CN113831314A - 一种2-(r)-橙皮素的制备方法 - Google Patents
一种2-(r)-橙皮素的制备方法 Download PDFInfo
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- CN113831314A CN113831314A CN202111363639.2A CN202111363639A CN113831314A CN 113831314 A CN113831314 A CN 113831314A CN 202111363639 A CN202111363639 A CN 202111363639A CN 113831314 A CN113831314 A CN 113831314A
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- Prior art keywords
- hesperetin
- hydrolysate
- methanol
- monomer
- acid
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
本发明提供了一种利用陈皮、青皮、橘红、化橘红、枳实、枳壳、香薷等中药材制备2‑(R)‑橙皮素的制备方法。将上述中药材水煎煮提取,大孔吸附树脂吸附,乙醇洗脱后得到总黄酮,酸水解总黄酮,水解物经硅胶柱层析、ODS柱层析分离纯化得到纯度大于98%的2‑(R)‑橙皮素单体。
Description
技术领域
本发明属于中药化学成分研究领域,具体涉及2-(R)-橙皮素的制备方法。
背景技术
橙皮素(hesperetin)是一种天然黄酮类化合物,主要存在于芸香科柑橘属植物的果实中,具有抗氧化、抗炎、抗肿瘤、抗癌、降血脂、抗病毒等多种生理功能。自然界中的橙皮素大部分以糖苷的形式存在,是陈皮、青皮、橘红、化橘红、枳实、枳壳、香薷等药材中大量存在的橙皮苷、新橙皮苷等二氢黄酮类化合物的母核,而游离的橙皮素在天然产物中含量较低。茜草科植物栗猪殃殃的地上部分,芸香科植物佛手、蕉柑、柑桔、柠檬、藜檬枸橼的果实,十字花科植物荠菜带根全草中都发现有橙皮素存在。有文献报道,以柑桔皮为原料经超声提取橙皮苷后以无水甲醇为溶剂在浓硫酸存在条件下回流7.5h可获得淡黄色的橙皮素。也有关于橙皮素化学全合成方面的文献报道。橙皮素和橙皮苷具有广泛的生理活性,橙皮素具有抗氧化、抗炎、抗***性反应、降血脂、保护心血管和抗肿瘤的药效作用。而橙皮苷的药效作用大多是通过生物机体内肠道微生态***中的代谢将其水解为橙皮素,橙皮素再被肠道吸收入血,通过血液循环***运输到各个组织器官发挥其作用(胡昆等,云南大学学报(自然科学版)2009 31(S1):427~429)。橙皮素的2号碳原子是一个手性碳,其立体结构存在R S异构现象。也就是说陈皮素存在2-(R)-橙皮素和2-(S)-橙皮素两种旋光异构体。但是至今为止无论是从天然产物中提取、半合成还是合成,均没有明确获得的橙皮素的立体构型,也就是说没有明确是2-(R)-橙皮素还是2-(S)-橙皮素。
众所周知,一个化合物的生物活性或毒性与它的立体结构有很大的相关性。因此先明确橙皮素的立体结构,然后去开发相应的制备方法是一项具有创新性的研究工作,具有重要的理论及应用意义。
发明内容
本发明提供了一种2-(R)-橙皮素的制备方法。本发明所述2-(R)-橙皮素的结构式如式(I)所示。
本发明是通过如下技术方案实现的,具体内容包括2-(R)-橙皮素的结构鉴定以及相应制备方法的研究:
为实现上述目的,本发明采用了以下技术方案:
(1)2-(R)-橙皮素的结构鉴定
首先以枳实提取物为原料,对其进行酸水解,将获得的酸水解物进行硅胶柱层析分离纯化,利用NMR以及圆二色光谱(CD)对分得的单体化合物E进行了结构鉴定,包括其立体结构。具体如下:
化合物E为浅黄色粉末,易溶于乙酸乙酯、甲醇。
化合物E的1H-NMR(600MHz,DMSO-d6)谱中出现了二氢黄酮的特征信号峰:δH 5.416(m,1H)的与氧相连的次甲基氢信号(H-2)和δH 2.689(dd,1H)和δH 3.169(dd,1H)的两个亚甲基(H-3a,3b)氢信号。
13C NMR谱(150MHz,DMSO-d6)中共给出16个碳原子信号,结合DEPT谱、可知,其中有1个甲基δC 55.65,1个亚甲基δC 42.04,6个次甲基(分别是δC 117.64,114.04,111.96,95.77,94.96,78.20),8个季碳(分别是δC 196.19,166.62,163.45,162.78,147.86,146.44,131.13,101.78)。其中δC 78.20次甲基C信号(C-2),δC 42.05亚甲基C信号(C-3)为二氢黄酮的特征信号峰,δC 196.19为羰基碳信号。δC 55.65为甲氧基碳信号。
结合1H-NMR,13C-NMR以及DEPT数据,通过与文献(张杰等,中国中药杂志,2012,37(2):238-242)数据对照,确定化合物E为橙皮素。所得化合物的1H-NMR,13C-NMR数据如下。
The 13C NMR and 1H NMR Data of Compound E(δ,ppm,DMSO-d6)
为了确定化合物E的立体构型,测定了其圆二色光谱,将测定结果与文献(Salvatore Caccamese*,Journal of Chromatography A,1076(2005)155–162)对照,确定其立体构型为R构型,即所得化合物为2-(R)橙皮素。
(2)2-(R)-橙皮素的制备方法。
中药材陈皮、青皮、橘红、化橘红、枳实、枳壳、香薷中含有较大量的橙皮苷和新橙皮苷。水解掉7位上的糖部分就可以获得其苷元橙皮素。水解方法可以是酸水解、碱水解或酶水解。本发明是通过酸水解获得了)2-(R)-橙皮素。酸水解是已知的技术,但是获得的橙皮素是R构型的)2-(R)-橙皮素,这是本发明的创新性和新颖性所在。
本发明的制备方法具体包括橙皮苷、新橙皮苷等化学成分的提取,大孔吸附树脂吸附橙皮苷、新橙皮苷等黄酮类成分获得总黄酮,酸水解总黄酮,水解物柱层析分离纯化等步骤。提取采用水煎煮提取,柱层析包括硅胶柱层析和/或ODS柱层析等。
以橙皮苷或新橙皮苷单体为原料或者以含有橙皮苷和/或新橙皮苷单体的植物提取物为原料进行酸水解获得水解物,水解物经硅胶柱层析分离纯化,得到高纯度的2-(R)-橙皮素单体或利用反相色谱进行进一步分离纯化,获得纯度更高的2-(R)-橙皮素。
所述含有橙皮苷和/或新橙皮苷单体的植物提取物为中药陈皮或青皮或橘红或化橘红或枳实或枳壳或香薷的提取物或其基源植物的提取物。
所述含有橙皮苷和/或新橙皮苷单体的植物提取物的制备方法为将相应药材水煎煮提取、提取液过大孔吸附树脂柱吸附,有机溶剂洗脱,洗脱液减压回收溶剂,即得。
酸水解物的制备方法为将橙皮苷和/或新橙皮苷单体的植物提取物进行加热酸水解,水解液加碱中和至中性,过大孔吸附树脂柱吸附,有机溶剂解吸,回收溶剂,得水解物。
所述酸为盐酸或硫酸或硝酸或醋酸。
所述的大孔吸附树脂选自AB-8、D101、D4020、DM301中的一种。
所述的有机溶剂为乙醇或甲醇或丙酮或它们的混合溶剂。
所述盐酸的浓度为2mol/L。
硅胶柱层析用洗脱剂为二氯甲烷、三氯甲烷、乙酸乙酯、甲醇、水的任意两种或两种以上混合溶液。
反相色谱流动相为甲醇:水,固定相为ODS。
流动相甲醇:水体积比为43:57。
附图说明
图1为2-(R)-橙皮素的1H-NMR谱图
图2为2-(R)-橙皮素的13C-NMR谱图
图3为2-(R)-橙皮素的DEPT谱图
图4为2-(R)-橙皮素的CD谱图
具体实施方式
以下对本发明的优选实施例进行说明。应当理解,此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
实施例1
取枳实1Kg粉碎,水煎煮提取三次,每次水用量均为药材重量的25倍(W/V),时间分别为2h、1.5h、1h,合并三次提取液,过DM-301大孔吸附树脂吸附,用8倍柱体积的90%的乙醇溶液洗脱,洗脱液用氯仿-甲醇-水(12.5:5.5:0.8)为展开剂进行薄层层析检验,结果显示洗脱液中主要含有橙皮苷、新橙皮苷、芸香柚皮苷、柚皮苷,获得的总黄酮质量为496g。
取30g总黄酮,加入1.2升2mol/L HCl水溶液,搅拌,溶解,水浴加热,80℃回流反应4h。冷却后水解液加6mol/L氢氧化钠中和至pH=8-9。
将上述水解液过DM-301大孔吸附树脂吸附,用6倍柱体积的90%的乙醇溶液洗脱,洗脱液用氯仿-甲醇-水(21:7:1)为展开剂进行薄层层析检验,结果显示此时洗脱液中主要成分是橙皮素、柚皮素、橙皮素单糖苷、普鲁宁。得到的水解物总质量为15.6g。
取上述水解物,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以石油醚:乙酸乙酯=10:3.5、10:3.7、10:6、(v/v)为洗脱剂进行梯度洗脱。氯仿-乙酸乙酯-甲醇(13:2:1.2)为展开剂进行薄层层析检验,合并含有橙皮素的组分(简称组分A)。组分A中除了橙皮素外还含有少量柚皮素。
取组分A用甲醇:水体积比为43:57为流动相利用制备型高效液相色谱进行纯化,得到橙皮素单体化合物E。
得到的橙皮素单体HPLC-UV检测其纯度为98.3%。
实施例2
取青皮1Kg粉碎,用纯水加热回流提取三次,每次纯水用量均为药材重量的20倍(W/V),时间分别为2h、1.5h、1h,合并三次提取液,过AB-8大孔吸附树脂吸附,用7倍柱体积的90%的乙醇溶液洗脱,洗脱液用三氯甲烷-甲醇-水(12.5:5.5:0.8)为展开剂进行薄层层析检验,结果显示洗脱液中主要含有橙皮苷、新橙皮苷、芸香柚皮苷、柚皮苷,获得的总黄酮质量为465g。
取30g总黄酮,加入1.2升2mol/L H2SO4水溶液,搅拌,溶解,水浴加热,80℃回流反应4h。冷却后水解液加6mol/L氢氧化钠溶液中和至pH=8-9。
将上述水解液过AB-8大孔吸附树脂吸附,用6倍柱体积的90%的甲醇溶液洗脱,洗脱液用氯仿-甲醇-水(21:7:1)为展开剂进行薄层层析检验,结果显示此时洗脱液中主要成分是橙皮素单糖苷、普鲁宁、橙皮素和柚皮素。得到的水解物总质量为16.2g。
取上述水解物,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以二氯甲烷:乙酸乙酯:甲醇=12:2:1、6:3:1(v/v)为洗脱剂进行梯度洗脱。洗脱液用氯仿-乙酸乙酯-甲醇(13:2:1.2)为展开剂进行薄层层析检验,合并含有橙皮素的组分(简称组分B)。组分B中除了橙皮素外还含有少量柚皮素。组分B的质量为2.2735g。
取上述组分B,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以二氯甲烷:甲醇=18:2.7、18:7(v/v)为洗脱剂进行梯度洗脱。洗脱液用氯仿-乙酸乙酯-甲醇(18:2:1)为展开剂进行薄层层析检验,得到橙皮素单体化合物。
得到的橙皮素单体化合物的CD谱证明是2-(R)-橙皮素,HPLC-UV检测其纯度为97.6%。
实施例3
取陈皮1Kg粉碎,用水煎煮提取三次,每次纯水用量均为药材重量的25倍(W/V),时间分别为2h、1.5h、1h,合并三次提取液,过D4020大孔吸附树脂吸附,用10倍柱体积的90%的乙醇溶液洗脱,洗脱液用三氯甲烷-甲醇-水(12.5:5.5:0.8)为展开剂进行薄层层析检验,结果显示洗脱液中主要含有橙皮苷、新橙皮苷、芸香柚皮苷、柚皮苷,获得的总黄酮质量为502g。
取30g总黄酮,加入1.2升2mol/L HNO3水溶液,搅拌,溶解,水浴加热,80℃回流反应4h。冷却后水解液加6mol/L氢氧化钠溶液中和至pH=8-9。
将上述水解液过D4020大孔吸附树脂吸附,用6倍柱体积的90%的乙醇溶液洗脱,洗脱液用氯仿-甲醇-水(21:7:1)为展开剂进行薄层层析检验,结果显示此时洗脱液中主要成分是橙皮素单糖苷、普鲁宁、橙皮素和柚皮素。得到的水解物总质量为14.8g。
取上述水解物,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以二氯甲烷:乙酸乙酯:甲醇=12:2:1、6:3:1(v/v)为洗脱剂进行梯度洗脱。洗脱液用氯仿-乙酸乙酯-甲醇(13:2:1.2)为展开剂进行薄层层析检验,合并含有橙皮素的组分(简称组分C)。组分C中除了橙皮素外还含有少量柚皮素。组分C的质量为2.5g。
取上述组分C,按照1:3的质量比拌入硅胶,干法上样,按照1:100的质量比进行ODS柱层析分离,以甲醇:水=3:5(v/v)为洗脱剂洗脱。洗脱液用甲醇:水=3:1为展开剂进行薄层层析检验,合并含有橙皮素的组分,得到橙皮素单体化合物452mg。
纯化得到的橙皮素单体HPLC-UV检测其纯度为98.8%。
实施例4
取橙皮苷单体5g,加入200mL2mol/L HCL水溶液,溶解,水浴加热,80℃回流反应4h。冷却后水解液加6mol/L氢氧化钠溶液中和至pH=8-9。
将上述水解液过DM-301大孔吸附树脂吸附,依次用40%、60%乙醇溶液洗脱,分段收集,以氯仿-乙酸乙酯-甲醇(13:2:1.2)为展开剂进行薄层层析检验,合并含有橙皮素的组分。
取上述含有橙皮素的组分,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以二氯甲烷:乙酸乙酯:甲醇=12:2:1、6:3:1(v/v)为洗脱剂进行梯度洗脱。用氯仿-乙酸乙酯-甲醇(13:2:1.2)为展开剂进行薄层层析检验,合并含有橙皮素的组分(简称组分D)。
取上述组分D,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以三氯甲烷:甲醇=18:2.7、18:7(v/v)为洗脱剂进行梯度洗脱。用氯仿-乙酸乙酯-甲醇(18:2:1)为展开剂进行薄层层析检验,得到橙皮素单体化合物。
纯化得到的橙皮素为R型单体,HPLC-UV检测其纯度为98.3%。
实施例5
称取新橙皮苷单体化合物5g,加入200mL2mol/L H2SO4水溶液,搅拌,溶解,水浴加热,80℃回流反应4h。冷却后水解液加6mol/L氢氧化钠溶液中和至pH=8-9。
将上述水解液过D4020大孔吸附树脂吸附,用6倍柱体积的90%的乙醇溶液洗脱,用氯仿-甲醇-水(21:7:1)为展开剂进行薄层层析检验,结果显示此时洗脱液中主要成分是橙皮素单糖苷、橙皮素和少量的新橙皮苷。得到的水解物总质量为2.085g。
取上述水解物,按照1:3的质量比拌入硅胶,干法上样,按照1:50的质量比进行硅胶柱层析分离,依次以三氯甲烷:甲醇=16:1.8、16:4.5(v/v)为洗脱剂进行梯度洗脱。用氯仿-乙酸乙酯-甲醇(18:2:1)为展开剂进行薄层层析检验,得到含有橙皮素单体化合物的组分(简称组分E)。
取上述组分E,进行硅胶柱层析分离,得到的含有橙皮苷的组分再按照1:3的质量比拌入ODS,按照1:100的质量比进行ODS柱层析分离,以丙酮:水=3:5(v/v)为洗脱剂洗脱。用甲醇:水=3:1为展开剂进行薄层层析检验,合并含有橙皮素的组分,得到橙皮素单体化合物。
纯化得到的橙皮素为R型单体,HPLC-UV检测其纯度为98.7%。
Claims (10)
1.一种2-(R)-橙皮素的制备方法,其特征在于:以橙皮苷或新橙皮苷单体为原料或者以含有橙皮苷和/或新橙皮苷单体的植物提取物为原料进行酸水解获得水解物,水解物经硅胶柱层析分离纯化,得到高纯度的2-(R)-橙皮素单体或利用反相色谱进行进一步分离纯化,获得更高纯度的2-(R)-橙皮素。
2.权利要求1所述的制备方法,其特征在于:所述含有橙皮苷和/或新橙皮苷单体的植物提取物为中药陈皮或青皮或橘红或化橘红或枳实或枳壳或香薷的提取物或其基源植物的提取物。
3.权利要求1所述的制备方法,其特征在于:所述含有橙皮苷和/或新橙皮苷单体的植物提取物的制备方法为将相应药材水煎煮提取、提取液过大孔吸附树脂柱吸附,有机溶剂洗脱,洗脱液减压回收溶剂,即得。
4.权利要求1所述的制备方法,其特征在于:酸水解物的制备方法为将权利要求3获得的提取物进行加热酸水解,水解液加碱中和至中性,过大孔吸附树脂柱吸附,有机溶剂解吸,回收溶剂,得水解物。
5.权利要求1所述的制备方法,其特征在于:所述酸为盐酸或硫酸或硝酸或醋酸。
6.权利要求3或4所述的制备方法,其特征在于:所述的大孔吸附树脂选自AB-8、D101、D4020、DM301中的一种。
7.权利要求4所述的制备方法,其特征在于:所述的有机溶剂为乙醇或甲醇或丙酮或它们的混合溶剂。
8.权利要求4所述的制备方法,其特征在于:所述盐酸的浓度为2mol/L。
9.权利要求1所述的制备方法,其特征在于:硅胶柱层析用洗脱剂为二氯甲烷、三氯甲烷、乙酸乙酯、甲醇、水的任意两种或两种以上混合溶液。
10.权利要求1所述的制备方法,其特征在于:反相色谱流动相为甲醇:水,固定相为ODS。
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CN115896201B (zh) * | 2023-01-09 | 2023-05-26 | 成都欧康医药股份有限公司 | 一种4-甲氧基-3,5`,7`-三羟基黄烷酮的制备方法 |
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