CN106536468A - 甘草素前驱物质的制备方法 - Google Patents

甘草素前驱物质的制备方法 Download PDF

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CN106536468A
CN106536468A CN201580036037.2A CN201580036037A CN106536468A CN 106536468 A CN106536468 A CN 106536468A CN 201580036037 A CN201580036037 A CN 201580036037A CN 106536468 A CN106536468 A CN 106536468A
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glycyrrhizin
isoliquiritigenin
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肥后春男
增田俊哉
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Abstract

本发明提供一种最恰当的甘草素的量产方法。在本发明的甘草素前驱物质的制备方法中，通过弗里德尔‑克拉夫茨反应(A)将式(I)所示的4‑烷氧基肉桂酸和式(II)所示的1，3‑烷氧基苯耦合而合成式(III)所示的三烷氧基异甘草素，并使其结晶化，去掉保护基而获得式(IV)所示的异甘草素。通过将式(IV)所示的异甘草素作为甘草素的前驱物质而投药到体内，从而在体内获得甘草素(‑)的药理效果。

Description

甘草素前驱物质的制备方法
技术领域
本发明涉及一种制备作为甘草素前驱物质的异甘草素的方法
背景技术
甘草素是其药效得到广泛认可的优异的中药，通常从甘草中提取。然而，作为其提取方法，需要对甘草根进行热萃取之后，去掉水解后的糖类(葡萄糖或芹菜塘)，对所获得的甘草素进行反相层析而精制出。因此，从甘草中提取甘草素的成本较高且比较贵重，售价约为1万日元/g。而且，甘草的种植比较困难，因此甘草的产量趋于减少，导致其价格上涨难以购买。
对此，人们试图人工合成甘草素。如图2所示，以往的第一方法为，将p-羟基苯甲醛作为起始原料合成4-羧基肉桂酸，并对其加成1,3-羟基苯而获得异甘草素(专利文献1)的方法。但是该方法存在产量低的缺点。对此提出了第二方法，如图3所示，该方法中，将p-羟基苯甲醛作为起始原料，用MOM试剂保护p位的羟基，并且用MOM试剂保护1,3-羟基苯的羟基，并使两者加成(非专利文献2)。然而，实际验证结果，几乎在整个(产量或生成物为油状等)阶段需要基于柱层析的精制工艺。而且，在本发明人等的重新实验中，扩大了实验规模后的耦合工艺的产量下降到了42％，而且在最终工艺的从异甘草素转换为甘草素的闭环反应中，原料和目的物成为平衡状态，其产率没有上升。并且，在闭环反应中的原料和目的物的分离比较困难，在最后的层析精制条件下甘草素加尾(tailing)，导致回收率大幅下降。而且，MOM保护试剂具有致癌性，并且在保护和脱保护中需要两个阶段的多余的工艺，因此第二方法在实验室制备中是有效的，却不适于量产。
专利文献1：药学学报Acta Pharmaceutica Sinica 1994，29(11):877～880
非专利文献2：Hu etc.European Journal of Medical Chemistry，2010，45，3453-3458
发明内容
对此，本发明人等根据在甘草素的量产中不使用层析法、使目的物质结晶、不使用具有致癌性的MOM保护试剂、在人工将异甘草素转换为甘草素时随着平衡反应其产量无法上升、有机合成的甘草素不同于天然物同时存在(+)体和(-)体，需要重新进行毒性试验等问题，提供了一种适于甘草素的量产的制备方法。
本发明人等发现，将异甘草素在以柠檬酸为代表的有机酸水溶液中培养，则会转换成甘草素(-)体，因此，通过量产异甘草素并将其添加到有机酸水溶液中进行培养，即可将其投药而获得甘草素(-)体的药理效果。其中，将p-烷氧基肉桂酸作为起始原料，并且利用弗里德尔-克拉夫茨反应对其耦合p-烷氧基苯，高效地形成三烷氧基异甘草素并使其结晶化，接着对其进行脱保护而量产异甘草素，并且将异甘草素在有机酸中培养而使其成为甘草素(-)体，从而获得甘草素(-)体的药理效果。
根据本发明的方法，通过结晶方法可以高产量地获得目的物质。并且，由于不使用气相色谱法(gas chromatography)，因此能够降低制造成本。
并且，即使直接投药异甘草素，其也能够在体内转换成甘草素(-)体，但是，优选通过在以柠檬酸为代表的有机酸水溶液中进行培养而转换成甘草素(-)体。根据日本专利公报第5611394号，甘草素(-)体的药理效果如下：在甘草素为10μg/ml时，针对人肝脏癌细胞SMMC7721显示为96.08，针对人胃低分化腺癌BGC-823显示为73.76，针对人早幼粒细胞白血病细胞HL-60显示为64.40，针对人肺癌细胞A549则稍低、显示为35.06，其均超过阿霉素对癌细胞的抑制效果。
[表2]
表2.甘草素(liquiritigenin)对癌细胞的抑制作用
[表3]
表3.阿霉素(adriamycin)对癌细胞的抑制作用
并且，根据本发明，在进行有机合成时，甘草素(+)体和(-)体不会同时存在，因此能够有效地利用产量高的异甘草素。并且，通过在人体有益的有机酸，尤其是在以柠檬酸为主要成分的有机酸水溶液中进行培养即可获得上述药理效果较高的甘草素(-)体，因此，与进行有机合成的情况相比，甘草素(-)体的产量增加。并且，由于不像有机合成时那样同时存在甘草素(+)体，因此无需进行毒性试验。
本发明的反应式如图1所示，第一步为耦合反应(A)，从式(I)所示的p-烷氧基肉桂酸和式(II)所示的p-二烷氧基苯(dialkoxy benzene)合成式(III)所示的三烷氧基异甘草素，并去掉保护基而合成异甘草素。在式(I)、式(II)以及式(III)中的RO优选是R为甲基、乙基或丁基的烷氧基，通常使用容易得到的R为甲基的甲氧基。反应如下：第一，对式(I)所示的p-烷氧基肉桂酸添加卤化剂进行卤化，对其添加式(II)所示的p-烷氧基苯，接着在有触媒(金属卤化物，例如氯化铝等)存在的状态下对规定的芳香环的氢进行亲电子取代，获得式(IIIa)所示的三烷氧基异甘草素。第二，在反应式(B)中，若去掉该保护基，则获得式(IV)所示的目的物即异甘草素。通过闭环反应(C)，式(IV)所示的异甘草素转换成式(V)所示的甘草素，但是，由于获得(+)体和(-)体，因而需要通过手性拆分分离两者。在此，从甘草获得的甘草素为(-)体，因而可以使用异甘草素的异构酶从异甘草素获得甘草素(-)体，但是优选在有机酸水溶液中进行培养而获得甘草素(-)体。
作为p-烷氧基肉桂酸优选使用p-甲氧基肉桂酸，但是也可以使用p-乙氧基肉桂酸、p-丁氧基肉桂酸。在下面的实施例中，主要对由式(Ia)所示的p-甲氧基肉桂酸和式(IIa)所示的1,3-二甲氧基苯合成式(IIIa)所示的三甲氧基异甘草素，并去掉保护基而合成异甘草素的方法进行说明。
附图说明
图1是表示本发明所涉及的异甘草素的制备例的反应图，其中图1(A)是表示第一反应的反应图，图1(B)是表示第二反应的反应图。
图2是表示以往第一方法的甘草素的制备例的反应图。
图3是表示以往第二方法的甘草素的制备例的反应图。
具体实施方式
以下，根据实施例说明本发明的具体例。
(实施例1)
[化1]
将10g的4-甲氧基肉桂酸(式(Ia))溶解于含有0.25mL的二甲基甲酰胺的50mL的无水甲叉二氯中，并在室温下，以不产生气泡的方式滴入草酰氯10分钟且共计滴入9.6mL。接着，在室温下搅拌两个小时后，在减压下去除溶剂。对所获得的残渣添加7.4mL的1，3-二甲氧基苯(1，3-Dimethoxybenzene)(式(IIa))和200mL的无水乙醚，并且在冰浴中，缓慢添加粉末化的触媒无水三氯铝15分钟且共计添加了22.4g。接着，在室温下放置一晚之后，将内容物投放于冰上(500g)，添加6M盐酸10mL，等冰溶解后，用乙酸乙酯(300mL)提取4次。然后，用无水硫酸钠干燥提取液之后，在减压下进行浓缩，用乙醚-己烷混合液使残渣结晶化，从而得到14.2g的目的物(式(IIIa))结晶。产量85％1H-NMR(CDCl3)δ7.73(1H，d，J＝8.1Hz)，7.64(1H，d，J＝15.1Hz)，7.54(2H，d，J＝7.7Hz)，7.38(1H，d，J＝15.1Hz)，6.90(2H，d，J＝7.7Hz)，6.55(1H，brd，J＝8.1Hz)，6.49(1H，brs)，3.89(3H，s)，3.85(3H，s)，3.83(3H，s)。
[化2]
将上述生成物3g溶解于60mL的氯甲烷中，并在0℃下滴入1MBBr3氯甲烷溶液。接着，使其升温至室温后，搅拌两天。添加含有罗谢尔盐34g的冰冷水700mL和甲醇350mL，并在室温下搅拌一晚。对所获得的黄色溶液用乙酸乙酯提取两次，用1M罗谢尔盐-饱和盐水进行清洗之后，用无水硫酸钠进行干燥、浓缩。用乙醚-己烷使残渣结晶化，从而得到1.95g的目的物(式(IV))。并且，对其母液进行浓缩之后，再次用乙醚-己烷使其结晶化，从而得到0.59g的目的物第二晶。累计产量98％1H-NMR(acetone-d6)δ13.5(1H，s)，8.10(1H，d，J＝8.3Hz)，7.82(1H，d，J＝15.4Hz)，7.74(1H，d，J＝15.4Hz)，7.72(2H，d，J＝8.2Hz)，6.90(2H，d，J＝8.2Hz)，6.44(1H，dd，J＝8.3and1.7Hz)，6.34(1H，d，J＝1.7Hz)。
在日本食品分析中心对上述目的物(异甘草素)进行了急性毒性试验，其结果确认到其没有毒性。
(实施例2)
[化3]
将200mg的原料(式(IV))添加到将pH值调整为2以上且4左右的柠檬酸水溶液中，进行搅拌，使其充分分散后，在常温下放置一晚。对其悬浮液进行浓缩，并用乙醚使其结晶化，从而获得粗结晶(式(V))。其分析值如下，且转换为甘草素(-)。
1H-NMR(DMSO-d6)δ9.65(1H，brs)，7.58(1H，m)，7.27(2H，m)，6.74(2H，m)，6.45(1H，m)，6.28(1H，m)，5.39(1H，brd，J＝11.6Hz)，3.65(1H，brt，J＝15.0Hz)，2.58(1H，brd，J＝15.7Hz)。
(实施例3)
以难消化糊精、N-乙酰氨基葡萄糖、糊精、几丁寡糖、壳寡糖、乳酸、抗坏血酸(维生素C)为主要成分的清凉饮料500ml(株式会社国际MEDICAL研究所销售)的pH值为3.9。对其添加作为甘草素的异甘草素(下述日本专利第5611394号的说明书中记载的表2“甘草素对癌细胞的抑制作用”中所示出的用量(针对老鼠的有效量)的大约100～2000倍)，形成了用于增强免疫的附录。
根据专利公报第5611394的表2明确可知，甘草素(-)体的药理效果如下：甘草素为10μg/ml时，针对人肝脏癌细胞SMMC7721显示为96.08，针对人胃低分化腺癌BGC-823显示为73.76，针对人早幼粒细胞白血病细胞HL-60显示为64.40，针对人肺癌细胞A549则稍低、显示为35.06。

Claims (3)

1.一种甘草素前驱物质的制备方法，其特征在于，
通过弗里德尔-克拉夫茨反应(A)将式(I)所示的4-烷氧基肉桂酸和式(II)所示的1，3-烷氧基苯耦合而合成式(III)所示的三烷氧基异甘草素，并使其结晶化，去掉保护基而获得式(IV)所示的异甘草素，即
2.根据权利要求1所述的甘草素前驱物质的制备方法，其特征在于，在式(I)、式(II)以及式(III)中，保护基RO的R为甲基，即，
3.一种甘草素的制备方法，其特征在于，
在以有机酸为主要成分的酸性有机酸水溶液中培养式(IV)所示的异甘草素，从而得到甘草素(V)，即，
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