andneuroprotective activity of bergenin derivatives with antioxidant activity.[J].Bioorganic&Medicinal Chemistry,2003,11(8):1781-1788.)从野梧桐中获得岩白菜素,通过测试发现岩白菜素对DPPH自由基和超氧化物阴离子有较好的清除作用,抗氧化作用显著。通过与多种脂肪酸的结合修饰岩白菜素的糖键,可以增强其抗氧化活性,说明对岩白菜素的结构修饰为获得新型的抗氧化物提供可能。
硫辛酸(1ipoic acid,LA)亦称α-硫辛酸(α-lipoic acid,ALA),是一种天然的二硫化合物,它是在1951年由Reed首次从猪肝中分离出来的,属于一种B族维生素。作为天然的抗氧化剂,硫辛酸是兼具水溶性及脂溶性的两性分子,无论是氧化型还是还原型在水、脂环境中均能发挥很强的抗氧化作用。此外,硫辛酸可以通过抑制肿瘤新生血管生成,增强机体免疫力,增加肿瘤对化疗药物敏感性,逆转肿瘤耐药等作用来发挥抗肿瘤作用,所以硫辛酸具有很高的医用价值以及抗衰老潜能。
本发明中通过岩白菜素11位羟基与硫辛酸羧基脱水缩合形成酯键,从而获得一种新型的岩白菜素油脂衍生物,通过阐述该化合物的合成方法结合初步的抗氧化实验验证该化合物具有优良的抗氧化活性,在抗氧化保健品领域具有较高的医药研究与应用价值。
发明内容
本发明的一个目的是提供一种新型岩白菜素硫辛酸酯,其可作为一种优良的抗氧化、制备清除自由基产品应用于食品、保健品、医药领域。
本发明所述的化合物的结构式如式Ⅰ所示:
本发明的另一个目的是提供上述新型岩白菜素硫辛酸酯的制备方法。
本发明的技术方案是采用以岩白菜素和硫辛酸为原料,在催化剂作用下于有机溶剂中合成,反应过程采用氮气保护,反应结束后减压浓缩除去溶剂,加入水与氯仿洗涤,取下层有机相干燥浓缩即得该岩白菜素硫辛酸酯。
本发明提供的所述化合物的合成路线如下所示:
为了实现上述合成路线,本发明的合成步骤如下:
(1)将适量岩白菜素和硫辛酸用有机溶剂溶解,置于三口烧瓶中,同时通入氮气保护,在磁力搅拌下加入一定量催化剂于反应体系中,加热至50℃~60℃,反应10~12小时。
(2)薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。
(3)将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入水与氯仿洗涤,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品。
上述步骤(1)中的有机溶剂优选乙腈或四氢呋喃,进一步优选为乙腈。
上述步骤(1)中的岩白菜素和硫辛酸的摩尔比优选为1:1~1:1.5,进一步优选为1:1.2。
上述步骤(1)中的催化剂优选DCC、EDC和浓硫酸等,进一步优选为EDC。
上述步骤(1)中的反应温度优选为60℃。
上述步骤(1)中的反应时间优选为12小时。
本发明的优点在于:反应原料价廉易得,反应步骤少,操作安全性高,反应过程采用氮气保护对环境友好,适用于工业化生产,化合物结构新颖且具有较高的研究价值。
附图说明
图1DPPH自由基清除实验结果。
具体实施方式
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是出于解释说明的目的,而不限制本发明的范围和实质。
实施例1
化合物岩白菜素硫辛酸酯的制备
于100mL三口烧瓶中,按投料比(岩白菜素:硫辛酸(1:1.2))将岩白菜素100mg(0.31mmol)、硫辛酸77mg(0.37mmol)溶于40mL乙腈,同时通入氮气保护,在磁力搅拌下缓慢滴入催化量的EDC,升温至60℃,反应12小时,薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入一定量的水与氯仿多次洗涤后,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品88mg,总收率为54.2%。
1H-NMR(300MHz,DMSO-d6)δ(ppm):9.45-9.38(2H,d),6.87(1H,s),5.37(1H,d),5.05(1H,m),4.41-4.32(3H,m),4.12-4.05(3H,m),3.63-3.56(4H,m),2.51(2H,m),2.28-2.24(3H,m),1.67-1.50(6H,m),1.12(2H,m);13C-NMR(75MHz,DMSO-d6)δ(ppm):167.7,160.3,143.1,140.3,139.0,119.6,111.5,103.1,75.5,73.4,70.0,68.4,55.3,53.9,50.3,32.8,28.7,27.0,23.6,22.1;MS(ESI)for(M+H)+:571.6.
实施例2
化合物岩白菜素硫辛酸酯的制备
于100mL三口烧瓶中,按投料比将(岩白菜素:硫辛酸(1:1.2))将岩白菜素150mg(0.45mmol)、硫辛酸111mg(0.54mmol)溶于40mL乙腈,同时通入氮气保护,在磁力搅拌下缓慢滴入催化量的DCC,升温至60℃,反应12小时,薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入一定量的水与氯仿多次洗涤后,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品119mg,总收率为52.3%。
实施例3
化合物岩白菜素硫辛酸酯的制备
于100mL三口烧瓶中,按投料比将(岩白菜素:硫辛酸(1:1.2))将岩白菜素100mg(0.31mmol)、硫辛酸77mg(0.37mmol)溶于40mL乙腈,同时通入氮气保护,在磁力搅拌下缓慢滴入催化量的浓硫酸,升温至60℃,反应12小时,薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入一定量的水与氯仿多次洗涤后,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品77mg,总收率为48.4%。
实施例4
化合物岩白菜素硫辛酸酯的制备
于100mL三口烧瓶中,按投料比将(岩白菜素:硫辛酸(1:1.2))将岩白菜素150mg(0.45mmol)、硫辛酸111mg(0.54mmol)溶于40mL四氢呋喃,同时通入氮气保护,在磁力搅拌下缓慢滴入催化量的EDC,升温至60℃,反应12小时,薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入一定量的水与氯仿多次洗涤后,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品113mg,总收率为48.9%。
实施例5
化合物岩白菜素硫辛酸酯的制备
于100mL三口烧瓶中,按投料比将(岩白菜素:硫辛酸(1:1.2))将岩白菜素100mg(0.31mmol)、硫辛酸77mg(0.37mmol)溶于40mL四氢呋喃,同时通入氮气保护,在磁力搅拌下缓慢滴入催化量的DCC,升温至60℃,反应12小时,薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入一定量的水与氯仿多次洗涤后,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品77mg,总收率为48.2%。
实施例6
化合物岩白菜素硫辛酸酯的制备
于100mL三口烧瓶中,按投料比将(岩白菜素:硫辛酸(1:1.2))将岩白菜素150mg(0.45mmol)、硫辛酸111mg(0.54mmol)溶于40mL四氢呋喃,同时通入氮气保护,在磁力搅拌下缓慢滴入催化量的浓硫酸,升温至60℃,反应12小时,薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入一定量的水与氯仿多次洗涤后,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品108mg,总收率为46.7%。
实施例7
DPPH自由基清除实验
实验原理:
DPPH分子中,由于存在多个吸电子的-NO2和苯环的大π键,所以,氮自由基能稳定存在。其乙醇溶液呈紫色,在517nm处有最大吸收峰。加入抗氧化剂以后,DPPH捕捉一个电子与游离电子配对,紫色褪去,变为黄色物质,在517nm处的吸收消失,其褪色程度与其接受的电子数成定量关系。依此原理用分光光度计检测DPPH自由基与试样液反应后吸光值的变化,可检定试样提供氢原子、清除自由基抗氧化的能力。
实验方法:
(a)DPPH测试液的配制:精确称取一定量的1,1-二苯基-2-苦基肼自由基,用甲醇溶解为2*10-4mol/L的DPPH溶液,避光冷藏放置。
(b)待测液的配制:Vc(阳性对照)、岩白菜素硫辛酸酯(样品)、岩白菜素(对照品)、硫辛酸(对照品)、岩白菜素和硫辛酸的混合液(对照品),用乙腈将样品液进行梯度稀释,同时采用一定量的甲醇将4组对照分别溶解于试管中,制成与样品相同的浓度梯度。得到相应的4组对照溶液(梯度设置见表1)。
表1待测液稀释梯度
编号 | 待测液 | 浓度梯度/ppm |
Vc | Vc | 7.02,140.4,702,2808,7020,17550 |
B | 岩白菜素硫辛酸酯 | 7.02,140.4,702,2808,7020,17550 |
C | 岩白菜素 | 7.02,140.4,702,2808,7020,17550 |
D | 硫辛酸 | 7.02,140.4,702,2808,7020,17550 |
E | 岩白菜素和硫辛酸混合液(1:1) | 7.02,140.4,702,2808,7020,17550 |
(c)操作方法:
样品液吸光度测定:取样品液(表1B)2mL,加入浓度为2*10-4mol/L的DPPH溶液2mL,混匀后在室温下避光反应30min,以甲醇调零,在517nm处测定其吸光度Ai,同时测定2mL甲醇与2mL样品溶液混合后的吸光度Aj以及2mL DPPH溶液与2mL乙腈混合后的吸光度Ao(实验结果见表2)。
对照品吸光度测定:取(b)步骤对照品溶液(表1C、D、E)2mL,加入浓度为2*10-4mol/L的DPPH溶液2mL,混匀后在室温下避光反应30min,以甲醇调零,在517nm处测定其吸光度Ai,同时测定2mL甲醇与2mL对照品溶液混合后的吸光度Aj以及2mL DPPH溶液与2mL甲醇混合后的吸光度Ao(实验结果见表2)。
表2各待测液吸光度测试结果
(d)清除率的计算:清除率(%)=[1-(Ai-Aj)/Ao]*100%
表3 DPPH清除率实验结果
根据图1实验结果可知,化合物岩白菜素硫辛酸酯(B)以浓度依赖性方式表现出对DPPH明显的清除作用。其对DPPH的清除率从27.56%(7.02ppm)到97.64%(7020ppm),与单一的岩白菜素(C)、硫辛酸(D)以及岩白菜素和硫辛酸混合液(1:1)(E)相比B对DPPH的能力明显比较好,同时在浓度达到2808ppm的浓度以上时B的对DPPH的清除作用接近于Vc的清除能力,以上实验结果证明该化合物具有优良的抗氧化活性,具有较好的应用前景。
Claims (8)
1.一种新型岩白菜素硫辛酸酯,其特征在于,结构式如式Ⅰ所示:
2.一种新型岩白菜素硫辛酸酯的其合成方法,其特征在于,以岩白菜素和硫辛酸为原料,在催化剂作用下于有机溶剂中合成,反应过程采用氮气保护,反应结束后减压浓缩除去溶剂,加入水与氯仿洗涤,取下层有机相干燥浓缩即得该岩白菜素硫辛酸酯,合成路线如下所示:
具体的制备过程如下:
(1)将适量岩白菜素和硫辛酸用有机溶剂溶解,置于三口烧瓶中,同时通入氮气保护,在磁力搅拌下加入一定量催化剂于反应体系中,加热至50℃~60℃,反应10~12小时。
(2)薄层层析法跟踪反应至完全,停止加热,撤去保护装置。将反应混合体系转移至分液漏斗,静止待其分层,取下层油脂相得到岩白菜素硫辛酸酯粗品。
(3)将该岩白菜素硫辛酸酯粗品加入到梨形分液漏斗,加入水与氯仿洗涤,取下层有机相加入无水硫酸钠干燥,减压浓缩即得该岩白菜素硫辛酸酯精品。
3.根据权利要求2所述的一种新型岩白菜素硫辛酸酯的其合成方法,其特征在于,所述步骤(1)中的有机溶剂选择乙腈或四氢呋喃,进一步优选为乙腈。
4.根据权利要求2所述的一种新型岩白菜素硫辛酸酯的其合成方法,其特征在于,所述述步骤(1)中的岩白菜素和硫辛酸的摩尔比为1:1~1:1.5,进一步优选为1:1.2。
5.根据权利要求2所述的一种新型岩白菜素硫辛酸酯的其合成方法,其特征在于,所述述步骤(1)中的催化剂选择DCC、EDC和浓硫酸,进一步优选为EDC。
6.根据权利要求2所述的一种新型岩白菜素硫辛酸酯的其合成方法,其特征在于,所述述步骤(1)中的反应温度优选为60℃。
7.根据权利要求2所述的一种新型岩白菜素硫辛酸酯的其合成方法,其特征在于,所述述步骤(1)中的反应时间优选为12小时。
8.根据权利要求1所述的一种新型岩白菜素硫辛酸酯,其特征在于,作为一种优良的抗氧化剂在食品、保健品、医药领域的应用。
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