WO2014008851A1 - 一种高含量玉米黄素的制备方法 - Google Patents

一种高含量玉米黄素的制备方法 Download PDF

Info

Publication number
WO2014008851A1
WO2014008851A1 PCT/CN2013/079069 CN2013079069W WO2014008851A1 WO 2014008851 A1 WO2014008851 A1 WO 2014008851A1 CN 2013079069 W CN2013079069 W CN 2013079069W WO 2014008851 A1 WO2014008851 A1 WO 2014008851A1
Authority
WO
WIPO (PCT)
Prior art keywords
zeaxanthin
reaction
content
lutein
crystal
Prior art date
Application number
PCT/CN2013/079069
Other languages
English (en)
French (fr)
Inventor
邵斌
张莉华
许新德
孙晓霞
Original Assignee
浙江医药股份有限公司新昌制药厂
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江医药股份有限公司新昌制药厂 filed Critical 浙江医药股份有限公司新昌制药厂
Priority to US14/412,170 priority Critical patent/US9376357B2/en
Priority to EP13816427.2A priority patent/EP2873659B1/en
Publication of WO2014008851A1 publication Critical patent/WO2014008851A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0202—Alcohols or phenols
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
    • B01J2231/52—Isomerisation reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the invention relates to a method for preparing high content zeaxanthin by catalytic isomerization reaction of natural plant extracted lutein crystal or its fatty acid ester.
  • Zeaxanthin is a class of oxygenated carotenoids widely found in nature. It is an important coloring agent and a component with unique physiological functions. Zeaxanthin and lutein are isomers and are the only two carotenoids present in the retina of the human eye, the main difference being the difference in the position of the terminal double bonds.
  • Zeaxanthin plays an important role in eye health. Its mechanism of action includes two aspects. One is the filtration of high-energy blue light in visible light. Zeaxanthin can absorb blue light of near-ultraviolet light. These blue light have photoreceptors and retinal cells in the eye. Great damage; the second is anti-oxidation, the molecular structure of zeaxanthin contains 11 conjugated double bonds, which has strong antioxidant activity, can quench singlet oxygen and scavenge free radicals, inhibit various causes Oxidative damage of tissues such as the retina and lens, and because the number of conjugated double bonds in the molecular structure is higher than that of lutein, zeaxanthin has stronger antioxidant capacity than lutein, which may be more important for human eye health. The role.
  • the sources of zeaxanthin can be basically divided into three categories: full chemical synthesis, fermentation, and lutein isomerization.
  • the disadvantage of the full chemical synthesis method is that many reaction steps are usually required, the reaction conditions are harsh, the side reactions are many, and the yield of the final product is low; the microorganisms used in the fermentation method are mainly the Flavobacterium cells, and the defect of the fermentation method for producing zeaxanthin is Most microbial fermentation units are low, and the fermentation product undergoes a relatively cumbersome subsequent extraction and purification step; compared with the above two methods, the production of zeaxanthin by lutein isomerization is a promising The method, because only one kind of reaction is involved in the process, and the reaction conditions are controlled, the product yield is high and the purity is good.
  • U.S. Pat. No. 5,780,639 (Chinese Patent Licensing Bulletin No. CN 1082507 C) discloses a route for the production of zeaxanthin from lutein, mainly using dimethyl sulfoxide or a mixture of a saturated alkane and/or an aromatic organic solvent as a solvent, using an alkali metal hydroxide as a catalyst. Translocation of lutein to produce zeaxanthin, the amount of alkali used in this process is large, the reaction time is long, and the yield of the product is low (repeated test shows that the yield of the product obtained by this method is less than 30%), which is not suitable for industrialization. produce.
  • organic solvents such as n-hexane, n-heptane, dichloromethane, and methanol are used in the reaction, and it is obviously inappropriate to use these toxic solvents to produce edible or pharmaceutical grade zeaxanthin.
  • the authorization notice number is CN 101182302
  • the Chinese patent of B discloses a preparation method of a composition containing zeaxanthin, which is mainly prepared by a catalyst composed of a base catalyst and an auxiliary agent (formic acid, acetic acid, oxalic acid, propionic acid or sodium borohydride). Preparation of zeaxanthin by isomerization of flavin.
  • the disadvantage of this process is that the reaction time is long, it takes 12-36 hr, and the final product content is 30-80%. The recrystallization process is required to obtain a higher content of the product.
  • an organic solvent such as hexane, heptane, methanol, benzene or toluene is used in the reaction, and these solvents are not suitable for use in foods.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the prior art mentioned above, and to provide a mild reaction condition, high product yield, purification treatment of products without recrystallization, and industrial production of high content zeaxanthin suitable for consumption. Preparation.
  • the present invention is achieved by the following technical scheme: a preparation method of high content zeaxanthin, which uses lutein crystal or its fatty acid ester as a reaction raw material to obtain zeaxanthin by isomerization reaction, It is characterized in that the isomerization reaction uses a mixed catalyst composed of an organic base catalyst and a cocatalyst, and the cocatalyst is palladium carbon.
  • the use of a cocatalyst in the above reaction is advantageous for reducing the activation energy of the reaction, shortening the reaction time, lowering the reaction temperature, and increasing the conversion rate and reaction yield of lutein.
  • the mechanism of action of cocatalyst palladium on carbon is as follows: Pd and the double bond electron cloud on the 4', 5' carbon atom on the benzene ring at the end of the lutein molecule greatly reduce the energy required for the terminal carbon to capture protons. The requirements of the sexual environment are reduced, and protons are more likely to migrate from one negative carbon ion site (6' carbon atom) to another (4' carbon atom), thereby accelerating the double bond from the 4', 5' carbon position. The transfer of 5', 6' position is transferred to achieve the purpose of converting lutein to zeaxanthin, the amount of alkali is decreased, and the reaction time is greatly shortened.
  • step 5 is to recover the promoter palladium on carbon.
  • the volume percentage of ethanol is 30-90%; the conventional separation methods such as suction filtration, pressure filtration, centrifugation and the like.
  • an inert environment is created during the reaction, that is, the reaction system is filled with nitrogen gas.
  • the reaction system In the process of separating crystals, it can be continuously rinsed with water and ethanol until the effluent is nearly colorless. After drying under vacuum, zeaxanthin crystals can be obtained, and the total carotenoid content in the product is analyzed by ultraviolet-visible spectrophotometry. The ratio of zeaxanthin and lutein in total carotenoids was analyzed by high performance liquid chromatography.
  • the organic base catalyst is preferably sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.
  • the method for preparing the high content of zeaxanthin wherein the amount of the organic base catalyst is preferably 4-8 times the molar amount of the reaction raw material; the amount of the promoter added is preferably 0.1-5.0% of the mass of the reaction raw material;
  • the organic solvent is preferably ethylene glycol, propylene glycol or a mixed solvent of the former two.
  • the temperature of the isomerization reaction is preferably between 60-95 ° C, more preferably between 60-75 ° C; the time of the isomerization reaction is preferably 2.0-8.0 h.
  • the preparation method of the above high content of zeaxanthin, the reaction raw material lutein fatty acid ester or lutein crystal used is derived from marigold flower, the former is refined from marigold oleoresin, and the latter is obtained by marigold oleoresin The crystal obtained after the saponification treatment.
  • the product obtained by the above method has a total carotenoid content of more than 80%, and the product yield is high, up to 70%, and zeaxanthin accounts for about 90% of the total carotenoid content, and does not require purification treatment such as recrystallization, which simplifies
  • the process is suitable for industrial production. No toxic and harmful organic solvent residues are detected in the product, and it is suitable for use as a food additive or a medicine.
  • the zeaxanthin in the reaction solution was determined to account for 90.5% of the whole carotenoid ratio.
  • the temperature of the reaction solution was lowered to 70 ° C, and the reaction liquid was diluted with a mixture of 1000 ml of deionized water and 600 ml of food grade ethanol, and the diluted reaction solution was separated by suction filtration, and the filter cake was washed with 1000 ml of ethyl acetate.
  • the product does not contain toxic organic solvents and is suitable for use in the form of nutritional supplements and food additives.
  • the application form of the crystal may be an oil suspension (mixed with vegetable oil), beads (microcapsules obtained by spray condensation), dry powder (microcapsules obtained by spray drying), and the like.
  • the liquid temperature is lowered to 70 ° C, and the reaction liquid is diluted by adding a mixture of 1000 ml of deionized water and 600 ml of food grade ethanol under stirring, and the diluted reaction liquid is separated and crystallized by suction filtration, and the filter cake is used in the filtration process.
  • the mixture with ethanol was rinsed until the eluate was nearly colorless, and the filtrate was dried under vacuum to give 24.7 g of orange crystal.
  • the total carotenoid content in this crystal was 79.6% and the total carotenoid yield was 74.1% by UV-Vis spectrophotometry.
  • zeaxanthin only accounted for 67.4% of total carotenoids. Lutein accounted for total carotenoids. At 28.5%, some lutein is still not completely converted to zeaxanthin.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 1 was that the cocatalyst was not added in the comparative example, and the other test conditions were the same. It can be seen from the experimental results that under the same reaction conditions, the cocatalyst helps to increase the conversion rate of lutein, and the proportion of zeaxanthin in the final product is required to be required in a short reaction time.
  • the zeaxanthin in the reaction solution was found to account for 91.3% of the whole carotenoid ratio. Stop the reaction, reduce the temperature of the reaction solution to 70 ° C, dilute the reaction solution by adding 1000 ml of deionized water and 600 ml of food grade ethanol under stirring, and separate the diluted reaction solution by centrifugation. The filter cake is 1500 ml of acetic acid. After the ester is dissolved, it is filtered, and the palladium carbon is recovered. A mixture of 500 ml of deionized water and 300 ml of food grade ethanol is added to the filtrate, stirred for 0.5 hr, and then suction filtered.
  • the filter cake is rinsed with a mixture of water and ethanol during the filtration process. Until the eluate was nearly colorless, the filtrate was dried under vacuum to give 19.5 g of orange crystals.
  • the total carotenoid content in this crystal was 83.4% by UV-visible spectrophotometry, and the total carotenoid yield was 76.1%.
  • zeaxanthin accounted for 92.1% of total carotenoids
  • lutein accounted for 6.3% of total carotenoids. Both are in a free state.
  • zeaxanthin accounted for 76.7% of the whole carotenoid ratio in the reaction solution.
  • zeaxanthin accounted for 89.8% of the whole carotenoid ratio, and the reaction stopped.
  • the reaction liquid temperature was lowered to 70 ° C, and the reaction liquid was diluted by adding a mixture of 1000 ml of deionized water and 600 ml of food grade ethanol under stirring, and the diluted reaction solution was separated by centrifugation, and the filter cake was dissolved in 1500 ml of ethyl acetate.
  • the palladium charcoal is recovered, and a mixture of 500 ml of deionized water and 300 ml of food grade ethanol is added to the filtrate, stirred for 0.5 hr, and suction filtered, and the filter cake is used in the process of suction filtration. Leaching a mixture of ethanol, until the eluate nearly colorless, and dried in vacuo to give 14.4g filtrate orange crystals.
  • the total carotenoid content in the crystal was 80.2% by UV-visible spectrophotometry, and the total carotenoid yield was 53.8%.
  • zeaxanthin accounted for 91.3% of the total carotenoids
  • lutein accounted for 6.0% of the total carotenoids. Both are free.
  • Comparative Example 2 The difference between Comparative Example 2 and Example 2 is that no cocatalyst is added in this comparative example.
  • the reaction time is extended to 12.5 hr at a reaction temperature of 95 ° C in the case where the amount of alkali is increased. Part of the carotenoids degrade during the longer incubation period at this temperature, as can be seen from the yield of the final product. It can be seen from the experimental results that the cocatalyst helps to lower the temperature of the isomerization reaction, shorten the reaction time, and increase the conversion rate of lutein.
  • the zeaxanthin in the reaction solution was found to account for 88.7% of the whole carotenoid ratio.
  • the temperature of the reaction solution was lowered to 70 ° C, and the reaction liquid was diluted with a mixture of 1000 ml of deionized water and 600 ml of food grade ethanol, and the diluted reaction solution was separated by suction filtration, and the filter cake was washed with 1200 ml of ethyl acetate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了一种高含量玉米黄素的制备方法。现有的制备方法中，有的使用到一些有毒的有机溶剂；有的需要多步结晶过程；有的反应时间长，温度高，产品的收率比较低，不适于工业化生产。本发明以叶黄素晶体或其脂肪酸酯为反应原料，利用异构化反应得到玉米黄素，其特征在于，所述的异构化反应使用由有机碱催化剂和助催化剂组成的混合催化剂，所述的助催化剂为钯炭。本发明的工艺路线简单，反应温度低，反应时间短，产品纯度好、收率高，适合于工业化生产，并且产品中无有毒有害的有机溶剂残留，适于作为食品添加剂或药物使用。

Description

一种高含量玉米黄素的制备方法 技术领域
本发明涉及一种将天然植物提取的叶黄素晶体或其脂肪酸酯通过催化异构化反应制备高含量玉米黄素的方法。
背景技术
玉米黄素是自然界中广泛存在的一类含氧类胡萝卜素，是一种重要的着色剂和具有独特生理功能的成分。玉米黄素和叶黄素是同分异构体，是唯一存在于人眼视网膜中的两种类胡萝卜素，其主要区别在于其末端双键位置的不同。
玉米黄素对眼睛健康具有重要的作用，其作用机理包括两个方面，一是对可见光中高能量蓝光的过滤作用，玉米黄素能吸收近紫外光的蓝光，这些蓝光对眼睛中光感受器和视网膜细胞有很大的损伤；二是抗氧化作用，玉米黄素的分子结构中含有11个共轭双键，具有很强的抗氧化性，能淬灭单线态氧和清除自由基，抑制多种原因导致的视网膜、晶状体等组织的氧化损伤，而且，由于其分子结构中共轭双键的数目比叶黄素多，使得玉米黄素比叶黄素抗氧化能力更强，其对人眼健康可能起到更重要的作用。
玉米黄素与叶黄素一起构成了人眼中唯一存在的两种类胡萝卜素，在人眼健康中发挥着重要的功能，但是人体自身不能合成玉米黄素，必须从外界摄入，且随着年龄的增长，人体中玉米黄素的量会逐渐减少，所以非常有必要通过饮食或膳食补充剂来补充适宜于人类食用的高品质玉米黄素产品。
现有技术中，玉米黄素的来源基本上可分为三类：全化学合成法、发酵法和叶黄素异构化法。全化学合成法的缺点在于通常需要很多反应步骤，反应条件苛刻，副反应多，最终产品的收率低；发酵法使用到的微生物主要是黄杆菌属细胞，发酵法生产玉米黄素的缺陷是大多数微生物发酵单位较低，而且，发酵产物要经过较为繁琐的后续提取纯化步骤；与上述两种方法相比较而言，通过叶黄素异构化法生产玉米黄素不失为一种有前景的方法，因为此工艺中只涉及一种反应，控制好反应条件的情况下，产品收率较高、纯度好。但在叶黄素向玉米黄素转化过程中存在很多困难，到目前为止，只有一二家厂家能通过这种方法实现工业化生产玉米黄素，这是因为此异构化反应需要在强碱性、温度较高的环境下进行，碱性越强，温度越高，越有利于反应的发生，但此反应的反应底物叶黄素和反应产物都是一种很不稳定的类胡萝卜素，它们在强碱性和高温环境下非常不稳定，很容易被降解甚至碳化。这样，在反应过程中为了追求较高的转化率，就不得不使用到大量的强碱在较高的温度下进行反应，而这会使部分叶黄素和部分生成的玉米黄素降解、碳化，使反应收率很低。在先前公开的大部分专利中，通过叶黄素异构化生产玉米黄素的收率一般都是在30%左右，远达不到工业化生产的要求。
PCT专利公开WO96/02594中叙述了一种在受控的温度和压力条件下在强碱溶液中叶黄素异构化成玉米黄素的方法。但是其收率最高才达24%，不适合于工业化生产。
U.S.Pat.No.5,780,639（中国专利授权公告号CN 1082507 C）公开了一种由叶黄素为原料生产玉米黄素的路线，主要是以二甲基亚砜或与饱和烷烃和/或芳烃有机溶剂的混合物作溶剂，以碱金属氢氧化物做催化剂转位叶黄素生产玉米黄素，此工艺中碱的用量大，反应时间长，产品的收率低（重复试验显示，依此方法得到的产品的收率不足30%），不适合于工业化生产。而且，反应过程中使用到了正己烷、正庚烷、二氯甲烷、甲醇等有机溶剂，使用这些有毒的溶剂生产食用级或药用级的玉米黄素显然是不合适的。
授权公告号为CN 101182302 B的中国专利公开了一种含玉米黄素的组合物的制备方法，其主要是在碱催化剂和助剂(甲酸、乙酸、草酸、丙酸或硼氢化钠)组成的催化剂作用下，将叶黄素异构化制备玉米黄素。此过程的缺点是反应时间长，需要12-36hr，最终产品的含量为30-80%，要得到更高含量的产品时需要进行重结晶处理过程。而且，反应过程中使用到了己烷、庚烷、甲醇、苯、甲苯等有机溶剂，这些溶剂不适于在食品中使用。
U.S.Pat.No.7,485,738 B2（中国专利授权公告号CN 101153017 B）使用叶黄素为原料，在强有机碱催化下，差向异构化制备食用级玉米黄素。此过程的缺点是反应时间相对比较长（8-15hr），收率为60%。总之，以上这些专利描述的方法存在以下几个缺点：1）过程中使用到一些有毒的有机溶剂，这些溶剂比较困难或不可能完全去除，导致产品不适于人类食用；2）为了得到高含量的晶体，需要多步结晶过程；3）反应时间长，温度高，在反应过程中有部分反应原料和反应产物发生降解，产品的收率比较低，不适于工业化生产。
因此，有必要找到一种适于工业化规模生产高含量玉米黄素的方法，在此过程中尽量用到少的毒性有机溶剂和操作步骤，尽量减少强碱用量，缩短反应时间，降低反应温度，但拥有较高的反应收率，得到的产品适于人类食用。
 技术问题
本发明所要解决的技术问题是克服上述现在技术存在的缺陷，提供一种反应条件温和、产品收率高、产物不需要经过重结晶等纯化处理，适于食用的工业化生产高含量玉米黄素的制备方法。
 技术解决方案
为此，本发明采用如下技术方案来实现：一种高含量玉米黄素的制备方法，该方法以叶黄素晶体或其脂肪酸酯为反应原料，利用异构化反应得到玉米黄素，其特征在于，所述的异构化反应使用由有机碱催化剂和助催化剂组成的混合催化剂，所述的助催化剂为钯炭。实验证明，在上述反应中使用助催化剂有利于降低反应活化能，缩短反应时间，降低反应温度，提高叶黄素的转化率和反应收率。
助催化剂钯炭的作用机理如下：Pd与叶黄素分子末端苯环上的4’，5’碳原子上的双键电子云络合，大大降低了末端碳捕捉质子所需能量，对强碱性环境的要求降低了，质子更容易从一个负碳离子位点（6’碳原子）迁移到另一个位点（4’碳原子），从而加速了双键由4’，5’碳位置向转移5’，6’位置的转移，达到叶黄素转化为玉米黄素的目的，碱用量降低，反应时间大为缩短。
上述高含量玉米黄素制备方法的具体步骤如下：
①在有机溶剂中加入反应原料叶黄素晶体或其脂肪酸酯，在60-95℃温度下充分溶解；
②向①步得到的混合液中加入有机碱催化剂和助催化剂进行异构化反应，有机碱催化剂采用滴加的方式加入；
③在氮气保护下(即在惰性环境中)进行保温反应；
④用去离子水和乙醇的混合液稀释③步得到的反应液，并采用常规分离方法分离得到晶体；
⑤将④步得到的晶体溶于乙酸乙酯中，过滤；
⑥向⑤步得到的滤液中加入去离子水和乙醇的混合液，搅拌后过滤；
⑦真空干燥⑥步得到的结晶，即得玉米黄素晶体。
步骤⑤的目的是回收助催化剂钯炭。去离子水和乙醇的混合液中，乙醇所占的体积百分比为30-90%；所述的常规分离方法如抽滤、压滤、离心等。
为了保护反应原料叶黄素和生成的玉米黄素不被氧化，在反应过程中要创造一种惰性环境，即向反应体系中充入氮气保护。在分离晶体的过程中，可不断地用水和乙醇淋洗，直至流出液接近无色，经真空干燥后即可得玉米黄素晶体，采用紫外可见分光光度法分析产品中总类胡萝卜素含量，采用高效液相色谱法分析玉米黄素和叶黄素在总类胡萝卜素中的比例。
上述高含量玉米黄素的制备方法，所述的有机碱催化剂优选为甲醇钠、乙醇钠、甲醇钾或乙醇钾。
上述高含量玉米黄素的制备方法，所述有机碱催化剂的加入量优选为反应原料摩尔量的4-8倍；所述助催化剂的加入量优选为反应原料质量的0.1-5.0%；所述的有机溶剂优选乙二醇、丙二醇或前两者的混合溶剂。
上述高含量玉米黄素的制备方法，所述异构化反应的温度优选在60-95℃之间，更优选在60-75℃之间；所述异构化反应的时间优选为2.0-8.0h。
上述高含量玉米黄素的制备方法，所用的反应原料叶黄素脂肪酸酯或叶黄素晶体来源于万寿菊花中，前者由万寿菊油树脂精制得到，后者是通过对万寿菊油树脂进行皂化处理后得到的晶体。
 有益效果
通过上述方法得到的产品中总类胡萝卜素含量80%以上，产品收率高，可达70%以上，玉米黄素占总类胡萝卜素含量高达90%左右，不需要进行重结晶等纯化处理，简化了工艺，适合于工业化生产，产品中未检测到有毒有害的有机溶剂残留，适于作为食品添加剂或药物使用。
 本发明的最佳实施方式
实施例1
称取30g叶黄素晶体（总类胡萝卜素含量为88.5%，其中，叶黄素和玉米黄素占总类胡萝卜素的比例分别为91.5%和7.3%，其余为少量的其它类胡萝卜素），与360ml乙二醇混合，在60℃下搅拌溶解，加入0.03g钯炭，滴加5.0mol/L的甲醇钠溶液42.4ml，碱催化剂在45min内滴加完成，氮气保护并在60℃条件下保温反应2.0h后每隔0.5hr取样分析反应液中叶黄素和玉米黄素的比例，4.5hr后测得反应液中玉米黄素占整个类胡萝卜素比例的90.5%。将反应液温度降低至70℃，在搅拌情况下加入1000ml去离子水和600ml食用级乙醇组成的混合液稀释反应液，将稀释后的反应液抽滤的方式分离，滤饼用1000ml乙酸乙酯溶解后过滤，回收钯炭，在滤液中加入500ml去离子水和300ml食用级乙醇组成的混合液，搅拌0.5hr后抽滤，在抽滤过程中滤饼用水和乙醇的混合液淋洗，直至洗出液接近无色，真空干燥滤出物得22.1g桔红色结晶。经紫外可见分光光度法分析此结晶中总类胡萝卜素含量为85.7%，总类胡萝卜素收率为71.3%，其中玉米黄素占总类胡萝卜素的91.1%，叶黄素占总类胡萝卜素的6.0%。
产品中不含有毒的有机溶剂，适合于以营养补充剂和食品添加剂的形式使用。此结晶的应用形式可为油悬浮液（与植物油混合乳化）、珠粒（通过喷雾冷凝得到的微胶囊）、干粉（通过喷雾干燥得到的微胶囊）等。
 本发明的实施方式
对比实施例1
称取30.3g叶黄素晶体（总类胡萝卜素含量为88.5%，其中，叶黄素和玉米黄素占总类胡萝卜素的比例分别为91.5%和7.3%，其余为少量的其它类胡萝卜素），与360ml乙二醇混合，在75℃下搅拌溶解，滴加5.0mol/L的甲醇钠溶液42.4ml，碱催化剂在45min内滴加完成，氮气保护并在60℃条件下保温反应4.5hr后，将反应液温度降低至70℃，在搅拌情况下加入1000ml去离子水和600ml食用级乙醇组成的混合液稀释反应液，将稀释后的反应液抽滤的方式分离结晶，在抽滤过程中滤饼用水和乙醇的混合液淋洗，直至洗出液接近无色，真空干燥滤出物得24.7g桔红色结晶。经紫外可见分光光度法分析此结晶中总类胡萝卜素含量为79.6%，总类胡萝卜素收率为74.1%，但其中玉米黄素仅占总类胡萝卜素的67.4%，叶黄素占总类胡萝卜素的28.5%，仍有部分叶黄素未完全转化为玉米黄素。
对比实施例1与实施例1的区别在于对比实施例中未加入助催化剂，其它试验条件都相同。从实验结果可以看出，在相同的反应条件下，助催化剂有助于提高叶黄素的转化率，在较短的反应时间内使终产品中玉米黄素的比例达到要求。
实施例2
称取50.6g由万寿菊油树脂精制而得的叶黄素脂肪酸酯（其中总类胡萝卜素脂肪酸酯含量为78.2%，叶黄素和玉米黄素占总类胡萝卜素的比例分别为93.4%和6.1%，其余为少量的其它类胡萝卜素），与400ml丙二醇混合，在95℃下搅拌溶解，加入2.53g钯炭，滴加5.4mol/L的乙醇钠溶液71.1ml，氮气保护且于95℃下保温反应4hr后每隔0.5hr取样分析反应液中叶黄素和玉米黄素的比例，8.0hr后测得反应液中玉米黄素占整个类胡萝卜素比例的91.3%。停止反应，将反应液温度降低至70℃，在搅拌情况下加入1000ml去离子水和600ml食用级乙醇组成的混合液稀释反应液，将稀释后的反应液离心方式分离，滤饼用1500ml乙酸乙酯溶解后过滤，回收钯炭，在滤液中加入500ml去离子水和300ml食用级乙醇组成的混合液，搅拌0.5hr后抽滤，在抽滤过程中滤饼用水和乙醇的混合液淋洗，直至洗出液接近无色，真空干燥滤出物得19.5g桔红色结晶。经紫外可见分光光度法分析此结晶中总类胡萝卜素含量为83.4%，总类胡萝卜素收率为76.1%，其中玉米黄素占总类胡萝卜素的92.1%，叶黄素占总类胡萝卜素的6.3%，且都为游离态。
对比实施例2
称取50.8g由万寿菊油树脂精制而得的叶黄素脂肪酸酯（其中总类胡萝卜素脂肪酸酯含量为78.2%，叶黄素和玉米黄素占总类胡萝卜素的比例分别为93.4%和6.1%，其余为少量的其它类胡萝卜素），与400ml丙二醇混合，在95℃下搅拌溶解，滴加5.4mol/L的乙醇钠溶液82.0ml，氮气保护且于95℃下保温反应4hr后每隔0.5hr取样分析反应液中叶黄素和玉米黄素的比例，8.0hr后测得反应液中玉米黄素占整个类胡萝卜素比例的76.7%，继续反应4.5hr后玉米黄素占整个类胡萝卜素比例的89.8%，停止反应，将反应液温度降低至70℃，在搅拌情况下加入1000ml去离子水和600ml食用级乙醇组成的混合液稀释反应液，将稀释后的反应液离心方式分离，滤饼用1500ml乙酸乙酯溶解后过滤，回收钯炭，在滤液中加入500ml去离子水和300ml食用级乙醇组成的混合液，搅拌0.5hr后抽滤，在抽滤的过程中滤饼用水和乙醇的混合液淋洗，直至洗出液接近无色，真空干燥滤出物得14.4g桔红色结晶。经紫外可见分光光度法分析此结晶中总类胡萝卜素含量为80.2%，总类胡萝卜素收率为53.8%，其中玉米黄素占总类胡萝卜素的91.3%，叶黄素占总类胡萝卜素的6.0%，都为游离态。
对比实施例2与实施例2的区别在于此对比实施例中未加入助催化剂，为了使反应完全，在加大了碱量的情况下，反应温度在95℃时反应时间延长到12.5hr，在此温度下较长时间的保温过程中，部分类胡萝卜素发生降解，这一点从终产品的收率可以看出。从实验结果可以看出，助催化剂有助于降低异构化反应的温度，缩短反应时间，提高叶黄素的转化率。
实施例3
称取45g叶黄素晶体（总类胡萝卜素含量为88.5%，其中，叶黄素和玉米黄素占总类胡萝卜素的比例分别为91.5%和7.3%，其余为少量的其它类胡萝卜素），与350ml乙二醇和200ml丙二醇混合，在60℃下搅拌溶解，加入1.13g钯炭，滴加6.0mol/L的甲醇钾溶液80.0ml，碱催化剂在50min内滴加完成，氮气保护并在75℃条件下保温反应2.0hr后测得反应液中玉米黄素占整个类胡萝卜素比例的88.7%。将反应液温度降低至70℃，在搅拌情况下加入1000ml去离子水和600ml食用级乙醇组成的混合液稀释反应液，将稀释后的反应液抽滤的方式分离，滤饼用1200ml乙酸乙酯溶解后过滤，回收钯炭，在滤液中加入500ml去离子水和400ml食用级乙醇组成的混合液，搅拌0.5hr后抽滤，在抽滤过程中滤饼用水和乙醇的混合液淋洗，直至洗出液接近无色，真空干燥滤出物得34.9g桔红色结晶。经紫外可见分光光度法分析此结晶中总类胡萝卜素含量为86.2%，总类胡萝卜素收率为75.7%，其中玉米黄素占总类胡萝卜素的90.1%，叶黄素占总类胡萝卜素的8.4%。

Claims (10)

  1. 一种高含量玉米黄素的制备方法，该方法以叶黄素晶体或其脂肪酸酯为反应原料，利用异构化反应得到玉米黄素，其特征在于，所述的异构化反应使用由有机碱催化剂和助催化剂组成的混合催化剂，所述的助催化剂为钯炭。
  2. 根据权利要求1所述的高含量玉米黄素的制备方法，其特征在于，该方法的具体步骤如下：
    ①在有机溶剂中加入反应原料叶黄素晶体或其脂肪酸酯，在60-95℃温度下充分溶解；
    ②向①步得到的混合液中加入有机碱催化剂和助催化剂进行异构化反应，有机碱催化剂采用滴加的方式加入；
    ③在氮气保护下进行保温反应；
    ④用去离子水和乙醇的混合液稀释③步得到的反应液，并采用常规分离方法分离得到晶体；
    ⑤将④步得到的晶体溶于乙酸乙酯中，过滤；
    ⑥向⑤步得到的滤液中加入去离子水和乙醇的混合液，搅拌后过滤；
    ⑦真空干燥⑥步得到的结晶，即得玉米黄素晶体。
  3. 根据权利要求1或2所述的高含量玉米黄素的制备方法，其特征在于，所述的有机碱催化剂为甲醇钠、乙醇钠、甲醇钾或乙醇钾。
  4. 根据权利要求1或2所述的高含量玉米黄素的制备方法，其特征在于，所述有机碱催化剂的加入量为反应原料摩尔量的4-8倍。
  5. 根据权利要求1或2所述的高含量玉米黄素的制备方法，其特征在于，所述助催化剂的加入量为反应原料质量的0.1-5.0%。
  6. 根据权利要求1或2所述的高含量玉米黄素的制备方法，其特征在于所述的有机溶剂选用乙二醇、丙二醇或前两者的混合溶剂。
  7. 根据权利要求1或2所述的高含量玉米黄素的制备方法，其特征在于，所述异构化反应的温度在60-95℃之间。
  8. 根据权利要求7所述的高含量玉米黄素的制备方法，其特征在于，所述的异构化反应的温度在60-75℃之间。
  9. 根据权利要求1或2所述的高含量玉米黄素的制备方法，其特征在于，所述异构化反应的时间为2.0-8.0h。
  10. 根据权利要求1所述的高含量玉米黄素的制备方法，其特征在于，所用的反应原料叶黄素脂肪酸酯或叶黄素晶体来源于万寿菊花中，前者由万寿菊油树脂精制得到，后者是通过对万寿菊油树脂进行皂化处理后得到的晶体。
PCT/CN2013/079069 2012-07-12 2013-07-09 一种高含量玉米黄素的制备方法 WO2014008851A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US14/412,170 US9376357B2 (en) 2012-07-12 2013-07-09 Method for preparing high-content zeaxanthin
EP13816427.2A EP2873659B1 (en) 2012-07-12 2013-07-09 Method for preparing high level of zeaxanthin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210241214.9A CN102746203B (zh) 2012-07-12 2012-07-12 一种高含量玉米黄素的制备方法
CN201210241214.9 2012-07-12

Publications (1)

Publication Number Publication Date
WO2014008851A1 true WO2014008851A1 (zh) 2014-01-16

Family

ID=47026760

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/079069 WO2014008851A1 (zh) 2012-07-12 2013-07-09 一种高含量玉米黄素的制备方法

Country Status (4)

Country Link
US (1) US9376357B2 (zh)
EP (1) EP2873659B1 (zh)
CN (1) CN102746203B (zh)
WO (1) WO2014008851A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105618135B (zh) * 2016-01-10 2018-01-16 沧州普瑞东方科技有限公司 一种手性cbs催化剂的制备方法
CN114957072A (zh) * 2021-02-25 2022-08-30 内蒙古昶辉生物科技股份有限公司 由万寿菊油膏制备玉米黄质以及玉米黄质微丸的方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1114309A (zh) * 1994-03-25 1996-01-03 武田药品工业株式会社 制备胡萝卜素类化合物的方法
WO1996002594A2 (en) 1994-07-20 1996-02-01 Industrial Organica, S.A. De C.V. Process for the isomerization of lutein
US5780639A (en) 1997-08-14 1998-07-14 Mona Industries, Inc. Silicone monomers and oligomers having a carboxyl functional group thereon
CN1082507C (zh) 1996-10-04 2002-04-10 霍夫曼-拉罗奇有限公司 叶黄素的转化方法
US20060088631A1 (en) * 2004-10-26 2006-04-27 Frederick Khachik Process for the preparation of alpha- and beta-cryptoxanthin
CN101153017A (zh) * 2006-09-28 2008-04-02 浙江医药股份有限公司新昌制药厂 高含量食用级玉米黄质的制备方法
CN101182302B (zh) 2007-12-14 2010-08-18 大连医诺生物有限公司 含玉米黄质的组合物的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254701A (en) * 1991-05-20 1993-10-19 Eastman Kodak Company Process for the production of mixtures of 2-hydroxytetrahydrofuran and 4-hydroxybutanal
US5681969A (en) * 1996-05-03 1997-10-28 Eastman Chemical Company Continuous process for the conversion of 2,5-dihydrofuran to 2,3-dihydrofuran
US5998678A (en) * 1997-02-25 1999-12-07 Investigaciones Quimicas Y Farmaceutics, S.A. Process for preparing carotenoid pigments
IN189750B (zh) * 1997-10-31 2003-04-19 Bioquimex Reka S A De C V
US6818798B1 (en) * 2000-05-03 2004-11-16 University Of Maryland, College Park Process for making a (3R,3′R)-zeaxanthin precursor
US6420614B1 (en) * 2000-10-10 2002-07-16 Industrial Organica, S.A. De C.V. Process for obtaining 3′-epilutein
CN101473893A (zh) * 2008-11-19 2009-07-08 黑龙江省嘉宝生物技术开发有限公司 一种含叶黄素和玉米黄素的饲料添加剂及制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1114309A (zh) * 1994-03-25 1996-01-03 武田药品工业株式会社 制备胡萝卜素类化合物的方法
WO1996002594A2 (en) 1994-07-20 1996-02-01 Industrial Organica, S.A. De C.V. Process for the isomerization of lutein
CN1082507C (zh) 1996-10-04 2002-04-10 霍夫曼-拉罗奇有限公司 叶黄素的转化方法
US5780639A (en) 1997-08-14 1998-07-14 Mona Industries, Inc. Silicone monomers and oligomers having a carboxyl functional group thereon
US20060088631A1 (en) * 2004-10-26 2006-04-27 Frederick Khachik Process for the preparation of alpha- and beta-cryptoxanthin
CN101153017A (zh) * 2006-09-28 2008-04-02 浙江医药股份有限公司新昌制药厂 高含量食用级玉米黄质的制备方法
US7485738B2 (en) 2006-09-28 2009-02-03 Zhejiang Medicine Co., Ltd., Xinchang Pharmaceutical Factory Method for preparing high-content food-grade zeaxanthin
CN101153017B (zh) 2006-09-28 2010-12-22 浙江医药股份有限公司新昌制药厂 高含量食用级玉米黄质的制备方法
CN101182302B (zh) 2007-12-14 2010-08-18 大连医诺生物有限公司 含玉米黄质的组合物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2873659A4

Also Published As

Publication number Publication date
CN102746203B (zh) 2014-08-27
US9376357B2 (en) 2016-06-28
EP2873659A4 (en) 2015-08-05
CN102746203A (zh) 2012-10-24
US20150175510A1 (en) 2015-06-25
EP2873659A1 (en) 2015-05-20
EP2873659B1 (en) 2016-10-05

Similar Documents

Publication Publication Date Title
KR100782434B1 (ko) 올레오 수지로부터 안정한 상업 등급의 루테인 페이스트를분리, 정제 및 제조하는 방법
EP1911742B1 (en) Preparation method for high-content food-grade zeaxanthin
US20050038271A1 (en) Process for extraction and purification of lutein, zeaxanthin and rare carotenoids from marigold flowers and plants
Hua et al. Stereoselective additions of chiral. alpha.-sulfinyl ketimine anions to ene esters. Asymmetric syntheses of indolo [2, 3-a] quinolizidine and yohimban alkaloids
WO2012159446A1 (zh) 一种发酵法生产天然β-胡萝卜素的方法和应用
CN103180306B (zh) 鲁比前列酮的制备方法
CN107602651A (zh) 一种去氢表雄酮中间体及去氢表雄酮的制备方法
WO2014008851A1 (zh) 一种高含量玉米黄素的制备方法
CN101386879A (zh) 一种制备虾青素酯的方法
CN104447469B (zh) 叶黄素浸膏高效制备玉米黄质的方法
CN116970018B (zh) 麦角甾醇制备提取方法
WO2014186683A1 (en) PROCESS FOR A DIRECT ONE-POT TRANSFORMATION OF LUTEIN TO β-CRYPTOXANTHIN VIA ITS ACETATE ESTER
CN100484930C (zh) 一种吗替麦考酚酯的制备方法
EP1480932B1 (en) Method for production of beta-cryptoxanthin and alpha-cryptoxanthin from commercially available lutein
CN112778103B (zh) 一种氯苯甘油醚的脱色方法
CN102887848A (zh) 一种催化皂化万寿菊油膏制备叶黄素晶体的方法
JP2002223787A (ja) ルテインおよび高純度ルテインの取得方法
CN111116319A (zh) 一种高纯度1,6-二羟基萘的合成精制方法
US3904599A (en) Cardenolide-3-(2'-desoxy-glycosides)+0 and process for their manufacture
CN1176159C (zh) 高纯度番茄红素的制备方法
CN112679493A (zh) 一种长春胺的制备方法
CN109761829A (zh) 一种高手性纯度依非韦伦中间体的制备方法
CN101830938B (zh) N-乙酰-d-氨基葡萄糖的制备方法
CN114195761B (zh) 一种高纯度西他沙星3/2水合物的制备方法
CN114195845A (zh) 一种19-去甲-4-雄烯二酮的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13816427

Country of ref document: EP

Kind code of ref document: A1

REEP Request for entry into the european phase

Ref document number: 2013816427

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2013816427

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 14412170

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE