WO2020062545A1 - 一种延胡索中叔胺碱类组分的制备方法 - Google Patents

一种延胡索中叔胺碱类组分的制备方法 Download PDF

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WO2020062545A1
WO2020062545A1 PCT/CN2018/118603 CN2018118603W WO2020062545A1 WO 2020062545 A1 WO2020062545 A1 WO 2020062545A1 CN 2018118603 W CN2018118603 W CN 2018118603W WO 2020062545 A1 WO2020062545 A1 WO 2020062545A1
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acid
tertiary amine
preparation
rhizoma corydalis
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梁鑫淼
王超然
赵耀鹏
郭秀洁
乔健
高振华
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泰州医药城国科化物生物医药科技有限公司
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization

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  • the invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing tertiary amine base components in fumarate.
  • Yanhusuo (Yuanhu) is a tuber of the papaveraceous plant Corydalis Yanhusuo W.T.Wang, which has the effects of promoting blood circulation, removing blood stasis, regulating qi and analgesic effect.
  • Modern medicinal chemistry and pharmacology experiments show that the main active ingredients in Yanhusuo are tertiary amines and quaternary ammonium alkaloids, of which the tertiary amine base content is about 0.65% and the quaternary ammonium base content is about 0.3%.
  • the purpose of the present invention is to directly convert the berberine quaternary ammonium base in Yanhusuo extract to protoberberine tertiary amine base, so as to improve the analgesic activity of berberine tertiary amine base in Yanhusuo extract. Content to make it more targeted and effective.
  • the technical scheme of the present invention is: a method for preparing a tertiary amine base component in fumarus, the steps are as follows:
  • the Yanhusuo extract includes one or more of water, acid water, methanol or ethanol as a solvent, and a crude extract obtained by infiltration, decoction, reflux, ultrasonic or microwave-assisted extraction. Or the crude extract is purified by acid extraction, alkali precipitation, solvent distribution or resin column chromatography.
  • the method of step (1) is: dispersing the dry powder of Fructus fulvae to 10-100 times the mass of methanol or ethanol, and stirring uniformly at room temperature.
  • the method of step (2) is: adding K2CO3, NaOH or KOH of 0.1-2 times the mass, and stirring at room temperature for 10-30 minutes.
  • the method of step (3) is: adding 0.01-2.0 equivalents of NaBH4 (NaBH4 dissolved in 2-10 ml of 5% NaOH solution) dropwise, adding dropwise within 30min, and stirring at room temperature for 0.5-3h.
  • NaBH4 NaBH4 dissolved in 2-10 ml of 5% NaOH solution
  • step (4) after the reaction is detected by HPLC or spot plate, the solid is removed by filtration, washed with a large amount of reaction solvent, and the filtrate is concentrated under reduced pressure.
  • step (5) is: adjusting the pH of the concentrated solution to 6.5-8.0 with an organic or inorganic acid, removing the solvent under reduced pressure, desalting to obtain a white or yellow solid product; qualitative and quantitative analysis by HPLC, the tertiary amine base content> 50%.
  • organic or inorganic acid is dilute hydrochloric acid, dilute sulfuric acid, citric acid, and formic acid.
  • the obtained tertiary amine base is poor in water solubility and poor in bioavailability.
  • one or two or more kinds of acids compatible with biological systems such as acetic acid, nitric acid, hydrochloric acid, and sulfuric acid can be added to make it Reacts with alkaloids to become physiologically acceptable salts to improve solubility and bioavailability.
  • the reactions of the present invention are all carried out at normal temperature and pressure.
  • the reaction conditions are mild and easy to operate.
  • the reaction conversion efficiency is high.
  • the quaternary ammonium base in the extract can be almost 100% converted into the corresponding tertiary tertiary.
  • Amine bases; the alcohol solvents, reducing agents, and acids and bases used are bulk raw materials commonly used in the pharmaceutical industry, which are cheap and easy to obtain, and are suitable for industrial production.
  • the HPLC qualitative and quantitative method for tertiary amine base components obtained by this method is: Waters Alliance High Performance Liquid Chromatography System, on a Unitary C18 column (4.6 ⁇ 150mm, 5 ⁇ m), with acetonitrile (A) and water (containing 0.1 % Phosphoric acid, 0.2% triethylamine, pH 6.0) as mobile phase for gradient elution, the elution conditions are: 0-20min, 23% A; 20-30min, 23% -55% A; 30-45min, 55% A; 45-46min, 55% -23% A; 46-60min, 23% A.
  • the flow rate was 1 mL / min, the PDA detector, and the column temperature was 30 ° C.
  • a high content of tertiary amine base components can be prepared from Yanhusuo extract through a simple chemical reaction, which lays a good foundation for the development of targeted pharmaceutical preparations.
  • FIG. 1 is a chromatogram of the extract of Yanhusuo in Example 1 and ultraviolet spectra of 9 main tertiary amine base peaks;
  • FIG. 3 is a comparison spectrum of the sample liquid before and after the reaction in Example 1.
  • a method for preparing a tertiary amine base component in fumarate is implemented by the following examples.
  • Fructus humus extract (wherein the tertiary amine base content is 0.5% based on fumarate B, Figure 1), add 100ml of methanol, stir for 0.5h, add 3.0g of K 2 CO 3 , stir for 10min, drop in Add 2.4 ml of 5% sodium hydroxide solution containing 0.12 g of NaBH 4 and complete the addition for 2 min.

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Abstract

本发明提供了一种延胡索中叔胺碱类组分的制备方法。本发明所提供的类组分制备方法，将延胡索提取物中小檗碱类季铵碱还原为原小檗碱类叔胺碱，其中延胡索中两种含量最高的季铵碱——巴马汀和去氢紫堇碱分别被还原为延胡索乙素和延胡索甲素。反应上清液调pH至中性后蒸干，脱盐后干燥即得叔胺碱组分，其中总碱含量达到50％以上。该制备方法工艺简单，高效，回收率高，生产成本低，为"安全，有效，可控"的延胡索生物碱类组分制剂的开发提供了良好的技术方案。

Description

一种延胡索中叔胺碱类组分的制备方法 技术领域
本发明涉及药物合成领域，特别涉及一种延胡索中叔胺碱类组分的制备方法。
背景技术
延胡索(元胡)为罂粟科植物延胡索Corydalis yanhusuo W.T.Wang的块茎，具有活血散瘀、理气止痛的功效。现代药物化学和药理学实验表明，延胡索中的主要活性成分为叔胺和季铵型两类生物碱，其中叔胺碱含量约为0.65％，季铵碱含量约为0.3％。(贺凯,高建莉,赵光树.延胡索化学成分、药理作用及质量控制研究进展,中草药,2007,38(12):1909-1912)。这两类成分不仅在结构上有差异，在溶解性和药理作用上也有着很大的不同。以延胡索甲素，乙素，丙素，丁素等为代表的叔胺型生物碱几乎不溶于水，往往具有良好的镇痛镇静作用，是延胡索用于传统止痛治疗的主要活性成分(赵翡翠,赵晓琴,李永和.醋制延胡索中延胡索乙素含量及镇痛作用的对比研究,新疆中医药,2007,25(2):34-36)；而延胡索在抗心肌缺血、减少心肌氧耗等方面的显著作用，主要是缘于水溶性较好的季铵碱(程星烨.延胡索抗心肌缺血活性部位物质基础研究,中国协和医科大学硕士学位论文,2008)。显然，延胡索中的季铵碱并非其止痛活性的物质基础。如果能够将延胡索中含量较高的小檗碱类季铵碱直接转化为具有良好镇痛活性的原小檗碱类叔胺碱，则其镇痛作用将更具有针对性，也更容易对其进行质量控制。而目前，并无相关专利报道。为此，我们经过深入研究，发现了一种将延胡索提取物中小檗碱类季铵碱直接转化为原小檗碱类叔胺碱的方法，可大幅提高延胡索提取物中原小檗碱类叔胺活性化合物的含量，同时除去小檗碱类季铵碱。
有鉴于此，特提出本发明。
发明内容
本发明的目的是将延胡索提取物中的小檗碱类季铵碱直接转化为原小檗碱类叔胺碱，以提高延胡索提取物中具有镇痛活性的原小檗碱类叔胺碱的含量，使其作用方式和疗效更具有针对性。
本发明的技术方案为：一种延胡索中叔胺碱类组分的制备方法，步骤如下：
(1)将延胡索提取物干粉分散到5-100倍质量的醇溶剂体系中，搅拌均匀；
(2)加入0.1-2倍质量的碱，继续搅拌10-60min；
(3)滴加入0.01-2.0当量的NaBH4(NaBH4溶于NaOH溶液)，30min内滴加完，室温下搅拌0.5-3h；
(4)反应完全后，过滤，滤液浓缩；
(5)调节浓缩液pH至6.5-8.0，减压除去溶剂，脱盐得黄色固体产物。
进一步地，所述的延胡索提取物包括以水、酸水、甲醇或乙醇中的一种或二种以上为溶剂采用渗漉、煎煮、回流、超声或微波辅助等提取方式得到的粗提物，或该粗提物再经过酸提碱沉、溶剂分配或树脂柱层析等方式净化后的总碱提取物。
优选地，步骤(1)的方法为：将延胡索提取物干粉分散到10-100倍质量的甲醇或乙醇中，室温下搅拌均匀。
优选地，步骤(2)的方法为：加入0.1-2倍质量的K2CO3、NaOH或KOH，室温下搅拌10-30min。
优选地，步骤(3)的方法为：滴加入0.01-2.0当量的NaBH4(NaBH4溶于2-10ml的5％的NaOH溶液)，30min内滴加完，室温下搅拌0.5-3h。
进一步地，步骤(4)的具体方法为：HPLC或点板检测反应完全后，过滤除去固体，用大量反应溶剂洗涤，滤液减压浓缩。
进一步地，步骤(5)的具体方法为：用有机或无机酸调节浓缩液pH至6.5-8.0，减压除去溶剂，脱盐得白色或黄色固体产物；经HPLC定性定量分析，叔胺碱含量>50％。
进一步地，所述有机或无机酸为稀盐酸、稀硫酸、柠檬酸、甲酸。
进一步地，得到的叔胺碱因水溶性差，生物利用度较差，可在后续的脱盐步骤中，加入醋酸、硝酸、盐酸、硫酸等生物体系兼容的酸中一种或二种以上，使之与生物碱反应成为生理上可接受的盐，以提高溶解性和生物利用度。
本发明反应均在常温常压下进行，反应条件温和，易于操作；反应转化效率高，在NaBH4稍过量的情况下，即可将提取物中的季铵碱几乎100％地转化为对应地叔胺碱；所用的醇溶剂，还原剂，以及酸碱都是制药行业常用的大宗原料，价格便宜且容易获得，适用于工业化生产。
本方法所得叔胺碱类组分的高效液相色谱定性定量方法为：Waters Alliance高效液相色谱系统，在Unitary C18柱(4.6×150mm，5μm)上，以乙腈(A)和水(含0.1％磷酸，0.2％三乙胺，pH 6.0)为流动相进行梯度洗脱，洗脱条件为：0-20min,23％A；20-30min,23％-55％A；30-45min,55％A；45-46min,55％-23％A；46-60min,23％A。流速为1 mL/min，PDA检测器，柱温为30℃。对于叔胺碱类组分，以延胡索乙素为对照品制作外标工作曲线，所得回归方程为y＝2E+07x-16050,R2＝0.9999，检测波长280nm，线性范围0.008-1.6mg/mL。本方法所得叔胺碱类组分中10个主峰的含量以延胡索乙素(图1，峰5)计大于50％。
基于上述技术方法，可从延胡索提取物经简单化学反应制备得到高含量的叔胺碱类组分，为针对性的药物制剂开发奠定了良好基础。
附图说明
图1实施例1中的延胡索提取物的色谱图和9个叔胺碱主峰的紫外谱图；
图2叔胺碱类组分的色谱图和10个主峰的紫外谱图；
图3实施例1中反应前后样品液的对比谱图。
具体实施方式
下面结合实例对本发明做进一步阐述，但仅限于说明本发明，而不是对本发明的任何限制。
一种延胡索中叔胺碱类组分的制备方法，通过以下实施例实施。
实施例1
250ml反应瓶加入延胡索提取物2.0g(其中叔胺碱含量以延胡索乙素计为0.5％，图1)，加入甲醇100ml，搅拌0.5h，加入K 2CO 3 3.0g，搅拌10min，向内滴加含0.12g NaBH 4的2.4ml5％氢氧化钠溶液，2min滴加完毕，搅拌2h，过滤，滤液浓缩去甲醇，加入30ml水，用1N盐酸调节pH至7-8，加入30ml二氯甲烷萃取三次，合并，饱和氯化钠洗涤一次，无水硫酸钠干燥，浓缩得到黄色固体0.05g，经HPLC分析，其中叔胺碱含量以延胡索乙素计为50.2％，见图2，反应前后样品液的对比谱图如图3所示，提取物中两个主要季铵碱——巴马汀和去氢紫堇碱的峰在反应液中消失，延胡索乙素和甲素的峰明显增高，提取物中的季铵碱几乎100％地转化为对应地叔胺碱。
实施例2
250ml反应瓶加入延胡索提取物2.0g，加入乙醇100ml，搅拌0.5h，加入K2CO33.0g，搅拌10min，向内滴加0.12g NaBH4的2.4ml 5％氢氧化钠溶液，2min滴加完毕，搅拌2h，过滤，滤液浓缩去乙醇，加入30ml水，用1N盐酸调节pH至7-8，加入30ml乙酸乙酯萃取三次，合并，饱和氯化钠洗涤一次，无水硫酸钠干燥，浓缩得到黄色 固体0.04g，经HPLC分析，其中叔胺碱含量以延胡索乙素计为55.6％。
实施例3
250ml反应瓶加入延胡索提取物2.0g，加入乙醇50ml，搅拌0.5h，加入K2CO33.0g，搅拌10min，向内滴加0.1g NaBH4的2.0ml 5％氢氧化钠溶液，2min滴加完毕，搅拌2h，过滤，滤液浓缩去乙醇，加入30ml水，用1N硫酸调节pH至7-8，加入30ml乙酸乙酯萃取三次，合并，饱和氯化钠洗涤一次，无水硫酸钠干燥，浓缩得到黄色固体0.03g，经HPLC分析，其中叔胺碱含量以延胡索乙素计为60.5％。
以上所述实施例仅表达了本申请的具体实施方式，其描述较为具体和详细，但并不能因此而理解为对本申请保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请技术方案构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。

Claims (9)

  1. 一种延胡索中叔胺碱类组分的制备方法，其特征在于，步骤如下：
    (1)将延胡索提取物干粉分散到5-100倍质量的醇溶剂体系中，搅拌均匀；
    (2)加入0.1-2倍质量的碱，继续搅拌10-60min；
    (3)滴加入0.01-2.0当量的NaBH4(NaBH4溶于NaOH溶液)，30min内滴加完，室温下搅拌0.5-3h；
    (4)反应完全后，过滤，滤液浓缩；
    (5)调节浓缩液pH至6.5-8.0，减压除去溶剂，脱盐得黄色固体产物。
  2. 根据权利要求1所述制备方法，其特征在于，步骤(1)所述的延胡索提取物包括以水、酸水、甲醇或乙醇中的一种或二种以上为溶剂采用渗漉、煎煮、回流、超声或微波辅助等提取方式得到的粗提物，或该粗提物再经过酸提碱沉、溶剂分配或树脂柱层析等方式净化后的总碱提取物。
  3. 根据权利要求1所述制备方法，其特征在于，步骤(1)的方法为：将延胡索提取物干粉分散到5-100倍质量的甲醇或乙醇中，室温下搅拌均匀。
  4. 根据权利要求1所述制备方法，其特征在于，步骤(2)的方法为：加入0.1-2倍质量的K2CO3、NaOH或KOH，室温下搅拌10-60min。
  5. 根据权利要求1所述制备方法，其特征在于，步骤(3)的方法为：滴加入0.01-2.0当量的NaBH4(NaBH4溶于2-10ml的5％的NaOH溶液)，30min内滴加完，室温下搅拌0.5-3h。
  6. 根据权利要求1所述制备方法，其特征在于，步骤(4)的具体方法为：HPLC或点板检测反应完全后，过滤除去固体，用大量反应溶剂洗涤，滤液减压浓缩。
  7. 根据权利要求1所述制备方法，其特征在于，步骤(5)的具体方法为：用有机或无机酸调节浓缩液pH至6.5-8.0，减压除去溶剂，脱盐得白色或黄色固体产物；经HPLC定性定量分析，叔胺碱含量>50％。
  8. 根据权利要求7所述制备方法，其特征在于，所述有机或无机酸为稀盐酸、稀硫酸、柠檬酸、甲酸。
  9. 根据权利要求1所述制备方法，其特征在于，步骤7所述脱盐步骤中，加入醋酸、硝酸、盐酸、硫酸中一种或二种以上。
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