CN114409512B - 一种抑菌性抗氧化剂的制备方法与应用 - Google Patents
一种抑菌性抗氧化剂的制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种抑菌性抗氧化剂的制备方法与应用,属于精细化学品领域。本发明以α‑水芹烯和间苯三酚为原料,在路易斯酸催化下反应得到8,9‑二氢大麻三酚。本发明原料易得,所用催化剂廉价、使用量少、温和,反应收率高。8,9‑二氢大麻三酚具有良好的抑菌性和抗氧化活性。对大肠杆菌、金黄色葡萄球菌、粪肠球菌和蜡状芽孢杆菌四种细菌的最小抑菌浓度和最小杀菌浓度均低于100μg/mL。其对DPPH和ABTS自由基的清除能力均强于VC,温度对其抗氧化活性几乎没有影响,具有比VC更好的稳定性。
Description
技术领域
本发明涉及一种抑菌性抗氧化剂的制备方法与应用,属于精细化学品制备领域。
背景技术
目前,食品添加剂的种类日益增多,多功能添加剂的需求也日益增长。抑菌剂与抗氧化剂都是用途非常广泛、品种繁多和需求量大的精细化工产品,但同时兼具抑菌性和抗氧化性的产品并不多见。
发明内容
[技术问题]
本发明要解决的技术问题是现有技术缺少兼具抑菌性和抗氧化性的产品。
[技术方案]
本发明提供一种抑菌性抗氧化剂及其制备方法,以解决现有的食品添加剂功能单一的问题。
本发明提供的所述抑菌性抗氧剂是8,9-二氢大麻三酚,其结构如下式Ⅰ所示:
本发明提供所述抑菌性抗氧剂的制备方法,α-水芹烯、间苯三酚为原料,选择有机溶剂,在路易斯酸催化剂的作用下,反应得到目标产物。该制备方法的反应机理为:α-水芹烯质子化后形成碳正离子,进攻间苯三酚的苯环结构,与其完成亲电取代反应。反应机理如下:
所述路易斯酸催化剂为三氯化铝、三氟化硼一水合物、三氟化硼乙醚、三氯化铁六水合物和三氯化铁中的一种。可优选三氯化铁。所述路易斯酸催化剂的用量为间苯三酚的质量的0.25%-0.5%。
所述有机溶剂包括三氯甲烷、甲苯和乙腈中的一种或多种。优选以乙腈和氯仿作混合溶剂。以间苯三酚的质量计,所述有机溶剂的添加量为3.9-15.6L/kg。
进一步的,所述α-水芹烯与间苯三酚的摩尔比为(1.0-1.05):1.0。
进一步的,所述反应的时间为0.5-2.0h,反应温度为25℃。
进一步的,所述反应结束后,将反应液过滤回收催化剂、再水洗除掉反应液中的残余的三氯化铁。
进一步的,所述反应结束后,对产物进行分离纯化:根据TLC监测,确保原料反应完全后,过滤,取滤液,并用饱和食盐水洗涤3-5次,无水硫酸钠干燥后,减压蒸馏除去溶剂得到粗产品,将粗产品进行硅胶柱层析分离,并以石油醚和乙酸乙酯(石油醚:乙酸乙酯=5:1,v/v)混合液洗脱,借助TLC洗脱跟踪检测,收集含有目标产物的洗脱液,合并所述目标产物洗脱液,蒸发浓缩得到目标产物。
本发明制备的8,9-二氢大麻三酚可用作具有抑菌性的抗氧化剂。抑菌种类包括大肠杆菌、金黄色葡萄球菌、粪肠球菌和蜡状芽孢杆菌。所述抗氧化包括具有DPPH和ABTS自由基清除能力、铁离子还原能力、抗脂质过氧化能力和/或黄嘌呤氧化酶抑制能力。
[有益效果]
本发明合成的8,9-二氢大麻三酚具有抑菌和抗氧化性,其抑菌活性远远强于表没食子儿茶素没食子酸酯(EGCG),对大肠杆菌、金黄色葡萄球菌、粪肠球菌和蜡状芽孢杆菌四种细菌的最小抑菌浓度(MIC)和最小杀菌浓度(MBC)均低于100μg/mL。同时,对DPPH和ABTS自由基清除能力强于VC,铁离子还原能力和抗脂质过氧化能力与VC接近,可见8,9-二氢大麻三酚具有极强的抗氧化活性。另外,温度对8,9-二氢大麻三酚的抗氧化活性的影响很小,高温下,8,9-二氢大麻三酚表现出较VC更好的稳定性。
本发明制备8,9-二氢大麻三酚的方法具有:催化剂廉价易得(三氯化铁)、使用量少(间苯三酚质量的0.5%)、温和(路易斯酸),收率高(85%)的优点。
附图说明
图1是本发明实施例1中制备得到8,9-二氢大麻三酚的1HNMR核磁共振氢谱图。
图2是本发明实施例1中制备得到8,9-二氢大麻三酚的13CNMR核磁共振碳谱图。
图3是本发明实施例1中制备得到8,9-二氢大麻三酚的质谱图。
图4A是8,9-二氢大麻三酚最小抑菌浓度(MIC)。
图4B是8,9-二氢大麻三酚最小杀菌浓度(MBC)。
图5A是8,9-二氢大麻三酚对DPPH自由基的清除能力。
图5B是8,9-二氢大麻三酚对ABTS自由基的清除能力。
图6是8,9-二氢大麻三酚的铁离子还原能力和抗脂质过氧化能力。
图7是8,9-二氢大麻三酚对黄嘌呤氧化酶的抑制能力
具体实施方式
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
以下各实施例中,合成的目标化合物的定量分析方法为:使用配备有紫外检测器的HPLC进行分析。注入10μL样品并使用ACE C18-PFP(150mm×4.6mm×3μm)色谱柱实现分离。流动相为乙腈:水=62:38(v/v)。流速设定为1mL·min-1,柱温保持在30℃。在220nm监测目标化合物的吸光度。
实施例1制备及鉴定8,9-二氢大麻三酚
向25L反应瓶中依次加入间苯三酚1.26kg(10mol)、三氯化铁6.3g(0.04mol)、乙腈(5L)和氯仿(5L)。25℃下搅拌5min,加入α-水芹烯1.43kg(10.5mol),25℃下搅拌反应1h。过滤,取滤液,并用饱和食盐水洗涤3-5次,无水硫酸钠干燥后,减压蒸馏除去溶剂,用硅胶柱层析分离粗产品,并以石油醚和乙酸乙酯的混合液梯度洗脱(石油醚:乙酸乙酯=10:1至5:1,体积比),借助TLC(展开剂:石油醚:乙酸乙酯=5:1)跟踪检测。收集合并含有目标产物的硅胶柱洗脱液,浓缩得到8,9-二氢大麻三酚白色固体2.23kg(产品收率为85%,产品收率=实际得到的产物质量÷理论上底物完全转化时能够得到的产物质量×100%)。所得8,9-二氢大麻三酚的核磁共振氢谱图和核磁共振碳谱图分别见图1和图2,质谱图见图3。
8,9-二氢大麻三酚(2'-异丙基-5'-甲基-1',2'-二氢-3',4'-四氢-[1,1'-联苯]-2,4,6-三醇):1H NMR(400MHz,CDCl3)δ6.23(s,2H,3-H and 5-H),5.93(s,2H,2-OH and 6-OH),5.48(s,1H,6'-H),3.74(dd,J=8.1,5.2Hz,1H,1'-H),2.39(s,1H,2'-H),2.17~2.03(m,2H,4'-H),1.74(s,3H,7'-Me),1.62~1.51(m,2H,3'-H),1.42~1.32(m,1H,8'-H),1.28~1.24(m,1H,4-OH,D,O exch),0.83(d,J=6.8Hz,6H,9'-Me and 10'-Me).13C NMR(101MHz,CDCl3)δ155.02(C-4),140.25(C-1and C-6),124.97(C-5'),109.67(C-6'),97.08(C-1),95.65(C-3and C-5),43.90(C-2'),35.21(C-1'),30.65(C-4'),27.76(C-8'),23.62(C-3'),22.09(C-7'),21.70(C-9'),16.36(C-10').HRMS(ESI-TOF)m/z 262.1550[M-H]-(calcd for C16H22O3,262.1569).
实施例2-5,对比例1-2:催化剂对收率的影响
实施例2-5,对比例1-2的合成方法与实施例1类似,区别在于所采用的催化剂不同。各实施例、对比例采用的路易斯酸催化剂及相应的产品收率如表1所示。
表1实施例1-5、对比例1-2采用的催化剂及相应的收率
催化剂 | 收率(%) | |
实施例1 | 三氯化铁 | 85 |
实施例2 | 三氟化硼一水合物 | 55 |
实施例3 | 三氟化硼乙醚 | 55 |
实施例4 | 三氯化铁六水合物 | 49 |
实施例5 | 三氯化铝 | 56 |
对比例1 | 氯化镍 | Trace(<5) |
对比例2 | 氯化锌 | Trace(<5) |
从表1的结果可以看出,本发明的合成方法需要选择合适的路易斯酸催化剂,当选择氯化镍或氯化锌作为催化剂时,8,9-二氢大麻三酚的收率低于5%;选择三氯化铝、三氟化硼一水合物、三氟化硼乙醚和三氯化铁六水合物作为催化剂时,目标化合物的收率均高于45%;其中以三氯化铁作为催化剂时,目标化合物的收率达到了85%,为最佳的催化剂。
实施例6:催化剂三氯化铁的用量对收率的影响
实施例6的合成方法以及对比例3的合成方法与实施例1类似,区别在于催化剂的用量不同。各实施例采用的催化剂用量及相应的收率如表2所示。
表2实施例1,6和对比例3采用的催化剂用量及相应的收率
三氯化铁用量(wt%) | 收率(%) | |
实施例6 | 0.25 | 65 |
实施例1 | 0.5 | 85 |
对比例3 | 1.0 | 85 |
从表2的结果可以看出,随着三氯化铁用量增加,收率也随之升高;当三氯化铁的用量为0.5%时,收率达到最高85%;继续增加三氯化铁的用量,产物收率并不会继续升高。因此可见三氯化铁催化剂用量为0.5%时反应收率就可以高达85%。
实施例7-11:溶剂对收率的影响
实施例7-11的合成方法与实施例1类似,区别在于采用的有机溶剂不同。各实施例采用的有机溶剂及相应的收率如表3所示。
表3实施例1,7-11采用的有机溶剂及相应的收率
溶剂 | 收率(%) | |
实施例1 | 三氯甲烷/乙腈 | 85 |
实施例7 | 三氯甲烷 | 60 |
实施例8 | 甲苯 | 57 |
实施例9 | 乙腈 | 49 |
实施例10 | 甲苯/三氯甲烷 | 60 |
实施例11 | 甲苯/乙腈 | 64 |
从表3的结果可以看出,本发明的合成反应可采用三氯甲烷/乙腈或甲苯/乙腈混合物作为有机溶剂,其中采用三氯甲烷/乙腈作为有机溶剂,目标化合物的收率达到了85%,为最佳有机溶剂。而使用三氯甲烷、甲苯和乙腈等作为溶剂也能使得反应有可观的收率。
实施例12-15:反应物配比对收率的影响
实施例12-15的合成方法与实施例1类似,区别在于α-水芹烯的用量不同。各实施例采用的α-水芹烯的用量及相应的收率如表4所示。
表4实施例1,12-15采用的α-水芹烯的用量及相应的收率
从表4的结果可以看出,当α-水芹烯的用量低于1.05当量时,随着α-水芹烯的用量的增加,目标化合物的收率随之提高;当α-水芹烯的用量高于1.05当量时,目标化合物的收率反而会随着α-水芹烯的用量的增加而降低。其中,α-水芹烯的用量为1.05当量时,反应收率达到了85%,为最佳用量。
实施例16-18:底物浓度对收率的影响
实施例16-18的合成方法与实施例1类似,区别在于甲苯的用量不同。各实施例采用的甲苯的用量及相应的收率如表5所示。
表5实施例1,16-18采用的三氯甲烷/乙腈混合溶剂的用量及相应的收率
从表5的结果可知,有机溶剂甲苯的用量对于目标化合物的收率具有一定的影响。当三氯甲烷/乙腈混合溶剂相对间苯三酚的用量不足7.8L/kg时,增加溶剂的用量对于提高目标化合物的收率具有一定的作用。当三氯甲烷/乙腈混合溶剂相对间苯三酚的用量超过7.8L/kg时,继续增加甲苯的用量,目标化合物的收率会随之下降。由此可见,有机溶剂的用量在7.8L/kg时,产物具有较好收率。
实施例19:反应时间对收率的影响
实施例19的合成方法以及对比例4的合成方法与实施例1类似,区别在于反应时间不同。各实施例的反应时间及相应的收率如表6所示。
表6实施例1,19和对比例4采用的反应时间及相应的收率
反应时间(h) | 收率(%) | |
实施例19 | 0.5 | 67 |
实施例1 | 1.0 | 85 |
对比例4 | 2.0 | 85 |
从表6的结果可知,反应时间对于反应收率具有一定的影响,反应时间在0.5h时,目标化合物的收率为67%。而当反应时间为1-2.0h时,目标化合物的收率可达85%。由此可见,反应时间1-2.0h属于比较理想的反应时间。
应用例1测试实施例1中制备得到的目标化合物对大肠杆菌、金黄色葡萄球菌、粪肠球菌和蜡状芽孢杆菌的最小抑菌浓度(MIC)、最小杀菌浓度(MBC)。
取无菌96孔板,第1至10孔每孔加入LB液体培养基100μL后,在第1孔中加入100μL待测样品(待测样品是将实施例1制备得到的白色固体用DMSO溶解,LB液体培养基稀释),使得每孔中8,9-二氢大麻三酚的浓度是1mg/mL),充分混匀后吸取100μL加入第2孔中,同样方法连续二倍稀释至第10孔,将100μL用LB液体培养基稀释至浓度为106CFU/mL的细菌稀释液加入至第1至10孔,同时设置阴性对照(第11孔只加菌液200μL,不加药物)、空白对照(第12孔只加LB液体培养基200μL)和采用表没食子儿茶素没食子酸酯(EGCG)的阳性对照。设置3个平行对照,于37℃恒温培养箱培养24小时,肉眼观察无细菌生长孔的最低药物浓度,即为受试菌的MIC。将以上96孔板含药菌液接种于相应的培养基平板,37℃继续培养24h。无细菌生长的药物浓度作为MBC。结果如图4所示(因无细菌生长的药物最低浓度孔与出现细菌生长的最高浓度孔浓度跨度过大,在两浓度之间(即62.5-125μg/mL)设置等差浓度进一步实验,以确定MIC的精确范围)。
应用例2测试实施例1中制备得到的目标化合物抗氧化活性。
自由基清除能力:
将100μL用DMSO溶解得到的不同浓度的待测液(0、10、20、40、80μg/mL)和100μL0.06mM的DPPH工作液依次加入96孔酶标板中,30℃反应30min,测定517nm处吸光度。
清除率按式(1)计算:DPPH自由基清除率/%=(1-(A-A1)/A0)×100 (1)
其中:A、A1和A0分别为样品组、无水乙醇对照组和空白对照组测定的吸光度。
80℃下8,9-二氢大麻三酚对DPPH自由基清除率的测定方法:将待测液和DPPH工作液分别于80℃水浴中预热10min后,将2mL不同浓度的待测液和2mL 0.06mmol/L的DPPH工作液依次加入5mL离心管中,80℃下反应30min后,测定517nm处吸光度。按照式(1)计算DPPH自由基清除率。
将ABTS水溶液(7mmol/L)和过硫酸钾水溶液(2.45mmol/L)按体积比1:2混合均匀,避光静置15h。将混合液用甲醇制成734nm下吸光度为(0.70±0.02)的ABTS工作液。将20μL用甲醇溶解得到的不同浓度的待测液(0、10、20、40、80μg/mL)和200μL ABTS工作液依次加入96孔酶标板中,30℃下反应10min,测定734nm处吸光度。清除率由公式计算:
ABTS自由基清除率/%=(1-A/A0)×100 (2)
其中:A和A0分别为样品组和空白对照组测定的吸光度。
结果如图5所示。80℃下8,9-二氢大麻三酚对DPPH自由基清除率如图5A所示。
铁离子还原能力:
向2mL 0.1mg/mL的样品溶液(磷酸盐缓冲液0.2M,pH 6.6)中加入2mL 1%的铁氰化钾溶液,在50℃下放置20min。然后,加入2mL 10%的三氯乙酸溶液,混匀后在4000rpm下离心10min。取2mL上清液,加入2mL去离子水和0.4mL 0.1%三氯化铁溶液,于50℃水浴中放置10min,测定700nm处吸光度,以0.1mg/mL VC溶液为阳性对照。
抗脂质过氧化能力:
在0.15mL 2mg/mL的过氧化氢水溶液中加入0.5mL的橄榄油乙醇溶液(质量比为1:3),加入1mL 0.1mg/mL的样品乙醇溶液和2mL 0.2wt%的硫代巴比妥酸溶液于37℃下反应25min。然后加入2mL 20%三氯乙酸水溶液,转移至90℃水浴中显色30min后冷却至室温,加入1mL三氯甲烷萃取有机相,测定上层溶液在532nm的吸光度,其抑制率计算公式如下:
抑制率/%=(1-(A-A1)/A0)×100 (3)
其中:A、A1和A0分别表示样品组、以去离子水代替过氧化氢溶液组和以乙醇代替样品组的吸光度。
铁离子还原能力、抗脂质过氧化能力的实验结果如图6所示。
黄嘌呤氧化酶抑制能力:
将2mL不同浓度的样品(磷酸盐缓冲液溶液,0.2M,pH7.5)、20μL XOD(10μM)和1mL黄嘌呤底物(6mM)加入到比色皿中,测定295nm处溶液的吸光度,分别读取0s和60s的吸光度。以2mL磷酸盐缓冲液代替样品作空白。计算抑制率如下:
抑制率/%=(1-ΔA/ΔA0)×100 (4)
其中:ΔA和ΔA0分别为样品组和空白对照组;ΔA=A60s-A0s。
黄嘌呤氧化酶抑制能力的实验结果如图7所示。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (2)
1.制备8,9-二氢大麻三酚的方法,其特征在于,以α-水芹烯、间苯三酚为原料,在路易斯酸催化剂的作用下,反应得到8,9-二氢大麻三酚,反应式如下:
,
所述路易斯酸催化剂为三氯化铁,
路易斯酸催化剂的用量为间苯三酚的质量的0.5%,
α-水芹烯、间苯三酚溶于有机溶剂,所述有机溶剂是三氯甲烷和乙腈的混合物,
所述α-水芹烯与间苯三酚的摩尔比为1.05:1.0,
所述反应的时间为1.0-2.0 h,反应温度为25 ℃。
2.根据权利要求1所述的方法,其特征在于,所述反应结束后,将反应液过滤回收催化剂、再水洗除掉反应液中的残余的三氯化铁。
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