WO2022056827A1 - 一种β-胡萝卜素的制备方法 - Google Patents

一种β-胡萝卜素的制备方法 Download PDF

Info

Publication number
WO2022056827A1
WO2022056827A1 PCT/CN2020/116157 CN2020116157W WO2022056827A1 WO 2022056827 A1 WO2022056827 A1 WO 2022056827A1 CN 2020116157 W CN2020116157 W CN 2020116157W WO 2022056827 A1 WO2022056827 A1 WO 2022056827A1
Authority
WO
WIPO (PCT)
Prior art keywords
carotene
vitamin
preparation
hydrogen peroxide
organic phosphine
Prior art date
Application number
PCT/CN2020/116157
Other languages
English (en)
French (fr)
Inventor
黄聿魏
叶艳秋
谢德刚
赵家宇
Original Assignee
厦门金达威维生素有限公司
厦门金达威集团股份有限公司
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 厦门金达威维生素有限公司, 厦门金达威集团股份有限公司 filed Critical 厦门金达威维生素有限公司
Priority to CN202080002023.XA priority Critical patent/CN112262126B/zh
Priority to PCT/CN2020/116157 priority patent/WO2022056827A1/zh
Publication of WO2022056827A1 publication Critical patent/WO2022056827A1/zh

Links

Classifications

    • 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

Definitions

  • the invention belongs to the field of compound preparation, in particular to a preparation method of beta-carotene.
  • ⁇ -Carotene is a source of vitamin A, which can be used in medicine, food, cosmetics, feed additives, and dye industries, and has a good market application prospect.
  • preparation methods of beta-carotene disclosed at present The process of synthesizing beta-carotene with vitamin A and its derivatives as starting materials mainly includes Wittig condensation reaction and oxidative coupling.
  • the specific process of the Wittig condensation reaction is an organic phosphine salt obtained by reacting vitamin A alcohol or its derivative with triarylphosphine, and then the organic phosphine salt is further condensed with vitamin A aldehyde through Wittig reaction to obtain ⁇ -carotene,
  • the specific reaction process is shown in formula (1). Because the Wittig reaction requires anhydrous and oxygen-free conditions, and the conditions are harsh, and the chemical properties of vitamin A aldehyde are unstable, it is not easy to prepare industrially.
  • the specific process of the oxidative coupling is to react vitamin A alcohol or its derivative with triarylphosphine to obtain an organic phosphine salt, and then two molecules of the above-mentioned organic phosphine salt are subjected to oxidative coupling to obtain ⁇ -carotene.
  • the specific reaction process is As shown in formula (2). Due to the symmetrical structure of ⁇ -carotene, the process route for preparing ⁇ -carotene by oxidative coupling reaction between two molecules of organic phosphine salts is more concise.
  • ⁇ -carotene is obtained by oxidative coupling reaction of an organic phosphonium salt of vitamin A alcohol or its derivative in the presence of an oxidant, wherein the oxidant used is hypochlorite, chlorate, hydrogen peroxide, Sodium percarbonate, oxygen or air.
  • the reaction yields of ⁇ -carotene were all low.
  • the purpose of the invention is to provide a preparation method capable of improving the yield of ⁇ -carotene in order to overcome the defect of low reaction yield of ⁇ -carotene obtained by the existing method.
  • the reasons for the low reaction yield are mainly due to the following two points: one is that under alkaline conditions, the In the presence of high-valent metal ions, the hydrogen peroxide will decompose uncontrollably. Apart from a part of the added hydrogen peroxide that participates in the reaction, the other part is uncontrollably decomposed, resulting in an uncontrollable reaction; the second is because vitamin A organic phosphine Salt has more side reactions under the oxidation of hydrogen peroxide.
  • the inventors of the present invention found that by adding nano-silver colloids to the hydrogen peroxide oxidative coupling reaction system of vitamin A organic phosphine salts, the nano-silver colloids simultaneously act as stabilizers and catalysts, which can not only improve the The stability of hydrogen peroxide solves the problem of uncontrollable decomposition under alkaline conditions, and can also reduce the probability of side reactions and improve the selectivity of the oxidation of vitamin A organic phosphine salt to beta-carotene. Based on this, the present invention has been completed.
  • the present invention provides a preparation method of ⁇ -carotene, which comprises: oxidative coupling of vitamin A organic phosphine salt represented by formula (1) and hydrogen peroxide in an alkaline system containing nano-silver colloids reaction;
  • R 1 , R 2 and R 3 are each independently an aliphatic group, an alicyclic group or an aromatic group, preferably each independently a C 1 -C 10 substituted or unsubstituted alkane base, C 3 -C 10 substituted or unsubstituted cycloalkane group or C 6 -C 10 substituted or unsubstituted aryl group;
  • X is an organic or inorganic strong acid group, preferably halogen, sulfate, hydrogen sulfate, phosphoric acid root, tetrafluoroborate, acetate, tosylate or besylate.
  • the method of the oxidative coupling reaction is as follows: dissolving vitamin A organic phosphine salt and alkali in a solvent to form a mixed solution, then dropping the mixture of nano-silver colloid and hydrogen peroxide into the mixed solution, stirring until oxidation The coupling reaction is complete.
  • the mass concentration of the nano-silver colloid in the mixed solution of the nano-silver colloid and hydrogen peroxide is 0.01-0.1%.
  • the particle size of the nano-silver colloid is 2-100 nm.
  • the molar ratio of the vitamin A organic phosphine salt to the alkali is 1:(1-10), preferably 1:(2-4).
  • the molar ratio of the vitamin A organic phosphine salt to hydrogen peroxide is 1:(1-10), preferably 1:(2-4).
  • the solvent is selected from at least one of water, methanol and ethanol, preferably water.
  • the base is selected from at least one of ammonia, ammonium carbonate, alkali metal carbonate, alkali metal hydroxide, alkaline earth metal hydroxide and alkali metal alcoholate.
  • alkali metal carbonate is sodium carbonate and/or potassium carbonate.
  • alkali metal hydroxide is sodium hydroxide and/or potassium hydroxide.
  • alkaline earth metal hydroxide is barium hydroxide.
  • the alkali metal alcoholate is selected from at least one of sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
  • the conditions for the oxidative coupling reaction include a reaction temperature of -20°C to 60°C, preferably 0°C to 30°C, and a reaction time of 0.5 to 6 hours, preferably 1 to 2 hours.
  • the preparation method of ⁇ -carotene provided by the present invention further comprises successively filtering, washing with water, alcohol washing and recrystallizing the oxidative coupling reaction product to obtain ⁇ -carotene crystals.
  • the invention uses nano-silver colloid as stabilizer and catalyst, which can significantly improve the selectivity and yield of ⁇ -carotene.
  • the beta-carotene prepared by the method provided by the invention can be used in the fields of medicine, food, cosmetics, feed additives, dyes and the like.
  • the inventors of the present invention found that when the nano-silver colloid is mixed and added with hydrogen peroxide, the pre-stabilization of hydrogen peroxide can be achieved before adding the oxidative coupling reaction system, and whether it is during the addition process or in the hydrogen peroxide.
  • the oxidative coupling reaction a large number of nano-silver colloids are closely distributed around the hydrogen peroxide, which can protect it from decomposition, thus ensuring the controllable progress of the entire oxidative coupling reaction process and improving the ⁇ -carotene. selectivity and yield.
  • the vitamin A organic phosphine salt has the structure shown in formula (1):
  • R 1 , R 2 and R 3 are each independently an aliphatic group, an alicyclic group or an aromatic group, preferably each independently a C 1 -C 10 substituted or unsubstituted alkane C 3 -C 10 substituted or unsubstituted cycloalkane group or C 6 -C 10 substituted or unsubstituted aryl group, more preferably each independently a C 1 -C 5 substituted or unsubstituted alkyl group, C 3 ⁇ C 8 substituted or unsubstituted cycloalkane group or C 6 ⁇ C 10 substituted or unsubstituted aryl group;
  • X is an organic or inorganic strong acid group, preferably halogen, sulfate, hydrogen sulfate, phosphate, tetrafluoro Borate, acetate, tosylate or benzenesulfonate, more preferably chlorine, bromine or hydrogen sulfate.
  • C 1 -C 5 substituted or unsubstituted alkyl groups include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl base, n-pentyl, isopentyl, tert-amyl, neopentyl, etc.
  • Specific examples of the C 3 -C 8 substituted or unsubstituted cycloalkane groups include, but are not limited to, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane and the like.
  • C 6 -C 10 substituted or unsubstituted aryl groups include, but are not limited to: phenyl, o-tolyl, m-tolyl, p-tolyl, o-ethylphenyl, m-ethylphenyl, p-ethylbenzene base, naphthyl, etc.
  • R 1 , R 2 and R 3 are all phenyl, and X is hydrogen sulfate.
  • R 1 , R 2 and R 3 are all cyclohexyl, and X is bromine.
  • R 1 , R 2 and R 3 are all tolyl, and X is hydrogen sulfate.
  • R 1 , R 2 and R 3 are all phenyl and X is chlorine.
  • R 1 , R 2 and R 3 are all n-butyl groups, and X is hydrogen bromide.
  • R 1 , R 2 and R 3 are all phenyl and X is sulfate.
  • R 1 , R 2 and R 3 are all phenyl, and X is besylate.
  • the vitamin A organic phosphine salt can be obtained commercially, and can also be prepared according to various existing methods. For example, it can be obtained by reacting vitamin A alcohol and/or vitamin A fatty acid ester with organic phosphine. The specific reaction process and reaction The conditions are well known in the art and will not be repeated here.
  • the nano-silver colloid acts as a stabilizer and a catalyst at the same time.
  • it can promote the stable existence of hydrogen peroxide under alkaline conditions to solve the problem that the decomposition of hydrogen peroxide under alkaline conditions is uncontrollable and causes the oxidative coupling reaction to fail.
  • it can promote the selectivity of the oxidation of vitamin A organic phosphine salt to ⁇ -carrot and reduce the occurrence of side reactions.
  • the particle size of the nano-silver colloid is 1-100 nm, preferably 2-100 nm.
  • the nano-silver colloid can be added alone or mixed with vitamin A organic phosphine salt, hydrogen peroxide or solvent, and is especially preferably added with hydrogen peroxide.
  • the oxidative coupling reaction is performed by: dissolving vitamin A organic phosphine salt and alkali in a solvent to form a mixed solution, and then adding a mixture of nano-silver colloid and hydrogen peroxide into the mixed solution stirring until the oxidative coupling reaction is complete.
  • the molar ratio of the vitamin A organic phosphine salt to the alkali is preferably 1:(1-10), more preferably 1:(2-4).
  • the molar ratio of the vitamin A organic phosphine salt to hydrogen peroxide is preferably 1:(1-10), more preferably 1:(2-4).
  • the mass concentration of the nano-silver colloid in the mixed solution of the nano-silver colloid and hydrogen peroxide is preferably 0.01-0.1%.
  • the solvent is an inert liquid reaction medium capable of dissolving vitamin A organic phosphine salt, alkali and hydrogen peroxide, and can be water and/or an organic solvent that is miscible with water, specifically water, C 1 -C 6 alcohol and the like.
  • specific examples of the C 1 -C 6 alcohol include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, 1-butanol, 1-pentanol, 1-hexanol, and the like.
  • the solvent is preferably at least one selected from the group consisting of water, methanol and ethanol, and is particularly preferably water.
  • the base may be selected from at least one of ammonia, ammonium carbonate, alkali metal carbonates, alkali metal hydroxides, alkaline earth metal hydroxides and alkali metal alcoholates.
  • the alkali metal carbonate can be specifically sodium carbonate and/or potassium carbonate.
  • the alkali metal hydroxide can be specifically sodium hydroxide and/or potassium hydroxide.
  • the alkaline earth metal hydroxide may specifically be barium hydroxide.
  • the alkali metal alcoholate may be selected from at least one of sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
  • the conditions of the oxidative coupling reaction are not particularly limited in the present invention, as long as two molecules of vitamin A organic phosphine salts can react to generate ⁇ -carotene.
  • the conditions of the oxidative coupling reaction include the reaction temperature.
  • the temperature is -20°C ⁇ 60°C, preferably 0°C ⁇ 30°C; the reaction time can be 0.5 ⁇ 6h, preferably 1 ⁇ 2h.
  • the hydrogen peroxide is added to the reaction system by dropwise addition, the temperature of the system during the dropwise addition also needs to be controlled within the above range, and the above reaction time refers to the time for continuing the reaction after the dropwise addition is completed.
  • the preparation method of ⁇ -carotene provided by the present invention further comprises sequentially filtering, washing with water, alcohol washing and recrystallization of the oxidative coupling reaction product to obtain high-purity ⁇ -carotene crystals.
  • the temperatures of the water washing and alcohol washing are independently 50 to 70°C.
  • the alcohol used in the alcohol washing can be methanol and/or ethanol.
  • the solvent used in the recrystallization can be dichloromethane.
  • the ⁇ -carotene was prepared according to the method of Example 3, except that the nano-silver colloid was not added to the hydrogen peroxide, and the remaining conditions were the same as those of Example 3, and 2.87 g of ⁇ -carotene crystals were obtained. According to the test of "GB8821-2011", the content of ⁇ -carotene was 92.5% (w%), and the total yield was 39.5% (based on phosphonium salt yield).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明属于化合物制备领域，具体涉及一种β-胡萝卜素的制备方法，包括：将式(1)所示的维生素A有机膦盐与双氧水在含有纳米银胶体的碱性体系中进行氧化偶联反应；R1、R2和R3各自独立地为脂肪族基团、脂环族基团或芳香族基团；X为有机或无机强酸基团。本发明提供的β-胡萝卜素的制备方法以纳米银胶体作为稳定剂和催化剂，能够显著提高β-胡萝卜素的收率。

Description

一种β-胡萝卜素的制备方法 技术领域
本发明属于化合物制备领域，具体涉及一种β-胡萝卜素的制备方法。
背景技术
β-胡萝卜素是维生素A源物质，可用于医药、食品、化妆品、饲料添加剂、染料行业，具有很好的市场应用前景。目前公开的β-胡萝卜素的制备方法很多，以维生素A及其衍生物为起始原料合成β-胡萝卜素的工艺主要包括Wittig缩合反应以及氧化偶联。
所述Wittig缩合反应的具体过程为将维生素A醇或其衍生物与三芳香基膦反应得到的有机膦盐，之后将该有机膦盐进一步与维生素A醛通过Wittig反应缩合得到β-胡萝卜素，具体反应过程如式(1)所示。由于Wittig反应要求无水无氧，条件苛刻，且维生素A醛化学性质不稳定，不易工业制备。
Figure PCTCN2020116157-appb-000001
所述氧化偶联的具体过程为将维生素A醇或其衍生物与三芳香基膦反应得到有机膦盐，之后将两分子的上述有机膦盐通过氧化偶联得到β-胡萝卜素，具体反应过程如式(2)所示。由于β-胡萝卜素结构对称，因此两分子有机膦盐之间进行氧化偶联反应制备β-胡萝卜素的工艺路线更为简洁。
Figure PCTCN2020116157-appb-000002
CN101081829A和CN101041631A均公开了将维生素A醇或其衍生物的有机膦盐在氧化剂存在下通过氧化偶联反应得到β-胡萝卜素，其中，采用的氧化剂为次氯酸盐、氯酸盐、双氧水、过碳酸钠、氧气或空气。然而，β-胡萝卜素的反应收率都较低。
发明内容
发明的目的是为了克服采用现有的方法所得β-胡萝卜素的反应收率较低的缺陷，而提供一种能够提高β-胡萝卜素收率的制备方法。
针对维生素A有机膦盐通过氧化偶联反应合成β-胡萝卜素的反应体系，当采用双氧水作为氧化剂时，造成反应收率较低的原因主要归于以下两点：一是因为在碱性条件下特别是在有高价金属离子存在的条件下，双氧水会发生不可控分解，加入的双氧水除了一部分参与反应之外，另一部分则被不可控地分解，从而导致反应不可控；二是因为维生素A有机膦盐在双氧水的氧化下副反应较多。本发明的发明人经过广泛和深入研究之后发现，在维生素A有机膦盐的双氧水氧化偶联反应体系中加入纳米银胶体，所述纳米银胶体同时起作稳定剂和催化剂的作用，不仅能够提高双氧水的稳定性，解决其在碱性条件下不可控分解的问题，而且还能够降低发生副反应的概率，提高维生素A有机膦盐氧化成β-胡萝卜素的选择性。基于此，完成了本发明。
具体地，本发明提供了一种β-胡萝卜素的制备方法，该方法包括：将式(1)所示的维生素A有机膦盐与双氧水在含有纳米银胶体的碱性体系中进行氧化偶联反应；
Figure PCTCN2020116157-appb-000003
式(1)中，R 1、R 2和R 3各自独立地为脂肪族基团、脂环族基团或芳香族基团，优选各自独立地为C 1～C 10的取代或非取代烷基、C 3～C 10的取代或非取代环烷烃基或C 6～C 10的取代或非取代芳基；X为有机或无机强酸基团，优选为卤素、硫酸根、硫酸氢根、磷酸根、四氟硼酸根、乙酸根、甲苯磺酸根或苯磺酸根。
进一步的，所述氧化偶联反应的方式为：将维生素A有机膦盐和碱溶于溶剂中形成混合溶液，之后将纳米银胶体和双氧水的混合液滴入所述混合溶液中，搅拌直至氧化偶联反应完全。
进一步的，所述纳米银胶体和双氧水的混合液中纳米银胶体的质量浓度为 0.01～0.1％。
进一步的，所述纳米银胶体的颗粒大小为2～100nm。
进一步的，所述维生素A有机膦盐与碱的摩尔比为1:(1～10)，优选为1:(2～4)。
进一步的，所述维生素A有机膦盐与双氧水的摩尔比为1:(1～10)，优选为1:(2～4)。
进一步的，所述溶剂选自水、甲醇和乙醇中的至少一种，优选为水。
进一步的，所述碱选自氨、碳酸铵、碱金属碳酸盐、碱金属氢氧化物、碱土金属氢氧化物和碱金属醇化物中的至少一种。
进一步的，所述碱金属碳酸盐为碳酸钠和/或碳酸钾。
进一步的，所述碱金属氢氧化物为氢氧化钠和/或氢氧化钾。
进一步的，所述碱土金属氢氧化物为氢氧化钡。
进一步的，所述碱金属醇化物选自甲醇钠、甲醇钾、乙醇钠和乙醇钾中的至少一种。
进一步的，所述氧化偶联反应的条件包括反应温度为-20℃～60℃、优选为0℃～30℃，反应时间为0.5～6h、优选为1～2h。
进一步的，本发明提供的β-胡萝卜素的制备方法还包括将氧化偶联反应产物依次进行过滤、水洗、醇洗和重结晶以获得β-胡萝卜素晶体。
本发明在采用双氧水氧化维生素A有机膦盐获得β-胡萝卜素的过程中，以纳米银胶体作为稳定剂和催化剂，能够显著提高β-胡萝卜素的选择性和收率。采用本发明提供的方法制备的β-胡萝卜素可用于医药、食品、化妆品、饲料添加剂、染料等领域。
本发明的发明人经过广泛和深入研究之后还发现，当将纳米银胶体与双氧水混合添加时，能够在加入氧化偶联反应体系之前实现对双氧水的预稳定，并且无论是在添加过程中还是在氧化偶联反应过程中，双氧水周围均紧密分布有大量纳米银胶体，能够对其起到保护作用以避免分解，从而确保了整个氧化偶联反应过程可控地进行，提高了β-胡萝卜素的选择率和收率。
具体实施方式
在本发明中，所述维生素A有机膦盐具有式(1)所示的结构：
Figure PCTCN2020116157-appb-000004
式(1)中，R 1、R 2和R 3各自独立地为脂肪族基团、脂环族基团或芳香族基团，优选各自独立地为C 1～C 10的取代或非取代烷基、C 3～C 10的取代或非取代环烷烃基或C 6～C 10的取代或非取代芳基，更优选各自独立地为C 1～C 5的取代或非取代烷基、C 3～C 8的取代或非取代环烷烃基或C 6～C 10的取代或非取代芳基；X为有机或无机强酸基团，优选为卤素、硫酸根、硫酸氢根、磷酸根、四氟硼酸根、乙酸根、甲苯磺酸根或苯磺酸根，更优选为氯、溴或硫酸氢根。
所述C 1～C 5的取代或非取代烷基的具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、新戊基等。所述C 3～C 8的取代或非取代环烷烃基的具体实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基等。所述C 6～C 10的取代或非取代芳基的具体实例包括但不限于：苯基、邻甲苯基、间甲苯基、对甲苯基、邻乙苯基、间乙苯基、对乙苯基、萘基等。
在一种具体实施方式中，R 1、R 2和R 3均为苯基，X为硫酸氢根。
在一种具体实施方式中，R 1、R 2和R 3均为环己基，X为溴。
在一种具体实施方式中，R 1、R 2和R 3均为甲苯基，X为硫酸氢根。
在一种具体实施方式中，R 1、R 2和R 3均为苯基，X为氯。
在一种具体实施方式中，R 1、R 2和R 3均为正丁基，X为溴氢酸根。
在一种具体实施方式中，R 1、R 2和R 3均为苯基，X为硫酸根。
在一种具体实施方式中，R 1、R 2和R 3均为苯基，X为苯磺酸根。
所述维生素A有机膦盐可以通过商购得到，也可以按照现有的各种方法制备得到，例如，可以将维生素A醇和/或维生素A脂肪酸酯与有机膦反应得到，具体反应过程和反应条件均为本领域公知，在此不作赘述。
在本发明中，所述纳米银胶体同时起作稳定剂和催化剂的作用，一方面能 够促使双氧水在碱性条件下稳定存在以解决双氧水在碱性条件下分解不可控而导致氧化偶联反应不可控的问题，另一方面能够促使维生素A有机膦盐氧化成β-胡萝卜的选择性，减少副反应的发生。所述纳米银胶体的颗粒大小为1～100nm，优选为2～100nm。所述纳米银胶体可以单独添加，也可以与维生素A有机膦盐、双氧水或者溶剂混合添加，特别优选与双氧水混合添加。
在一种优选实施方式中，所述氧化偶联反应的方式为：将维生素A有机膦盐和碱溶于溶剂中形成混合溶液，之后将纳米银胶体和双氧水的混合液滴入所述混合溶液中，搅拌直至氧化偶联反应完全。其中，所述维生素A有机膦盐与碱的摩尔比优选为1:(1～10)，更优选为1:(2～4)。所述维生素A有机膦盐与双氧水的摩尔比优选为1:(1～10)，更优选为1:(2～4)。所述纳米银胶体和双氧水的混合液中纳米银胶体的质量浓度优选为0.01～0.1％。
所述溶剂为能够溶解维生素A有机膦盐、碱和双氧水的惰性液态反应介质，可以为水和/或能与水互溶的有机溶剂，具体可以为水、C 1～C 6的醇等。其中，所述C 1～C 6的醇的具体实例包括但不限于：甲醇、乙醇、正丙醇、异丙醇、1-丁醇、1-戊醇、1-己醇等。从原料来源广泛性的角度考虑，所述溶剂优选选自水、甲醇和乙醇中的至少一种，特别优选为水。
所述碱可以选自氨、碳酸铵、碱金属碳酸盐、碱金属氢氧化物、碱土金属氢氧化物和碱金属醇化物中的至少一种。其中，所述碱金属碳酸盐具体可以为碳酸钠和/或碳酸钾。所述碱金属氢氧化物具体可以为氢氧化钠和/或氢氧化钾。所述碱土金属氢氧化物具体可以为氢氧化钡。所述碱金属醇化物具体可以选自甲醇钠、甲醇钾、乙醇钠和乙醇钾中的至少一种。
本发明对所述氧化偶联反应的条件没有特别的限定，只要能够使得两分子的维生素A有机膦盐反应生成β-胡萝卜素即可，例如，所述氧化偶联反应的条件包括反应温度可以为-20℃～60℃，优选为0℃～30℃；反应时间可以为0.5～6h，优选为1～2h。其中，当所述双氧水采用滴加的方式加入反应体系中时，滴加过程中体系的温度也需控制在以上范围之内，并且以上反应时间是指滴加完毕之后继续反应的时间。
本发明提供的β-胡萝卜素的制备方法还包括将氧化偶联反应产物依次进 行过滤、水洗、醇洗和重结晶以获得高纯β-胡萝卜素晶体。其中，所述水洗和醇洗的温度各自独立地为50～70℃。所述醇洗所采用的醇可以为甲醇和/或乙醇。所述重结晶所采用的溶剂可以为二氯甲烷。
以下将通过实施例对本发明进行详细描述。
实施例1
将500mL浓度为0.5mol/L的碳酸钾水溶液和250mL浓度为0.1mol/L的维生素A三苯基膦硫酸氢盐(具有式(1)所示的结构，R 1、R 2和R 3均为苯基，X为硫酸氢根)水溶液混合，在15℃下，滴加0.1mol双氧水(30％/w％)，双氧水中含有0.01％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在15℃反应1h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体4.48g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为98.9％(w％)，总收率为66.1％(基于膦盐收率
Figure PCTCN2020116157-appb-000005
Figure PCTCN2020116157-appb-000006
下同)。
实施例2
将500mL浓度为0.5mol/L的氢氧化钾水溶液和250mL浓度为0.1mol/L的维生素A三环己基溴氢酸盐(具有式(1)所示的结构，R 1、R 2和R 3均为环己基，X为溴)水溶液混合，在15℃下，滴加0.05mol双氧水(30％/w％)，双氧水中含有0.01％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在15℃反应2h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体3.66g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为98.0％(w％)，总收率为53.5％(基于膦盐收率)。
实施例3
将500mL浓度为0.25mol/L的碳酸钠水溶液和250mL浓度为0.1mol/L的维生素A三甲苯基膦硫酸氢盐(具有式(1)所示的结构，R 1、R 2和R 3均为甲苯基，X为硫酸氢根)水溶液混合。在15℃下，滴加0.125mol双氧水(30％/w％)，双氧水中含有0.1％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在15℃反应2h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体5.16g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为98.4％(w％)，总收率为75.6％(基于膦盐收率)。
实施例4
将500mL浓度为0.1mol/L的甲醇钠甲醇溶液和250mL浓度为0.1mol/L的维生素A三苯基膦盐酸盐(具有式(1)所示的结构，R 1、R 2和R 3均为苯基，X为氯)甲醇溶液混合。在-20℃下，滴加0.15mol双氧水(30％/w％)，双氧水中含有0.05％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在-20℃反应3h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体3.35g。根据《GB8821-2011》检测，β-胡萝卜素的含量为97.4％(w％)，总收率为48.6％(基于膦盐收率)。
实施例5
将500mL浓度为0.25mol/L的碳酸钾溶液(乙醇:水体积比＝1:1)和250mL浓度为0.1mol/L的维生素A三苯基膦盐酸盐(具有式(1)所示的结构，R 1、R 2和R 3均为苯基，X为氯)溶液(乙醇:水体积＝1:1)混合，在60℃下，滴加0.25mol双氧水(30％/w％)，双氧水中含有0.1％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在60℃反应2h。反应完成后，将沉淀物过滤出来， 用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体3.59g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为98.4％(w％)，总收率为52.6％(基于膦盐收率)。
实施例6
将500mL浓度为0.25mol/L的碳酸铵水溶液和250mL浓度为0.1mol/L的维生素A三丁基膦溴氢酸盐(具有式(1)所示的结构，R 1、R 2和R 3均为正丁基，X为溴)水溶液混合。在5℃下，滴加0.25mol双氧水(30％/w％)，双氧水中含有0.1％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在5℃反应4h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体3.53g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为98.1％(w％)，总收率为51.6％(基于膦盐收率)。
实施例7
将250mL浓度为0.1mol/L的碳酸铵水溶液和250mL浓度为0.1mol/L的维生素A三苯基硫酸盐(具有式(1)所示的结构，R 1、R 2和R 3均为苯基，X为硫酸根)水溶液混合。在0℃下，滴加0.05mol双氧水(30％/w％)，双氧水中含有0.1％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在5℃反应5h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体3.29g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为95.1％(w％)，总收率为46.6％(基于膦盐收率)。
实施例8
将500mL浓度为0.2mol/L的碳酸铵水溶液和250mL浓度为0.1mol/L的维生素A三苯基苯磺酸盐(具有式(1)所示的结构，R 1、R 2和R 3均为苯基， X为苯磺酸根)水溶液混合。在30℃下，滴加0.15mol双氧水(30％/w％)，双氧水中含有0.1％(w％)纳米银胶体(2～100nm)，滴加完毕后将反应温度保持在30℃反应6h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体3.08g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为92.1％(w％)，总收率为42.3％(基于膦盐收率)。
对比例1
在5℃下，往250mL浓度为0.1mol/L的维生素A三苯基苯硫酸盐的甲醇:水＝1:1(w:w)溶液中同时滴加10％有效氯的次氯酸钠水溶液25.5g与饱和碳酸钠水溶液，饱和碳酸钠水溶液的量以保证反应结束后pH值在8-10之间，滴加完毕后将反应温度保持在5℃下反应4h。反应完成后，将沉淀物过滤出来，用65℃温水洗涤、过滤，再用甲醇在50～60℃洗涤处理以除去三甲苯基氧膦，之后将β-胡萝卜素溶解到二氯甲烷中，浓缩、结晶干燥得β-胡萝卜素晶体2.75g。根据《GB 8821-2011》检测，β-胡萝卜素的含量为98.2％(w％)，总收率为40.2％(基于膦盐收率)。
对比例2
按照实施例3的方法制备β-胡萝卜素，不同的是，未在双氧水中加入纳米银胶体，其余条件与实施例3相同，得到β-胡萝卜素晶体2.87g。根据《GB8821-2011》检测，β-胡萝卜素的含量为92.5％(w％)，总收率为39.5％(基于膦盐收率)。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (13)

  1. 一种β-胡萝卜素的制备方法，其特征在于，该方法包括：将式(1)所示的维生素A有机膦盐和碱溶于溶剂中形成混合溶液，之后将纳米银胶体和双氧水的混合液滴入所述混合溶液中，搅拌直至氧化偶联反应完全；
    Figure PCTCN2020116157-appb-100001
    式(1)中，R 1、R 2和R 3各自独立地为C 1～C 10的取代或非取代烷基、C 3～C 10的取代或非取代环烷烃基或C 6～C 10的取代或非取代芳基；X为卤素、硫酸根、硫酸氢根、磷酸根、四氟硼酸根、乙酸根、甲苯磺酸根或苯磺酸根。
  2. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述纳米银胶体和双氧水的混合液中纳米银胶体的质量浓度为0.01～0.1％。
  3. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述纳米银胶体的颗粒大小为2～100nm。
  4. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述维生素A有机膦盐与碱的摩尔比为1:(1～10)。
  5. 根据权利要求4所述的β-胡萝卜素的制备方法，其特征在于，所述维生素A有机膦盐与碱的摩尔比为1:(2～4)。
  6. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述维生素A有机膦盐与双氧水的摩尔比为1:(1～10)。
  7. 根据权利要求6所述的β-胡萝卜素的制备方法，其特征在于，所述维生素A有机膦盐与双氧水的摩尔比为1:(2～4)。
  8. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述溶剂选自水、甲醇和乙醇中的至少一种。
  9. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述碱选自氨、碳酸铵、碱金属碳酸盐、碱金属氢氧化物、碱土金属氢氧化物和碱金属醇化物中的至少一种。
  10. 根据权利要求9所述的β-胡萝卜素的制备方法，其特征在于，所述碱金属碳酸盐为碳酸钠和/或碳酸钾；所述碱金属氢氧化物为氢氧化钠和/或氢氧化钾；所述碱土金属氢氧化物为氢氧化钡；所述碱金属醇化物选自甲醇钠、甲醇钾、乙醇钠和乙醇钾中的至少一种。
  11. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，所述氧化偶联反应的条件包括反应温度为-20℃～60℃，反应时间为0.5～6h。
  12. 根据权利要求11所述的β-胡萝卜素的制备方法，其特征在于，所述氧化偶联反应的条件包括反应温度为0℃～30℃，反应时间为1～2h。
  13. 根据权利要求1所述的β-胡萝卜素的制备方法，其特征在于，该方法还包括将氧化偶联反应产物依次进行过滤、水洗、醇洗和重结晶以获得β-胡萝卜素晶体。
PCT/CN2020/116157 2020-09-18 2020-09-18 一种β-胡萝卜素的制备方法 WO2022056827A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202080002023.XA CN112262126B (zh) 2020-09-18 2020-09-18 一种β-胡萝卜素的制备方法
PCT/CN2020/116157 WO2022056827A1 (zh) 2020-09-18 2020-09-18 一种β-胡萝卜素的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/116157 WO2022056827A1 (zh) 2020-09-18 2020-09-18 一种β-胡萝卜素的制备方法

Publications (1)

Publication Number Publication Date
WO2022056827A1 true WO2022056827A1 (zh) 2022-03-24

Family

ID=74225420

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/116157 WO2022056827A1 (zh) 2020-09-18 2020-09-18 一种β-胡萝卜素的制备方法

Country Status (2)

Country Link
CN (1) CN112262126B (zh)
WO (1) WO2022056827A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114890929A (zh) * 2022-04-11 2022-08-12 万华化学集团股份有限公司 一种β-胡萝卜素固体除磷纯化的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113651743B (zh) * 2021-08-30 2023-03-14 万华化学集团股份有限公司 一种β-胡萝卜素的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105855A (en) * 1975-02-12 1978-08-08 Basf Aktiengesellschaft Manufacture of symmetrical carotenoids
RU2225394C2 (ru) * 2000-12-22 2004-03-10 Общество С Ограниченной Ответственностью "Научно-Технологическая Фармацевтическая Фирма "Полисан" СПОСОБ ПОЛУЧЕНИЯ β-КАРОТИНА
CN101041631A (zh) * 2006-03-24 2007-09-26 浙江医药股份有限公司维生素厂 改进的β－胡萝卜素合成工艺
CN101081829A (zh) * 2006-06-02 2007-12-05 浙江医药股份有限公司新昌制药厂 β－胡萝卜素的合成工艺
CN108822015A (zh) * 2018-07-24 2018-11-16 厦门金达威集团股份有限公司 β-胡萝卜素的合成方法
CN110452147A (zh) * 2019-07-30 2019-11-15 万华化学集团股份有限公司 一种β-胡萝卜素的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105855A (en) * 1975-02-12 1978-08-08 Basf Aktiengesellschaft Manufacture of symmetrical carotenoids
RU2225394C2 (ru) * 2000-12-22 2004-03-10 Общество С Ограниченной Ответственностью "Научно-Технологическая Фармацевтическая Фирма "Полисан" СПОСОБ ПОЛУЧЕНИЯ β-КАРОТИНА
CN101041631A (zh) * 2006-03-24 2007-09-26 浙江医药股份有限公司维生素厂 改进的β－胡萝卜素合成工艺
CN101081829A (zh) * 2006-06-02 2007-12-05 浙江医药股份有限公司新昌制药厂 β－胡萝卜素的合成工艺
CN108822015A (zh) * 2018-07-24 2018-11-16 厦门金达威集团股份有限公司 β-胡萝卜素的合成方法
CN110452147A (zh) * 2019-07-30 2019-11-15 万华化学集团股份有限公司 一种β-胡萝卜素的制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114890929A (zh) * 2022-04-11 2022-08-12 万华化学集团股份有限公司 一种β-胡萝卜素固体除磷纯化的方法
CN114890929B (zh) * 2022-04-11 2024-02-02 万华化学集团股份有限公司 一种β-胡萝卜素固体除磷纯化的方法

Also Published As

Publication number Publication date
CN112262126B (zh) 2021-12-03
CN112262126A (zh) 2021-01-22

Similar Documents

Publication Publication Date Title
WO2022056827A1 (zh) 一种β-胡萝卜素的制备方法
JPS6042233B2 (ja) パラ−ニトロソジフエニルアミン塩酸塩の製造方法
CN112574101B (zh) 一种阻聚剂701的制备方法
US7763748B2 (en) Process for preparation of highly pure isotretinoin
EP0026154B1 (de) Verfahren zur Herstellung von 4,4'-Dinitrostilben-2,2'-disulfonsäure und deren Salzen und deren Verwendung
KR20150084165A (ko) 나파모스탯 메실레이트의 제조방법
CN109384698B (zh) 一种双萜烯类畜禽用抗生素的制备方法
CN109092310B (zh) 铜基催化剂及其制备方法和使用该催化剂制备醚化级乙二醇的方法
JP2512532B2 (ja) ４，４´−ジニトロスチルベン−２，２´−ジスルホン酸の製造方法
JP6209776B2 (ja) ４−アルカノイルオキシ−２−メチルブタン酸の製造方法
CN113861034A (zh) 2-氟-3-硝基苯甲酸的制备方法
CN113651743B (zh) 一种β-胡萝卜素的制备方法
CN112592286A (zh) 一种阿司匹林与碱性氨基酸的络合物的制备方法
JPH0782207A (ja) フルオレノンの製造方法およびそれに用いる酸化触媒
JP3996274B2 (ja) モノビニルアセチレンの製造方法
CN110885284A (zh) 一种2-溴丙二醛合成方法
CN113816884B (zh) 芳硫基萘酚、萘胺类化合物以及苯硫基吲哚类化合物的合成方法
CN114920670B (zh) 一种5-氯-2-氨基苯磺酰胺的制备方法
JP6166996B2 (ja) ヒドラジノアリールカルボン酸類の製造方法
CN113117753B (zh) 一种疏水性催化剂及其制备方法、β-紫罗兰酮的制备方法
KR20140051149A (ko) 메시톨의 산화 방법
CN107325026A (zh) 一种含有多个极性头的两性表面活性剂的制备方法
US3108123A (en) Process for the preparation of the 20-ketoxime of 16-dehydropregnenolone
CN114163323A (zh) 一种3-氧代环丁烷羧酸的合成方法
CN115304541A (zh) 一种3-氯-4-(2-吡啶基甲氧基)苯胺的制备方法

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: 20953685

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20953685

Country of ref document: EP

Kind code of ref document: A1