CN113061084B - 一种制备阿魏酸的新方法 - Google Patents
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- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 title claims abstract description 56
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- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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Abstract
本发明提供一种制备阿魏酸的新方法,属于药物合成领域。本发明以香兰素和米氏酸为起始原料,有机酸为催化剂,反应得到阿魏酸。本发明的制备工艺采用廉价易得的起始原料,合成过程绿色环保,反应体系及后处理中产生的废液及有机溶剂较少。操作过程较为简便,投料程序简单,不需要增加特殊设备,均为常规的步骤,相关参数的控制也可以在一定范围内,微小参数改变不会影响到产品的最终的产率及纯度,工艺稳定、适合工业化生产。
Description
技术领域
本发明属于药物合成领域,具体涉及一种阿魏酸的合成方法。
背景技术
阿魏酸化学名为4-羟基-3-甲氧基肉桂酸,分子式为C10H10O4,其结构式如下:
以阿魏酸、六水哌嗪为原料反应可以制备得到阿魏酸哌嗪。阿魏酸哌嗪是中药川芎的主要活性成分,具有抗凝血、抗血小板聚集、改善微循环、解除血管痉挛和增加冠状动脉流量的作用,临床上适用于伴有镜下血尿和高凝状态的肾小球肾病以及冠心病、脑梗塞、脉管炎等辅助治疗。
阿魏酸的制备主要有三种方法:碱液水解法、酶水解法和化学合成法。
1、碱液水解法是一种半合成制备阿魏酸的方法,植物中阿魏酸多通过酯键与多糖和木质素交联形成高分子聚合物的一部分,一般用碱法或酶法打断酯键释放阿魏酸,再采用合适的溶剂进行提取。通常采用低浓度的氢氧化钠溶液,在适当的提取温度下能将麦鼓中的大部分阿魏酸释放出来,提取过程中添加亚硫酸钠保护剂或持续充入氮气可增加阿魏酸的回收率。在制作阿魏酸的整个过程,该种方法的重点和难点在于提纯,通常提取粗阿魏酸采用萃取法,而阿魏酸的提纯需要采用色谱柱分离提纯,工艺繁琐,提纯困难,难以大规模工业化。
2、酶水解法是培养一种酶将阿魏酸甲酯、低聚糖阿魏酸酯和多糖阿魏酸之中的阿魏酸游离出来。比如以黑曲霉作菌种,采用液体深层发酵法,制备出含有阿魏酸酯酶和***木聚糖酶的混合酶制剂,采用混合酶制剂作用于去淀粉的麦麸,麦麸降解后释放出阿魏酸。利用生物酶分解原料制作阿魏酸是一种应用前景广阔的理想方法,但目前仍未能研究出高效的生产方法,对于如何高效培养并富集该特种酶制剂还有待进一步研究。
3、化学合成法,通过对相关文献的检索和总结,发现阿魏酸的合成路线主要有以下2条:第一种化合合成方法:中国医药工业杂志Chines e Journal of Pharmaceuticals1997,28(4)
该反应所用的催化剂为吡啶,苯胺等,溶剂和带水剂为甲苯。吡啶具有强烈的恶臭,毒性较大;苯胺具有强烈的致癌作用;甲苯也是易挥发的中强毒性的有机溶剂,不符合绿色化学的要求。反应需要时间较长,长达几十个小时。
第二种化合合成方法:中国专利CN105566101A
以香兰素为原料,提出了一种新的阿魏酸合成路线,香兰素在碳酸钾存在下与乙酸酐高温经Perkin反应生成乙酰阿魏酸,经碱性条件下水解得到阿魏酸。
该合成路线仍以香兰素为起始物料,路线不复杂,但存在一些缺点:(1)该反应温度较高,长时间的高温反应容易造成阿魏酸的顺式构象异构化。(2)反应产率低,阿魏酸合成步骤收率约60%,大量未反应的香兰素不容易去除,造成合成的阿魏酸纯度低。
因此,阿魏酸合成领域开发一种节能、环保、工艺简单的制备方法将极具应用性。
发明内容
本发明提供了一种制备阿魏酸的新方法,在已有报道的基础上,采用廉价易得的起始原料,合成过程绿色环保,操作简便,产物纯度高、工艺稳定、适合工业化生产。
本发明的以香兰素和米氏酸为起始原料,有机酸为催化剂,反应得到阿魏酸,制备方程式如下:
本发明所述的有机酸具体为羧酸,再进一步具体可以是:醋酸、甲酸、酒石酸、苹果酸中的一种或多种。
本发明所述的有机酸与香兰素摩尔比为0.1-0.5。
上述反应体系中采用的溶剂为极性溶剂,优选为水、乙醇、甲醇一种或者多种混合溶剂。
上述反应***中溶剂与香兰素的体质比V/M为3-5。
上述反应温度40-80℃,优选反应温度为70-80℃。
香兰素和米氏酸的摩尔数比例为1:1-1:1.2。
具体的操作步骤如下:
步骤1:反应体系中加入香兰素、米氏酸、有机酸催化剂,温度40-80℃在极性溶剂中反应,TLC监测反应完全后,降至室温,过滤得阿魏酸粗品;
步骤2:阿魏酸粗品加入有机醇的水溶液进行重结晶,析晶过滤,滤饼用水淋洗,鼓风干燥,得到阿魏酸。
进一步的,上述具体步骤中重结晶有机醇可以是乙醇或甲醇或异丙醇中的一种或多种。
进一步的,上述具体步骤中重结晶有机醇水的溶液中有机醇的体积含量为40-60%。
进一步的,上述具体步骤中鼓风干燥的稳定为40-65℃。
米氏酸在酸性条件下,缩合并且脱出丙酮,再经过脱羧得到阿魏酸,具体反应的作用机理如下:
香兰素化学名为4-羟基-3-甲氧基苯甲醛,又名甲基原儿茶醛、香草醛,广泛应用于食品、饮料、化妆品、日用化学品及医药等行业,毒性小,作为阿魏酸制备的起始物料,工艺安全性高。
米氏酸均为常见常用的化工原料和医药中间体,原料易得,并且容易保存,常态为固体,在工艺操作中使用非常方便。
以有机酸作为催化剂,例如羧酸:乙酸、甲酸等均为常见的羧酸,价格较为低廉,成分简单,配制简单。相较于文献公开报道的金合欢荚的水提取物作为催化剂廉价易得,金合欢荚的水提取物制备起来比较麻烦,并且产率不高。另外文献报道金合欢荚的水提取物作为催化剂的试验摩尔数较少,是否能够应对放大效应暂不可知。另外的文献用农作物和废水作为香兰素和米氏酸反应的溶剂,虽然绿色环保,可以利用废液,但是对于医药产品生产会引入大量的未知杂质及微生物,带来纯化及检测的复杂性,不适用与医药原料药的制备。
本发明的制备工艺采用廉价易得的起始原料,合成过程绿色环保,反应体系及后处理中产生的废液及有机溶剂较少。操作过程较为简便,投料程序简单,不需要增加特殊设备,均为常规的步骤,相关参数的控制也可以在一定范围内,微小参数改变不会影响到产品的最终的产率及纯度,工艺稳定、适合工业化生产。
具体实施方式
下面结合说明书具体的实施例,对本发明作详细描述。
TLC为:薄层层析。
石油醚沸程60-90℃。
体质比V/M为体积与质量的比例,单位为mL/g。
实施例1
100mL三口瓶中加10g香兰素,9.5g米氏酸,30mL水,加0.5g冰醋酸为催化剂,75℃反应,反应6hTLC(乙酸乙酯:石油醚:1:1)监测反应完全后,降至室温,过滤得阿魏酸粗品。
阿魏酸粗品加入50%的乙醇水溶液进行重结晶,析晶过滤,滤饼用水淋洗,60℃鼓风干燥,得到阿魏酸10.7g,产率84%。
实施例2
100mL三口瓶中加10g香兰素,9.5g米氏酸,50mL水,加0.3g甲酸为催化剂,75℃反应,反应7hTLC(乙酸乙酯:石油醚:1:1)监测反应完全后,降至室温,过滤得阿魏酸粗品。
阿魏酸粗品加入50%的乙醇水溶液进行重结晶,析晶过滤,滤饼用水淋洗,60℃鼓风干燥,得到阿魏酸10g,产率79%。
实施例3
100mL三口瓶中加10g香兰素,9.5g米氏酸,30mL水,加1g酒石酸为催化剂,75℃反应,反应10h,降至室温,过滤得阿魏酸粗品。
阿魏酸粗品加入50%的乙醇水溶液进行重结晶,析晶过滤,滤饼用水淋洗,60℃鼓风干燥,得到阿魏酸6.3g,产率50%。
实施例4
100mL三口瓶中加10g香兰素,9.5g米氏酸,30mL水,加1g苹果酸为催化剂,75℃反应,反应10h后,降至室温,过滤得阿魏酸粗品。
阿魏酸粗品加入50%的乙醇水溶液进行重结晶,析晶过滤,滤饼用水淋洗,60℃鼓风干燥,得到阿魏酸6.6g,产率52%。
实施例5-11
通用条件:100mL三口瓶中加10g香兰素,9.5g米氏酸,30mL水,加0.5g冰醋酸为催化剂,TLC(乙酸乙酯:石油醚:1:1)监测反应完全后,降至室温,过滤得阿魏酸粗品。阿魏酸粗品通过重结晶或者柱层析进行纯化。
不同反应温度下,不同结果如下:
总结结论,从实施例5-11经过比较得到,在温度不断变化的情况下,会影响到阿魏酸的产率,室温或温度较低情况下会中间体5-(4-羟基-3-甲氧基亚苄基)-2,2-二甲基-1,3-二恶烷-4,6-二酮,60℃以上反应会生成阿魏酸。但温度较高的情况下,反应体系能耗较高,同时会产生聚合杂质,反应产率反而下降。
Claims (6)
1.一种阿魏酸的制备方法,其特征在于,以香兰素和米氏酸为起始原料,有机酸为催化剂,反应得到阿魏酸;
所述的有机酸具体为羧酸;
所述的羧酸为醋酸和甲酸;
反应温度75-85℃;
所述反应体系中溶剂为水。
2.根据权利要求1所述的制备方法,其特征在于,所述的有机酸与香兰素摩尔比为0.1-0.5。
3.根据权利要求1所述的制备方法,其特征在于,反应***中溶剂与香兰素的体质比V/M为3-5。
4.根据权利要求1所述的制备方法,其特征在于,香兰素和米氏酸的摩尔数比例为1:1-1:1.2。
5.根据权利要求1所述的制备方法,其特征在于,具体的操作步骤如下:
步骤1:反应体系中加入香兰素、米氏酸、有机酸催化剂,温度75-85℃在水溶剂中反应,TLC监测反应完全后,降至室温,过滤得阿魏酸粗品;
步骤2:阿魏酸粗品加入有机醇的水溶液进行重结晶,析晶过滤, 滤饼用水淋洗,鼓风干燥,得到阿魏酸。
6.根据权利要求5所述的制备方法,其特征在于,所述有机醇为乙醇或甲醇或异丙醇中的一种或多种。
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