CN112094191B - 一种具抗氧化活性的羟基酪醇二氢咖啡酸酯及其合成方法 - Google Patents
一种具抗氧化活性的羟基酪醇二氢咖啡酸酯及其合成方法 Download PDFInfo
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Abstract
本发明涉及一类具有抗氧化活性的羟基酪醇二氢咖啡酸酯及其合成方法。该类化合物以羟基酪醇、二氢咖啡酸为原料，反应过程用N2保护，在催化剂作用下，于离子液体或有机溶剂中反应，合成了一类新型羟基酪醇二氢咖啡酸酯。该合成方法操作安全性高，反应条件温和，适用于工业化生产。经初步生物活性测试表明该化合物有较好的抗氧化活性，可作为安全高效的抗氧剂应用于食品、化妆品、保健品、药品领域。
Description
技术领域
本发明涉及一种具有抗氧化活性的羟基酪醇二氢咖啡酸酯及其合成方法，属于医药化学领域。
背景技术
油脂在人们日常生活中占有十分重要的地位，可以给人体提供能量，在人体内具有重要的生理功能。油脂氧化是指食品中的油脂在光、射线、空气和酶的作用下，食品表面和内部所发生的氧化反应。油脂氧化是油脂及含油食品败坏的主要原因之一，油脂氧化的产物不仅影响油脂食品的风味、色泽，降低食品品质，而且产生许多有毒物质影响食用者健康。油脂的过氧化会对膜、酶、蛋白质造成破坏，导致老年化的很多疾病，甚至还可以致癌，严重危害人体健康。为了延长油脂的货架寿命，在油脂中添加抗氧化剂是最为有效的手段之一。然而常用的几种人工合成抗氧化剂存在一定的安全隐患，因而对抗氧化剂的研究开始逐渐转向对天然抗氧化剂的应用研究。
羟基酪醇是一种天然多酚类化合物，具有多种生物和药理活性，可以在橄榄油中提取。羟基酪醇在防癌抗癌、抗炎症、心脑血管疾病的预防及治疗、防治冠心病、保护视网膜色素上皮细胞等方面均有作用。羟基酪醇分子结构不仅同其它酚类物质一样具有酚羟基，而且在连有苯环的乙醇链上还有醇羟基，因而羟基酪醇具有优良的抗氧化活性，可以通过控制很多不饱和脂肪酸的氧化，有效的去除外源性和内源性氧化物和自由基，其作为食品添加剂会促进人体健康且增加食品抗氧化能力。同时，羟基酪醇亲水性强，为了增强其脂溶性以提高生理活性，国际上开始对羟基酪醇的三羟基分子结构进行修饰得到亲脂性衍生物，其在治疗和预防心脑血管疾病与肿瘤方面药效明显，此方法成为新药研制的有效途径之一。
二氢咖啡酸别称3,4-二羟基苯基丙酸，来源广泛，可从杜仲，丹参，大蓟，白术和连钱草等提取分离，是一种具有邻苯二酚结构的酚酸，具有较强的抗氧化活性。
发明内容
本发明的目的是提供一种能应用于食品、化妆品、保健品、药品领域的新型抗氧化剂羟基酪醇二氢咖啡酸酯化合物及其制备方法。
本发明实现过程如下：
结构式（I）所示的化合物，
结构式（I）所示化合物的制备方法：以羟基酪醇和二氢咖啡酸为原料，在催化剂作用下，在离子液体或有机溶剂中进行反应，得到结构式（I）所示化合物。
具体地说，本发明提供的合成路线之一如下所示：
（1）将羟基酪醇和催化量的催化剂EDC溶于有机溶剂，并通入N2保护，加入反应量的二氢咖啡，在50~85℃温度下反应1~4小时，减压浓缩除去有机溶剂，所得浓缩液经水洗，乙酸乙酯萃取，干燥，浓缩，得到羟基酪醇二氢咖啡酸酯粗品；
（2）将羟基酪醇二氢咖啡酸酯粗品用硅胶柱进行吸附分离纯化，采用石油醚/乙酸乙酯混合溶剂作为洗脱剂洗脱富集，将洗脱液减压浓缩干燥后即得羟基酪醇二氢咖啡酸酯纯品。
上述步骤（1）中的有机溶剂选自甲苯、乙酸乙酯或乙腈，优选为乙腈。
上述步骤（1）中的羟基酪醇和二氢咖啡酸的摩尔比为1:1~1:1.3，优选为1:1.1。
上述步骤（1）中的反应温度优选为75℃。
上述步骤（1）中的反应时间优选为4小时。
上述步骤（2）中的洗脱剂优选为石油醚：乙酸乙酯=3:10（体积比）。
本发明提供的合成路线之二如下所示：
（1）将羟基酪醇和催化量的催化剂硅钼酸（CAS：11089-20-6）溶于离子液体1-丁基-3-甲基咪唑四氟硼酸盐（CAS：174501-65-6）中，通入N2保护，加入二氢咖啡酸于反应体系中，在20~50℃温度下反应5~10小时，将离子液体层与酯层分离，所得酯层为羟基酪醇二氢咖啡酸酯粗品；
（2）将羟基酪醇二氢咖啡酸酯粗品用甲醇重结晶干燥后即得羟基酪醇二氢咖啡酸酯纯品。
上述步骤（1）中，羟基酪醇和二氢咖啡酸的摩尔比为1:1~1:1.3，优选为1:1.1。
上述步骤（1）中的反应温度优选为25℃。
上述步骤（1）中的反应时间优选为8小时。
本发明利用羟基酪醇对二氢咖啡酸进行结构改造，获得结构式（I）所示的羟基酪醇二氢咖啡酸酯，初步的抗氧化实验验证了该化合物优良的抗氧化活性，其可作为一种新型抗氧化添加剂应用于食品、化妆品、保健品、药品领域。
说明书附图
图1为DPPH自由基清除实验结果。
具体实施方式
下面结合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
将100.2mg (0.65mmol) 羟基酪醇与124 mg (0.65mmol) EDC 置于100mL反应器中，加入50mL乙腈充分溶解后，通入氮气保护。将129.3mg (0.71mmol) 二氢咖啡酸溶解于15mL乙腈中，用分液漏斗缓慢地滴加到反应液中，滴加完毕后加热至75℃，反应4h。薄层色谱法跟踪反应至完全，停止加热，撤去保护装置。将反应混合体系减压浓缩，所得浓缩液经水洗涤，乙酸乙酯萃取，干燥，浓缩，得到羟基酪醇二氢咖啡酸酯粗品。利用硅胶柱层析对粗品进一步吸附纯化，石油醚：乙酸乙酯=3:10 作为洗脱剂，将洗脱液减压浓缩干燥即得羟基酪醇二氢咖啡酸酯精品150.2mg，总收率为72.65%。
1H-NMR (400MHz, DMSO-
d 6) δ (ppm): 8.64 (4H, d), 6.62 (4H, m), 6.45(2H, m), 3.52 (2H, t), 2.65 (2H, t), 2.52 (2H, d), 2.44 (2H, t); 13C-NMR(400MHz, DMSO-
d 6) δ (ppm): 174.4, 145.3, 143.8, 132.1, 130.6, 119.9, 119.2,116.7, 116.0, 115.8, 115.1, 63.1, 36.1, 30.2。
实施例2
将100.2mg (0.65mmol) 羟基酪醇与124 mg (0.65mmol) EDC 置于100mL反应器中，加入50mL甲苯充分溶解后，通入氮气保护。将129.3mg (0.71mmol) 二氢咖啡酸溶解于15mL甲苯中，用分液漏斗缓慢地滴加到反应液中，滴加完毕后加热至60℃，反应3h。薄层色谱法跟踪反应至完全，停止加热，撤去保护装置。将反应混合体系减压浓缩，所得浓缩液经水洗涤，乙酸乙酯萃取，干燥，浓缩，得到羟基酪醇二氢咖啡酸酯粗品。利用硅胶柱层析对粗品进一步吸附纯化，乙酸乙酯：石油醚=3:10作为洗脱剂，将洗脱液减压浓缩干燥即得羟基酪醇二氢咖啡酸酯精品115.2mg，总收率为55.72%。
实施例3
将100.2mg (0.65mmol) 羟基酪醇与 124 mg (0.65mmol) EDC 置于100mL反应器中，加入50mL四氢呋喃充分溶解后，通入氮气保护。将153.0mg (0.84mmol) 二氢咖啡酸溶解于15mL四氢呋喃中，用分液漏斗缓慢地滴加到反应液中，滴加完毕后在50℃下反应4h。薄层色谱法跟踪反应至完全，撤去保护装置。薄层色谱法跟踪反应至完全，停止加热，撤去保护装置。将反应混合体系减压浓缩，所得浓缩液经水洗涤，乙酸乙酯萃取，干燥，浓缩，得到羟基酪醇二氢咖啡酸酯粗品。利用硅胶柱层析对粗品进一步吸附纯化，乙酸乙酯：石油醚=3:10作为洗脱剂，将洗脱液减压浓缩干燥即得羟基酪醇二氢咖啡酸酯精品120.6mg，总收率为58.32%。
实施例4
将100.2mg (0.65mmol)羟基酪醇与124 mg (0.65mmol) EDC 置于100mL反应器中，加入50mL甲苯充分溶解后，通入氮气保护。将129.3mg (0.71mmol) 二氢咖啡酸溶解于15mL甲苯中，用分液漏斗缓慢地滴加到反应液中，滴加完毕后在65℃下反应2h。薄层色谱法跟踪反应至完全，停止加热，撤去保护装置。将反应混合体系减压浓缩，所得浓缩液经水洗涤，乙酸乙酯萃取，干燥，浓缩，得到羟基酪醇二氢咖啡酸酯粗品。利用硅胶柱层析对粗品进一步吸附纯化，乙酸乙酯：石油醚=3:10作为洗脱剂，将洗脱液减压浓缩干燥即得羟基酪醇二氢咖啡酸酯精品127.9mg，总收率为61.87%。
实施例5
将100.2mg (0.65mmol)羟基酪醇与124 mg (0.65mmol) EDC置于100mL反应器中，加入50mL四氢呋喃充分溶解后，通入氮气保护。将129.3mg (0.71mmol) 二氢咖啡酸溶解于15mL四氢呋喃中，用分液漏斗缓慢地滴加到反应液中，滴加完毕后在55℃下反应4h。薄层色谱法跟踪反应至完全，停止加热，撤去保护装置。将反应混合体系减压浓缩，所得浓缩液经水洗涤，乙酸乙酯萃取，干燥，浓缩，得到羟基酪醇二氢咖啡酸酯粗品。利用硅胶柱层析对粗品进一步吸附纯化，乙酸乙酯：石油醚=3:10作为洗脱剂，将洗脱液减压浓缩干燥即得羟基酪醇二氢咖啡酸酯粗品精品93.4mg，总收率为45.18%。
实施例6
将100.2mg (0.65mmol)羟基酪醇、129.3mg (0.71mmol) 二氢咖啡酸与12.0mg(0.007mmol) 硅钼酸置于100mL反应器中，加入50mL离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后，通入氮气保护，在25℃下反应8h。薄层色谱法跟踪反应至完全，撤去保护装置。将反应混合体系静止分层，至于分液漏斗中，将离子液体层与酯层分离，所得酯层为羟基酪醇二氢咖啡酸酯粗品。用50mL甲醇进行重结晶干燥即得羟基酪醇二氢咖啡酸酯精品170.2mg，总收率为82.34%。
实施例7
将100.2mg (0.65mmol)羟基酪醇、129.3mg (0.71mmol) 二氢咖啡酸与12.0mg(0.007mmol) 硅钼酸置于100mL反应器中，加入50mL离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后，通入氮气保护，滴加完毕后在50℃下反应4h。薄层色谱法跟踪反应至完全，撤去保护装置。将反应混合体系静止分层，至于分液漏斗中，将离子液体层与酯层分离，所得酯层为羟基酪醇二氢咖啡酸酯粗品。用50mL甲醇进行重结晶干燥后即得羟基酪醇二氢咖啡酸酯精品156.2mg，总收率为75.54%。
实施例8 DPPH自由基清除实验
实验原理：DPPH是一种很稳定的氮中心的自由基，其N上有一个游离电子，在517nm处有一强吸收，其甲苯溶液呈紫色。作为一种稳定的自由基，DPPH可以清除其他的自由基。加入抗氧化剂以后，DPPH捕捉一个电子与游离电子配对，使其在517nm处的吸收消失，溶液变为无色或浅黄色。其褪色程度与其接受的电子数量成定量关系，因而可用分光光度计进行快速的定量分析。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，可测定试样提供氢原子、清除自由基的能力。实验表明，该法简便可行，灵敏可靠。
实验方法：
（a）DPPH测试液的配制：称取1,1-二苯基-2-苦基肼自由基，用甲苯溶解为2×10-4 mol/L的DPPH溶液，避光冷藏放置。
（b）待测液的配制：Vc（阳性对照品）、羟基酪醇二氢咖啡酸酯（样品）、羟基酪醇（对照品）和二氢咖啡酸（对照品）。用甲苯将样品液进行梯度稀释，同时采用一定量的甲苯将3组对照品分别溶解于试管中，制成与样品相同的浓度梯度。得到相应的3组对照溶液（梯度设置见表1）。
（c）操作方法：样品液吸光度测定：取样品液 (表1A) 2mL，加入浓度为2×10-4 mol/L的DPPH溶液2mL，混匀后在室温下避光反应30min，以甲苯调零，在517nm处测定其吸光度Ai，同时测定2mL甲苯与2mL样品溶液混合后的吸光度Aj以及2mLDPPH溶液与2mL甲苯混合后的吸光度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1 Vc、B、C）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，以甲苯调零，在517nm处测定其吸光度Ai，同时测定2mL甲苯与2mL对照品溶液混合后的吸光度Aj以及2mL DPPH溶液与2mL甲苯混合后的吸光度Ao(实验结果见表2)。
（d）清除率的计算：清除率(%)=[1-(Ai-Aj)/Ao]×100%
根据图1与表1~3实验结果可知，羟基酪醇二氢咖啡酸酯（A）的抗氧化活性呈现浓度依赖关系，随着浓度的升高，该化合物A清除DPPH自由基的能力增强。在测定浓度范围内，其对DPPH自由基的清除率最高可达到91.22%，同时，与阳性对照Vc组相比，羟基酪醇二氢咖啡酸酯（A）的清除能力虽然较弱，但仍具有明显的清除能力。与单独加入羟基酪醇（B）对照组和二氢咖啡酸（C）对照组相比，同等浓度下羟基酪醇二氢咖啡酸酯（A）清除DPPH自由基的能力大部分都更优，且在较高浓度下抗氧化活性远高于同等浓度的加入羟基酪醇（B）对照组和二氢咖啡酸（C）的对照组。
以上实验结果证明该化合物具有优良的抗氧化活性，可以作为一种新型的抗氧化添加剂应用于食品、化妆品、保健品、药品领域。
Claims (2)
1.一种羟基酪醇二氢咖啡酸酯化合物的制备方法，其特征在于包括以下步骤：
（1）将羟基酪醇和催化量的催化剂硅钼酸溶于离子液体1-丁基-3-甲基咪唑四氟硼酸盐中，通入N2保护，加入二氢咖啡酸于反应体系中，在20~50℃温度下反应5~10小时，将离子液体层与酯层分离，所得酯层为羟基酪醇二氢咖啡酸酯粗品；
（2）将羟基酪醇二氢咖啡酸酯粗品用甲醇重结晶干燥后即得羟基酪醇二氢咖啡酸酯纯品。
2.根据权利要求1所述化合物的制备方法，其特征在于：上述步骤（1）中，羟基酪醇和二氢咖啡酸的摩尔比为1:1~1:1.3。
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Effective date of registration: 20230801 Address after: Room B601, Gazing Valley, No.1, Zone C, Entrepreneurship Research and Development Park, No. 69 Jinye Road, High tech Zone, Xi'an City, Shaanxi Province, 710065 Patentee after: XI'AN TAIKOMED MEDICAL TECHNOLOGY Co.,Ltd. Address before: 710021 Shaanxi city of Xi'an province Weiyang University Park Patentee before: SHAANXI University OF SCIENCE & TECHNOLOGY |
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Denomination of invention: A hydroxytyrosol dihydrocaffeic acid ester with antioxidant activity and its synthesis method Granted publication date: 20230407 Pledgee: Xi'an Caijin Financing Guarantee Co.,Ltd. Pledgor: XI'AN TAIKOMED MEDICAL TECHNOLOGY Co.,Ltd. Registration number: Y2024980003898 |
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