类胡萝卜素的制备方法 Preparation of carotenoids

类胡萝卜素是在自然界分布广泛的一类物质，具有很有用的性质。 Carotenoids are widely distributed in nature in a class of substances, having useful properties. 因而，人们对工业上能实现的合成方法很有兴趣。 Thus, people in the industry to achieve the synthesis of very interested. 维悌希反应在生成有关的多烯链方面起很重要的作用。 Wittig reaction plays a very important role in the generation related polyene chain. 这方面已被深入研究过并已在工业上应用。 This aspect has been thoroughly studied and has been used in the industry.

类胡萝卜素(中间产物和最终产品)，如胡萝卜素和叶黄素，是正常所需(全部E)的构型在大多数溶剂中溶解不良。 Carotenoids (intermediates and final products), such as carotene and lutein, are normally required (all E) configuration undesirable in most solvents dissolve. 芳烃和特别是卤代低级脂族烃，如氯仿和二氯甲烷，由于它们对类胡萝卜素溶解性能好，因而是类胡萝卜素的特定溶剂，并为此一直被优选地使用。 Aromatic hydrocarbons and especially halogenated lower aliphatic hydrocarbons, such as chloroform and dichloromethane, due to their good solubility of carotenoids, which is a particular solvent carotenoids, and to this end has been preferably used. 但是，现在使用这类溶剂逐渐减少，就已知的正当理由来说这是不利的。 However, the use of such solvents is now gradually reduced, it is known justification which is disadvantageous. 此外，类胡萝卜素具有典型的以非化学计算的量与溶剂相混合的性质。 Furthermore, carotenoids have a typical amount of solvent is mixed with a non-stoichiometric nature. 对于上述溶剂的残留量有严格的规定，而这规定不是处处都相同的。 For the residual amount of the solvent, there are strict rules, and this provision is not the same everywhere. 类胡萝卜素的热稳定性通常不高，因此难以除去已加入的微量溶剂，为了做到这一点就要遭受开始分解的损失。 Carotenoids thermal stability is usually not high, it is difficult to remove the traces of solvent have been added, in order to do this would suffer losses begin to decompose.

已知的工业方法可以分成以下几种：1)均相法，其中离析物和产品在全部反应中都留在溶液里；用沉淀法分离出最终产品，一般与异构化步骤有关。 Known industrial processes can be divided into the following categories: 1) homogeneous method, in which the educts and products are left in all the reactions in solution; the final product was isolated by precipitation, generally related to the isomerization step. 2)两相法，其中离析物溶解在加碱的有机溶剂中，但碱是在水溶液中。 2) two-phase method, wherein the educt is dissolved in an organic solvent in alkali, but the base is in an aqueous solution. 进行后处理时，把两相分开，有机相按1)法处理。 When the post-treatment, the phases were separated, the organic phase by a) treatment. 3)多相法，其中所用的离析物是非溶解状态。 3) multi-phase method, wherein the educts used in non-dissolved state. 但在反应过程中至少暂时形成过透明的溶液。 However, at least temporarily during the reaction a clear solution had formed. 另一方面，也有相反的实施方案，其中反应开始时是溶液而产物则在实际反应过程中或之后沉淀出来。 On the other hand, there are contrary embodiment, wherein when the start of the reaction solution and the product is then reacted during or after the actual precipitated.

维悌希反应通常是在碱性条件下或至少在一种与酸结合的物质存在下进行的。 Wittig reaction is usually carried out under alkaline conditions, or at least in the presence of an acid-binding substance carried. 维悌希反应常常产生一种当量的氧化三苯膦，它必需要从反应混合物中分出来。 Wittig reaction often produce an equivalent amount of triphenylphosphine oxide, it is necessary to carve out from the reaction mixture. 溶剂的选择对后处理有决定性的影响。 The choice of solvent has a decisive influence on the post-processing.

维悌希反应最常发生的主要副反应是鏻盐的水解：见以下的反应图解。 The main side effects Wittig reaction is the most frequently occurring phosphonium salt hydrolysis: See the following reaction scheme.

反应图解 Reaction Scheme

在此图解中，R1和R2，以及R4和R5分别每一个表示氢或一个任意取代的烷基，链烯基或芳基，如苯基，其中R1和R2中最多有一个，相应地R4和R5中也最多有一个代表氢；R3表示芳基，优选苯基，X-表示一个阴离子，如氯，溴，硫酸根或醋酸根。 In this illustration, R1 and R2, and R4 and R5 are each hydrogen or an optionally substituted alkyl, alkenyl or aryl, such as phenyl, wherein at most one of R1 and R2, R4 and correspondingly at most one of R5 also represents hydrogen; R3 represents an aryl group, preferably a phenyl group, X- represents an anion such as chloride, bromide, sulfate or acetate. 由于优选R3，(R3)3PO优选地表示氧化三苯膦。 Since the preferred R3, (R3) 3PO preferably represents triphenylphosphine oxide. 羰基化合物主要是醛(包括二醛)和酮，优选醛，这是类胡萝卜素化学领域的技术人员所熟知。 Carbonyl compound mainly aldehyde (including dialdehyde) and ketones, preferably aldehydes, which is a carotenoid chemistry skilled in the art. 2,7-二甲基-2,4,6-辛三烯-1,8-二醛(“C10-二醛”)是有代表性常用二醛的例子。 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde ("C10- dialdehyde") is a representative example of conventional dialdehyde. “鏻盐”也被认为是典型的用于合成类胡萝卜素的化合物，因而为本领域的技术人员所熟知。 "Phosphonium salts" is also considered a typical compound used in the synthesis of carotenoids, and thus known to those of skill in the art. 教科书“Carotenoids”，编者Otto Isler巴塞尔Birkhauser出版，1971，和“Carotenoids，卷2：合成”，编者G.Britton,S.Liaaen-Jensen和H.Pfander,巴塞尔-波士顿-柏林Birkhauser出版，1996，这两本书中有很多有关维悌希反应的实例。 Textbook "Carotenoids", published by Birkhauser Basel editor Otto Isler, 1971, and "Carotenoids, Volume 2: Synthesis", editor G.Britton, S.Liaaen-Jensen and H.Pfander, Basel - Boston - Berlin Birkhauser Publishing, 1996 these books, there are many relevant examples Wittig reaction.

为了避免上面提到并在图解中表述的副反应，碱的强度，水量和/或反应温度可以随反应基质的不同而有很大的变动范围。 In order to avoid side reactions mentioned and expressed in the illustration above, the strength of the base, water and / or the reaction temperature may vary with the reaction substrate and has a great range of variation. 因此，维悌希反应可以在水为溶剂中进行是已知的，而在其它情况下反应却必须严格地在无水条件下进行。 Thus, Wittig reaction can be carried out are known in the water as a solvent, and the reaction had to be strictly carried out under anhydrous conditions in other cases. 水解的速度随碱强度的增加和/或温度的提高而加快，因而优选的温度为-30℃至室温；但另一方面有些情况下，温度较高更为有利。 Hydrolysis rate increases with increasing alkali strength and / or increasing temperature to accelerate, and thus preferred temperature is -30 ℃ to room temperature; the other hand, in some cases, a higher temperature is more advantageous. 此外，取决于所用的基质，类胡萝卜素的异构化反应一般是在较高温度下进行的。 In addition, depending on the substrate used, the isomerization reaction of carotenoids generally carried out at higher temperatures.

维悌希反应实际上可以在所有的非酸性溶剂中进行。 Wittig reaction can be carried out in virtually all of the non-acidic solvent. 甚至本身能和鏻盐反应的丙酮有时也能成功地应用。 And even itself can sometimes acetone phosphonium salt can be successfully applied.

维悌希反应的上述已知实施方案有不利之处。 Embodiments of the known Wittig reaction has disadvantages. 从毒理学观点上最优选的溶剂是水、低级链烷醇、丙酮以及乙酸和其它有机酸的酯类。 From the toxicological point of view the most preferred solvents are water, lower alkanols, acetone and acetic acid and other esters of organic acids. 这类溶剂中，有机溶剂可以与水混合或不混合，通常溶解类胡萝卜素的能力很弱。 Such a solvent, the organic solvent may be mixed or not mixed with water, the ability to dissolve carotenoids generally weak. 因此常采用多相反应的方法。 Therefore, a method often used multiphase reactions. 一个实际的例子是欧洲专利公开(EP)0733619。 A practical example is the European Patent Publication (EP) 0733619. 这份EP中的这种局限性特别明显。 The EP of this limitation is particularly evident. 为了在用甲醇或乙醇时使离析物达到实际可行的浓度，两种组分必须预先加热溶解，而(作为一种手段)一种离析物必须用作异构物混合物。 With methanol or ethanol in order to make the time to reach practical educt concentration, the two components must be pre-heated and dissolved, and (as a means) one must be used as the educt mixture of isomers. 在此实例中，实际维悌希反应需要较低的温度，因而反应混合物又必须冷却下来。 In this example, the actual Wittig reaction requires a lower temperature, thus the reaction mixture must be cooled down again.

本发明的目的是提供一种在化学和工业上广泛应用的方法，能够生产结构差别很大的类胡萝卡素(不只是中间物，还有最终产品)，同时又避免了上述的问题。 Object of the present invention is to provide a method of chemically and widely used in industry, capable of producing very different structural classes Hu Radka pigment (not only the middle thereof, as well as the final product), while avoiding the problems described above. 本发明的方法包括在一极性的反应介质中进行生产类胡萝卜素的维悌希反应，同时使所有的反应物和生产出的类胡萝卜素都不显著地溶解在反应介质中。 The method of the present invention include production of carotenoids Wittig reaction in a polar reaction medium, while all of the reactants and to produce the carotenoid is not significantly dissolved in the reaction medium.

在有关的极性反应介质中特别适用的是极性的毒理学上无害的溶剂或溶剂的混合物，该溶剂或其混合物当水的加入量高达约30％(体积)时仍保持一个相，并且能很好地溶解生成的氧化三芳基膦。 In the relevant polar reaction medium is a mixture of particularly suitable innocuous solvents or polar solvents toxicologically, when the solvent is water or a mixture thereof added in an amount up to about 30% remains one phase (by volume), the and can well dissolve the formed oxidation triarylphosphine. 为此目的特别适用的是低级链烷醇和丙酮。 Particularly suitable for this purpose are lower alkanols and acetone. 它们可以单独用做溶剂，或彼此混合物或与水混合。 They can be used alone as a solvent, or a mixture with each other or mixed with water. 当采用这些特别适用的极性溶剂时，还可以再用其它的极性溶剂。 When these particularly suitable polar solvents, can also use other polar solvents. 这样的溶剂可以考虑的是有极性的酯类，特别是甲酸，乙酸或碳酸的甲酯或乙酯、甲基乙基酮、叔丁基甲基醚和二甲基甲酰胺。 Such a solvent may be considered are polar esters, in particular formic acid, acetic acid or carbonic acid methyl or ethyl esters, methyl ethyl ketone, tert-butyl methyl ether and dimethylformamide. 这类其它的极性溶剂也可以彼此混合使用。 Such other polar solvents may be mixed with one another. 在任何情况下，由上述几种极性溶剂组成的反应介质都必须是单相(均相)的。 In any case, by the reaction medium consisting of several polar solvent must be single phase (homogeneous) of.

进行本发明的方法时，无论是反应物，即有关的羰基化合物和相应的鏻盐，或生成的类胡萝卜素都不显著地溶于反应介质中，而反应生成的氧化三芳膦，特别是氧化三苯膦仍留在溶液中。 When the method of the present invention, both the reactants, i.e., the relevant carbonyl compounds and the corresponding phosphonium salt, or the resulting carotenoids are not significantly soluble in the reaction medium, and the reaction of an aryl phosphine oxide, in particular oxidation triphenylphosphine remain in solution. 实施本发明的方法得到了意外的好效率和高质量的最终产品。 The method of the present invention has been unexpectedly good efficiency and high quality end product.

在本发明的上述方法的范围内，“不显著地溶解”一词的含义是在反应的任何时间和后处理(包括精制)过程都未出现过透明的溶液。 Within the scope of the method of the present invention, "not significantly dissolve" in the meaning of the term is the reaction time and any post-treatment (including refining) process none appeared clear solution. 至少一种离析物、可能出现的中间产物、和所要求的最终产品是呈悬浮液或淤浆状。 At least one educt, intermediate products may occur, and the desired final product is a suspension or syrup. 随反应物或产品(类胡萝卜素)而定，其最多10％的重量是在溶液内。 With the reactant or product (carotenoid) may be, which is up to 10% by weight in the solution. 有代表性地，溶解的量仅占约0.5至约2％(重量)。 Representatively, the amount of dissolved only about 0.5 to about 2% (by weight). 在某些情况下，这一量甚至可能远小于0.5％(重量)。 In some cases, even this amount may be much less than 0.5% (by weight).

此外，“链烷醇”是指有1至6个碳原子特别是1-4个碳原子的链烷醇；例如甲醇、乙醇、正丙醇和异丙醇。 In addition, "alkanol" refers to 1 to 6 carbon atoms in particular alkanols having 1 to 4 carbon atoms; e.g., methanol, ethanol, n-propanol and isopropanol. 在本发明的范围内，几种这类醇彼此的混合物，或一种或更多的这种醇与丙酮的混合物，能够组成所要求的任何极性溶剂和混合物比率。 Within the scope of the present invention, each of a mixture of several such alcohols, or mixtures of one or more such alcohols and acetone, polar solvents and can be composed of any desired mixture ratio. 如果水也存在(在一种或多种低级链烷醇和/或丙酮的含水混合物中)，所述的极性有机溶剂之间的混合比可根据要求而变动。 If water is also present (in one or more lower alkanols and / or an aqueous mixture of acetone), a polar organic solvent, wherein the mixed ratio between the variation according to requirements. 在后者的情况下，水体积相对于含水有机溶剂的总体积而言一般不超过约30％，优选地不超过20％。 In the latter case, the volume of water relative to the total volume of the aqueous organic solvent in terms of generally not more than about 30%, preferably not more than 20%. 碳酸的甲酯或乙酯分别是二甲基或二乙基碳酸酯。 Carbonate of methyl or ethyl esters are dimethyl or diethyl carbonate. 在所考虑的极性溶剂中优选甲醇、乙醇、正丙醇和异丙醇。 In a polar solvent under consideration is preferably methanol, ethanol, n-propanol and isopropanol.

本发明的方法不仅适用于简单的(一个步骤)维悌希反应，而且也适用于两个当量的鏻盐和一种对称的二醛进行一步反应而不需要分离出中间产物。 The method of the present invention is applicable not only to a simple (one step) Wittig reaction, but also to two equivalents of a phosphonium salt and a symmetrical dialdehyde step reaction without the need to isolate the intermediate product. 这种过程在此称之为“双维悌希反应”。 This process is referred to herein as the "double Wittig reaction."

(双)维悌希的正常反应条件和反应温度、压力和时间等有关。 (Double) and other normal reaction conditions and Wittig reaction temperature, pressure and time related. 此外，反应完成后，反应混合物进行后处理分离出产品，产品的精制可以根据需要进行，这些都不需要特殊的手段。 In addition, after the completion of the reaction, the reaction mixture was treated product is separated, the product can be purified according to need, these do not require special means.

本发明的方法基本上适用于所有生产类胡萝卜素的维悌希反应，特别是适用于：由[5(4-羟基-2,6,6-三甲基-1-环己烯基)-3-甲基-2,4-戊二烯基]三苯基鏻氯化物和2,7-二甲基-2,4,6-辛三烯-1,8-二醛(C10-二醛)制备的玉米黄质；由[3,7,11-三甲基-十二烷基-2,4,6,10-四烯基]-三苯基鏻氯化物或醋酸化物，特别是(2E/Z,4E,6E,Z)异构物，和C10-二醛制备的番茄红素；由[3-甲基-5-(2,6,6-三甲基-环己烯基)-2,4-戊二烯基]三苯基鏻氯化物，特别是(2E,4E)异构物，和C10-醛制备的胡萝卜素；由[5-(2,6,6-三甲基-3-氧代-1-环己烯基)-3-甲基-2,4-戊二烯基]三苯基鏻氯化物和C10-双醛制备的鸡油菌黄质；由[5-(4-羟基-2,6,6-三甲基-3-氧代-1-环己烯基)-3-甲基-2,4-戊二烯基]三苯基鏻溴化物，特别是(2E,4E)异构物，和C10-二醛制备虾青素。 The method of the present invention is substantially applicable to all production of carotenoids Wittig reaction, in particular, in: from [5 (4-hydroxy-2,6,6-trimethyl-1-cyclohexen-yl) - 3-methyl-2,4-pentadienyl] triphenylphosphonium chloride and 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde (C10- dialdehyde ) produced zeaxanthin; from [3,7,11-trimethyl-- dodecyl -2,4,6,10- tetraene-yl] - triphenylphosphonium chloride or acetic acid compounds, especially ( 2E / Z, 4E, 6E, Z) isomer, and lycopene C10- dialdehyde prepared; from [3-methyl-5- (2,6,6-trimethyl - cyclohexenyl) 2,4-pentadienyl] triphenylphosphonium chloride, especially the (2E, 4E) isomers, and carotene C10- aldehyde prepared; from [5- (2,6,6-trimethoxy -3-oxo-1-cyclohexenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium chloride and canthaxanthin C10- dialdehyde prepared; by [ 5- (4-hydroxy-2,6,6-trimethyl-3-oxo-1-cyclohexenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium bromide , in particular (2E, 4E) isomers, and C10- dialdehyde prepared astaxanthin.

由[3-乙氧基羰基-J-2-烯基]三苯基鏻氯和/或溴化物，特别是(E)异构物，和C10-二醛制备的藏花酸二乙基酯；由3-羟基-12′-阿朴-β-胡萝卜-12′醛，特别是(R)-异构物，和[3-乙氧羰基-丁-2-烯基]三苯基鏻氯化物，特别是(E)异构物，制备的3-羟基-8′-阿朴-β-胡萝卜-8′-酸乙基酯；由[3-甲酰-丁-2-烯基]三苯基鏻氯化物的二甲基乙缩醛，特别是(E)异构物，和β-阿朴-8′-胡萝卜醛制备的β-阿朴-4′-胡萝卜醛；由[3-甲酰-2-丁烯基]三苯基鏻氯化物的二甲基乙缩醛，特别是(E)异构物，和β-阿朴-4′-胡萝卜醛制备的园红酵母醛；由[7-甲酰基-3,7-二甲基-辛-2,4,6-三烯基]三苯基鏻氯化物的二甲基乙缩醛和C10-二醛制备的二阿朴-4,4′-胡萝卜二醛；由β-阿朴-10′-胡萝卜醛和(1-2氧基羰基乙基)三苯基鏻溴化物制备的β-阿朴-8′-胡萝卜酸乙基酯；由β-阿朴-12′胡萝卜素醛和[3-2氧基羰基-丁-2-烯基]三苯基鏻氯化物，特别是(E)异构物，制备的β-阿朴-胡萝卜酸乙基酯；由β-阿朴-8′-胡萝卜醛和[7-乙氧基羰基-3,7-二甲基-2,4,6-庚三烯基]三苯基鏻氯化物经园红酵母素乙基酯制备的园红酵母素；以及由β-阿朴-12′-胡萝卜醛和[7-乙氧基羰基-3,7-二甲基-2,4,6-庚三烯基]三苯基鏻氯化物制备的链孢霉黄质。 From [3-ethoxycarbonyl--J-2- enyl] triphenylphosphonium chloride and / or bromide, especially the (E) isomer, and C10- dialdehyde prepared Crocein acid diethyl ester ; from 3-hydroxy -12'- apo -β- carrot -12 'aldehyde, in particular (R) - isomer, and [3-ethoxycarbonyl - 2-enyl] triphenylphosphonium chloro compounds, in particular (E) isomer, 3-hydroxy-8'-apo -β- prepared 8'acid ethyl ester carrot; by [3-formylamino - 2-enyl] three tetraphenylphosphonium chloride dimethyl acetal, in particular (E) isomer, and β- apo-4'-apo-8'-β- carrots carrots aldehyde aldehyde prepared; from [3- formyl-2-butenyl] triphenylphosphonium chloride in dimethyl acetal, especially garden Rhodotorula aldehyde (E) isomer, and β- apo-4'carrot aldehyde prepared; by [7-Formyl-3,7-dimethyl - oct-2,4,6-trienyl] triphenylphosphonium chloride prepared in dimethyl acetal and C10- dialdehyde bis apomorphine 4,4 carrot dialdehyde; β- apo-8'-apo carrot acid by β- -10'- carrot aldehyde and (1-2 butoxycarbonyl-ethyl) triphenylphosphonium bromide prepared ethyl ester; by β- apo -12 'carotenal and [3-2 oxycarbonyl - 2-enyl] triphenylphosphonium chloride, especially the (E) isomer, for preparing the β - A Park - carrot acid ethyl ester; by β- apo-8'carrot aldehyde and [7-ethoxycarbonyl-3,7-dimethyl-2,4,6-triene-yl] three Park Red Yeast tetraphenylphosphonium chloride by Park Red Yeast ethyl ester prepared; and by β- apo -12'- carrot aldehyde and [7- ethoxycarbonyl-3,7-dimethyl-2- 4,6 cycloheptatriene yl] triphenylphosphonium chloride prepared Neurospora crassa zeaxanthin.

本发明的方法具有很多实际的优点：-能使用浓度大得多的反应混合物(所用的溶剂比以前少)；对浓度的限制只是能否搅得动。 The method of the present invention has many practical advantages: - be able to use a much larger concentration of the reaction mixture (solvent used less than before); limitation on the concentration of the upsets can only move. 因而，空间/时间产率显著地提高了。 Thus, the space / time yield is significantly improved. 此外，溶剂的回收简化了，特别是可以省去加入增溶的溶剂，如四氢呋喃和二氯甲烷。 In addition, solvent recovery is simplified, in particular dispensed added solubilizing solvent, such as tetrahydrofuran and dichloromethane.

-不管反应是间歇的还是连续的，反应过程均得到了最优的简化。 - Regardless of the reaction is a batch or continuous reaction processes are simplified to obtain the optimal.

-完全避免了含卤的溶剂，并限制使用毒理学上可接受的极性溶剂，如优选的甲醇，乙醇，正-丙醇和异丙醇。 - Completely avoid the halogen-containing solvent, and to restrict the use of toxicologically-acceptable polar solvents, such as preferably methanol, ethanol, n - propanol, and isopropanol.

本发明的反应方法和经典学派的意见是矛盾的，根据经典学的意见是：只有在产品开始沉淀出来以前离析物已全部进入溶液中时，才能得到高收率和高质量产品。 Reaction method and the classical school of the invention is contradictory opinions, on the advice of the classic science is: only if the product begins to precipitate out of the past have all entered educt solution, in order to obtain high yields and high quality products. 对类胡萝卜素来说则更令人惊奇，因为这类物质的含量往往是非-化学计量的，并且类胡萝卜素的副产物由于共同的结构特点，不能用结晶的方法把它们分离开。 Carotenoids, it is even more surprising because the content of such substances are often non - stoichiometric, and the class-products because of carotenoids in common structural features, can not use the crystals to separate them.

很多商业上重要的类胡萝卜素的合成路线包含两种C15-维悌希盐和C10-二醛的双维悌希反应。 Many commercially important carotenoid synthesis route contains two double Wittig reaction Wittig salt C15- and C10- dialdehyde. 这种路线的不利之处主要是这类化合物在几乎所有的非-卤代溶剂中不能充分溶解。 The main disadvantage of this route are such compounds in almost all non - halogenated solvent can not be sufficiently dissolved. C25-中间产物在低级链烷醇中的溶解度也低而产品也总是难溶的。 C25- intermediate solubility in a lower alkanol in the product is low and is always insoluble. 因此出乎意料的是间接的多相反应过程，在收率和产品质量方面并未出现不利之处。 So unexpected was indirect heterogeneous reaction process, the yield and product quality does not appear disadvantages.

关于所述维悌希反应的多样性，很意外地是一个标准的反应过程竟如此成功地合成了各种结构的类胡萝卜素(由C20至C50)。 About the diversity of the Wittig reaction, very unexpectedly is a standard reaction process was so successful synthesis of carotenoids various structures (from C20 to C50).

本发明由以下的实施例说明：实施例1(全-E)-玉米黄素的制备32.88克(95.8％；2.03当量)[5-(4-羟基-2,6,6-三甲基-1-环己烯基)-3-甲基-2,4-戊二烯基]三苯基鏻氯化物和4.92克(1当量)2,7-二甲基-2,4,6-辛三烯-1,8-二醛(C10-二醛)和490毫升乙醇加至装有内部温度计，搅拌器和回流冷凝器的500毫升四颈磺化烧瓶中。 The present invention is described by the following examples: Example 1 (All -E) - Preparation of zeaxanthin 32.88 g (95.8%; 2.03 eq.) [5- (4-hydroxy-2,6,6-trimethyl - 1- cyclohexenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium chloride and 4.92 g (1 eq.) 2,7-dimethyl-2,4,6-oct- triene-1,8-dialdehyde (C10- dialdehyde) and 490 ml ethanol was added to equipped with an internal thermometer, a stirrer and a reflux condenser 500 ml four-necked sulfonation flask. 在搅拌下冷却至-10℃。 Cooled with stirring to -10 ℃. 将3.60克氢氧化钠在50毫升乙醇中的溶液在-10℃和搅拌下滴加至生成的黄色悬浮液中，反应混合物在-10℃下继续搅拌1小时。 The 3.60 g of sodium hydroxide in 50 ml of ethanol was stirred at -10 ℃ and added dropwise to the resulting yellow suspension, the reaction mixture was stirred at -10 ℃ 1 hour. 在30分钟内加热至内温约80℃，产品悬浮液在回流温度下再加热17小时。 Was heated over 30 minutes to an internal temperature of about 80 ℃, the product suspension was heated at reflux temperature for 17 hours. 然后冷却至0℃，再搅拌1小时，所得到的玉米黄素用吸滤分离。 Then cooled to 0 ℃, stirred for 1 hour, the resulting zeaxanthin isolated by suction filtration. 滤饼首先用乙醇洗涤，再用水洗除去中性盐。 The filter cake was washed first with ethanol, then with water to remove the neutral salt.

结晶物在100℃/40mbar(4KPa)下减压干燥约16小时。 Crystals at 100 ℃ / 40mbar (4KPa) and dried under reduced pressure for about 16 hours.

这样做后获得了16.0克结晶(全-E)-玉米黄素。 After doing obtained 16.0 g crystalline (full -E) - zeaxanthin. 根据高压液体色谱(HPLC)的分析，玉米黄素的含量超过99％。 The high-pressure liquid chromatography (HPLC) analysis, the content of zeaxanthin of over 99%. 收率为93.9％(以C10-双醛计)。 The yield was 93.9% (in C10- Dialdehyde dollars).

实施例2-12按和实施例1相似的方法进行了各种不同的维悌希反应，结果汇总在下表中。 Example 2-12 and the embodiment according to the method of Example 1 a similar variety of Wittig reaction, the results are summarized in the table below. C10-双醛用于每个实例的批量是30毫摩尔。 C10- Dialdehyde for each instance of the batch is 30 millimoles. 表中包含了各种简写词，其含义附在表后的说明中(常用的化学名词和其它词不需要仔细说明)。 The table contains a variety of short term, indicating that its meaning is attached to the table after the (common chemical nouns and other words do not need to be carefully explained).

表 Table

说明：Zeanyl:[5-(-羟基-2,6,6-三甲基-1环己烯基-3-甲基-2,4-戊二烯基]三苯基鏻Lycopyl:[(2E/Z,4E,6E,Z)-3,7,11-三甲基-十二2,4,6,10-四烯基]三苯基鏻Carotengl:[(2E,4E)-3-甲基-5-(2,6,6-三甲基-1-环己烯基)-2,4-戊二烯基]三苯基鏻Canthenyl:[5-(2,6,6-三甲基-3-氧代-1-环己烯基)-3-甲基-2,4-戊二烯基]三苯基鏻Astenyl:[(2E,4E)-5-(4-羟基-2,6,6-三甲基-3-氧代-环己烯基)-3-甲基-2,4-戊二烯基]三苯基鏻C5-维悌希酯：[(E)-3-2氧基羰基-丁-2-烯基]三苯基鏻MeOH,EtOH,iPrOH：甲醇，乙醇(无水)，异丙醇NaOMe,NaOEt：甲醇钠，乙醇钠实施例13(R)-3-羟基-8′-阿朴-β-胡萝卜-8′-酸乙酯的制备湿的(R)-3-羟基-12′-阿朴-β-胡萝卜-12′-醛(计算成干重32.86克；0.0896摩尔)在一装有温度计，搅拌器和氩气化器的1升弯颈吸滤瓶中悬浮在200毫升的异丙醇中。在搅拌和通入氩气下经漏斗(通过玻璃料)加入57.13克(0.1345摩尔)[(E)-3-乙氧基羰基-丁-2-烯基]-三苯基鏻氯化物和7.26克(0.1345摩尔)甲醇钠，用220毫升异丙醇冲洗，给出暗红色的悬浮状物。然后，反应混合物用55℃的油浴加热至内部温度为50℃，搅拌2+3/4小时，同时用薄层色谱(TLC)监控反应。后处理是用411毫升水和384毫升醋酸，然后将形成的暗红色悬浮液用100℃的油浴加热至回流温度。悬浮液在此温度下再加热约80分钟，然后冷却至室温，再搅拌1小时。 Description: Zeanyl: [5 - (- hydroxy-2,6,6-trimethyl-1-cyclohexene-3-methyl-2,4-pentadienyl] triphenylphosphonium Lycopyl: [(2E / Z, 4E, 6E, Z) -3,7,11- trimethyl - twelve 2,4,6,10- four-enyl] triphenylphosphonium Carotengl: [(2E, 4E) -3- A -5- (2,6,6-trimethyl-1-cyclohexenyl) -2,4-pentadienyl] triphenylphosphonium Canthenyl: [5- (2,6,6- trimethoxy -3-oxo-1-cyclohexenyl) -3-methyl-2,4-pentadienyl] triphenylphosphonium Astenyl: [(2E, 4E) -5- (4- hydroxy-2 , 6,6-trimethyl-3-oxo - cyclohexen-yl) -3-methyl-2,4-pentadienyl] triphenylphosphonium C5- Wittig ester: [(E) - 3-2 butoxycarbonyl - 2-enyl] triphenylphosphonium MeOH, EtOH, iPrOH: methanol, ethanol (anhydrous), isopropanol NaOMe, NaOEt: sodium methoxide, sodium ethoxide Example 13 (R) 3-hydroxy-8'-apo-8'-β- carrot wet preparation of ethyl (R) -3- hydroxy -12'- apomorphine -β- carrot -12'- aldehyde (calculated as dry weight of 32.86 g; 0.0896 mol) in one fitted with a thermometer, a stirrer and argon gasifier bent neck 1 liter flask by suction filtration was suspended in 200 ml of isopropanol under stirring and purged with argon through the funnel. (glass frit) was added 57.13 g (0.1345 mole) [(E) -3- ethoxycarbonyl - 2-enyl] - triphenylphosphonium chloride and 7.26 g (0.1345 mole) of sodium methoxide, 220 ml of isopropanol rinse to give a dark red suspension was obtained. Then, the reaction mixture was treated with an oil bath at 55 ℃ heated to an internal temperature of 50 ℃, stirred for 2 + 3/4 hours while (TLC) monitoring by thin layer chromatography reaction is treated with 411 ml of water and 384 ml of acetic acid, and then dark red suspension was formed with an oil bath at 100 ℃ was heated to reflux temperature. The suspension was heated at this temperature for about 80 minutes, then cooled to room temperature, stirred for 1 hour.

为了分离粗产品，将悬浮液在弯颈吸滤瓶中吸滤，滤饼用含水异丙醇(1∶1混合物)洗涤。 To isolate the crude product, and the suspension was suction filtered in the bent neck flask suction filtration, the filter cake washed with aqueous isopropanol (1 mixture).

为了使产物异构化，将滤饼在弯颈吸滤瓶中在弱氮气流下(通过玻璃料)悬浮在500毫升水中。 In order to make the product of the isomerization, the filter cake was suction filtered bent neck flask under a weak nitrogen stream (glass frit) was suspended in 500 ml of water. 用热至125℃的油浴使混合物加热到回流温度。 Heat to 125 ℃ oil bath and the mixture was heated to reflux temperature. 内部温度由85℃升至98℃，在30分钟内经分级冷凝器蒸出50毫升溶剂。 Internal temperature was raised to 85 ℃ 98 ℃, within 30 minutes graded condenser 50 milliliters of solvent was distilled off. 然后，将冷凝器再安装成回流冷凝器，混合物在内部温度为98℃下剧烈搅拌抑制强泡沫的生成。 Then, the reflux condenser mounted to the condenser and then, the internal temperature of the mixture was vigorously stirred at 98 ℃ were inhibited generation of foam. 在回流温度下保持16小时后，混合物冷却至室温，在弯颈吸滤瓶中吸滤，用水洗涤。 Maintained at reflux temperature for 16 hours, the mixture was cooled to room temperature, suction filtration flask bent neck suction filtration, washed with water. 然后将得到的晶体在-20℃下用丙酮洗涤。 The resulting crystals were washed with acetone at -20 ℃.

为了精制，滤饼在弯颈吸滤瓶中悬浮在850毫升丙酮中，在回流温度下溶解得到几乎透明的溶液。 In order to give the filter cake in the bent neck suction filtration flask was suspended in 850 ml of acetone, was dissolved at reflux temperature to give almost clear solution. 取走油浴后，混合物在搅拌下自然降温。 After the removal of the oil bath, and the mixture was stirred natural cooling. 在约45℃时，闪光的晶体结晶出来。 At about 45 ℃, the flash of crystal crystallized. 冷却混合物，在0℃下搅拌3小时，吸滤，用50毫升丙酮在20℃下洗涤两次。 The mixture was cooled, stirred at 0 ℃ 3 hours and filtered off with suction, washed with 50 ml of acetone at 20 ℃ twice. 晶体在真空干燥器中在50℃下干燥约6小时。 The crystals were dried for about 6 hours at 50 ℃ in a vacuum desiccator. 获得了26.91克酒-红色，闪光晶体的目的产品。 Obtained 26.91 g wine - red, flashing crystal desired product. 以(R)-3-羟基-12′-阿朴-β-胡萝卜-12′-醛计收率为63％。 With (R) -3- hydroxy -12'- apomorphine -β- carrot -12'- aldehyde total income was 63%. 根据高压液体色谱(HPLC)的分析，纯度为98.2％。 The high-pressure liquid chromatography (HPLC) analysis, the purity was 98.2%.

实施例14β-阿朴-4′-胡萝卜醛的制备为了制备[(E)-3-甲酰-丁-2-烯基]三苯基鏻氯化物的二甲基乙缩醛，将72.73克(0.1891摩尔)的鏻盐加至500毫升装有磁搅拌器和氩气化器的圆底烧瓶中，用100毫升甲醇处理。 Preparation Example 14β- apo-4'-aldehyde carrots To prepare [(E) -3- formyl - 2-enyl] triphenylphosphonium chloride in dimethyl acetal, to 72.73 g (0.1891 mole) of the phosphonium salt was added to 500 ml equipped with a magnetic stirrer and argon gasification round-bottomed flask, treated with 100 ml of methanol. 22.7毫升(0.2080摩尔)的原甲酸甲酯和3.55毫升的对-甲苯磺酸在甲醇中的4.59％溶液(0.0009摩尔酸)在搅拌和约25℃下加至混合物中。 22.7 ml (0.2080 mol) of methyl orthoformate and 3.55 ml of - p-toluenesulfonic acid in methanol solution of 4.59% (0.0009 mole acid) were stirred at about 25 ℃ added to the mixture. 混合物在25℃下搅拌，晶体迅速地进入溶液。 The mixture was stirred at 25 ℃, the crystal rapidly into solution. 暗棕色的反应溶液再搅拌1小时，用0.41毫升28.82％的甲醇钠溶液(含0.0022摩尔碱)使其呈碱性。 The dark brown reaction solution was stirred for one hour, 28.82% with 0.41 ml of sodium methoxide solution (containing 0.0022 moles of base) to make it alkaline.

为了进行维悌希反应，将75克(0.18摩尔)的β-阿朴-8′-胡萝卜醛加至装有搅拌器，冷凝器，温度计，自动剂量器(Dosimat)和氩气化器的2.5升磺化烧瓶中。 For the Wittig reaction, 75 g (0.18 mol) of β- -apo-8'-aldehyde was added to carrot equipped with a stirrer, a condenser, a thermometer, automatic dosage device (Dosimat) and argon gasifier 2.5 liter sulfonation flask. 然后将β-阿朴-8′-胡萝卜醛悬浮在900毫升干燥的异丙醇中，得到的红色不很稠的悬浮液加热至70℃。 Then β- apo-8'carrot aldehyde was suspended in 900 ml of dry isopropanol to give red is not very thick suspension was heated to 70 ℃. 加入由上述步骤制得的新鲜碱性乙缩醛溶液并用100毫升干燥的异丙酮冲洗。 Obtained by the above step was added fresh alkaline solution and acetal with 100 ml of dry isopropyl ketone rinse. 38.99毫升的甲醇钠溶液(含0.2080摩尔碱)用剂量计(Dosimat)在30分钟内加入。 38.99 ml of sodium methoxide solution (containing 0.2080 moles of base) is added over 30 minutes with the dosimeter (Dosimat). 接着混合物在70℃下继续搅拌1小时，然后用剂量计在70℃下和1小时内加入342.3毫升的0.5N硫酸(0.0858摩尔酸)。 Then the mixture was stirred for 1 hour at 70 ℃, and then at 70 ℃ dosimeter was added over 1 hour and 342.3 ml of 0.5N sulfuric acid (0.0858 mole of acid). 油浴用水浴置换，用剂量计在15分钟内加入342.3毫升的0.5N氢氧化钠溶液(0.1711摩尔碱)，使反应混合物冷却至25℃。 Bath was replaced with an oil bath, with the dosimeter was added over 15 minutes 342.3 ml of 0.5N sodium hydroxide solution (0.1711 mole base), and the reaction mixture was cooled to 25 ℃. 将红-棕色晶体淤浆再搅拌60分钟，然后在置有滤纸的开槽玻璃吸滤漏斗上过滤，滤饼每次用340毫升异丙醇洗两次，每次用340毫升去离子水洗涤三次。 Red - brown crystal slurry was stirred for 60 minutes, then set in paper-slotted suction filtration was filtered on a glass funnel, the filter cake washed each time with 340 ml of isopropanol twice, each time 340 ml of deionized water three times. 得到的酒-红色晶体物在真空干燥中在50℃和20-30mbar(2-3KPa)下干燥2天。 The resulting wine - red crystals were dried in vacuo at 50 ℃ and 20-30mbar (2-3KPa) dried for 2 days. 得到82.7克晶体状的目的产物，β-阿朴-4′-胡萝卜醛。 The purpose of the product obtained 82.7 g of crystals, β- apo-4'-carrot aldehyde. 以所用的β-阿朴-8′-胡萝卜醛计，重量收率为95.2％。 Β- apo-8'carrot aldehyde meter, used to weight yield of 95.2%. 产物的组成分别根据高压液体色谱或费歇尔滴定法得到：(全-E)异构体： 94.7％(Z)异构体： 1.5％残余β-阿朴-8′-胡萝卜醛：0.2％水： 0.2％实施例15园红酵醛的制备为了制备[(E)-3-甲酰-2-丁烯基]三苯基鳞氯化物的二四基乙缩醛，将43.93克(0.1151摩尔)的锛盐加入250毫升装有磁搅拌器和氩气化器的园底烧瓶中并用66毫升的甲醇处理。 Composition of the product were in accordance with the high-pressure liquid chromatography or a Karl Fischer titration method :( full -E) isomer: 94.7% (Z) isomer: 1.5% residual β- apo-8'carrot aldehyde: 0.2% Water: Preparation 15 Park red yeast aldehyde 0.2% Example To prepare [(E) -3- formyl-2-butenyl] triphenylphosphonium chloride twenty-four scales acetal group, the 43.93 g (0.1151 mol) in 250 ml of salt adze equipped with a magnetic stirrer and argon gasifier round bottom flask and treated with 66 ml of methanol. 在搅拌和约25℃下加入13.8毫升(0.1266摩尔)原甲酸甲酯以及4.59％的2.39毫升的对-甲苯磺酸在甲醇中的溶液(0.0006摩尔酸)。 Was added under stirring for about 25 ℃ in 13.8 ml (0.1266 mol) of methyl orthoformate and 4.59% of the 2.39 ml of - a solution of p-toluenesulfonic acid (0.0006 mole of acid) in methanol. 混合物在25℃搅拌下，晶体很快进入溶液。 The mixture was stirred at 25 ℃, crystals quickly into solution. 暗棕色的反应溶液再搅拌1小时，用0.32毫升29.37％甲醇钠溶液(0.0017摩尔碱)使其成碱性。 The dark brown reaction solution was stirred for 1 hour, with 0.32 ml 29.37% solution of sodium methoxide (0.0017 moles of base) to make it alkaline.

为了进行维悌希反应，将50.00克(0.1036摩尔)的β-阿朴-4′-胡萝卜醛加入2.5升装有搅拌器，冷凝器，温度计，自动计量器和氩气化器的磺化烧瓶中。 For the Wittig reaction, 50.00 g (0.1036 mol) of β- apo-4'carrots 2.5 liters equipped with a stirrer was added an aldehyde, a condenser, a thermometer, and argon automatic meter gasifier sulfonation flask in. 然后β-阿朴-4′-胡萝卜醛悬浮在650毫升干燥的异丙醇中，加热至65℃，生成闪光的红-棕色晶体。 Then β- apo-4'carrot aldehyde was suspended in 650 ml of dry isopropanol was heated to 65 ℃, generating flash red - brown crystals. 加入上一步新制成的碱性乙缩醛的溶液，用100毫升干燥的异丙醇冲洗。 Previous alkaline acetate was added freshly made solution of the acetal, 100 ml of dry isopropanol rinse. 用剂量计在30分钟内加入23.29毫升甲醇钠溶液(0.1266摩尔碱)。 Dosimeter with sodium methoxide solution was added 23.29 ml (0.1266 moles of base) in 30 minutes. 然后，有些粘稠的反应混合物在65℃下再搅拌2小时，用剂量计在65℃下加入250毫升0.5N硫酸(0.0625摩尔酸)。 Then, the reaction mixture was further stirred for some viscous at 65 ℃ 2 hours, the dosimeter was added 250 ml 0.5N sulfuric acid (0.0625 mol acid) at 65 ℃. 结晶的淤浆变得粘稠并呈暗棕色。 Crystallization slurry becomes viscous and dark brown. 用水浴置换油浴，用剂量计在20分钟内加入250毫升0.5N氢氧化钠溶液(0.1250摩尔碱)，反应混合物冷却至20-25℃。 Oil bath replaced with a water bath, with a dosimeter 0.5N sodium hydroxide solution was added 250 ml (0.1250 moles of base) in 20 minutes, the reaction mixture was cooled to 20-25 ℃. 搅拌晶体淤浆40分钟，在置有滤纸的开槽玻璃吸滤漏斗上过滤，每次用250毫升异丙醇洗涤两次。 Crystal slurry was stirred for 40 minutes, the home paper-slotted suction filtration on a glass filter funnel, washed twice each time with 250 ml of isopropanol. 得到了湿的，黑-棕色晶体。 Got wet, black - brown crystals.

为了精制，湿晶体放入一个1.5升装有搅拌器，回流冷凝器，温度计和氩气化器的磺化烧瓶中用750毫升异丙醇处理。 In order to give the wet crystals into a 1.5 l equipped with a stirrer, reflux with condenser, thermometer, and argon gasifier sulfonation flask, 750 ml isopropanol. 混合物在搅拌下用油浴加热至回流温度(83℃)。 The mixture was heated in an oil bath under stirring to reflux temperature (83 ℃). 结晶的淤浆在回流温度下搅拌1小时，用水浴冷却至25℃再搅拌1小时。 Crystalline slurry was stirred for 1 hour at reflux temperature, cooled with a water bath to 25 ℃ stirred for 1 hour. 然后，悬浮液在置有滤纸的开槽玻璃吸滤漏斗上过滤，晶体每次用250毫升异丙醇洗涤两次，然后每次用250毫升去离子水洗涤三次。 Then, the suspension was set paper-slotted suction filtration on a glass filter funnel, the crystal 250 ml and washed twice with isopropanol, and then 250 ml of deionized water three times, each time with. 得到的晶体物在50℃和20mbar(2KPa)下在真空干燥器中干燥约16小时。 Crystals were obtained at 50 ℃ and 20mbar (2KPa) was dried in a vacuum dryer at about 16 hours.

这样，得到了53.84克黑色，闪光晶体的目的产品-园红酵母醛。 Thus, a 53.84 g black, glitter crystals purpose product - Park Red yeast aldehyde. 以所用的β-阿朴-4′-胡萝卜醛计，重量收率为94.7％。 Β- apo-4'-aldehyde meter carrot, used to weight yield of 94.7%. 根据高压液体色谱或气体色谱的分析结果，产品的组成为：(全-E)-园红酵母醛 96.8％(Z)-园红酵母醛 0.9％残余β-阿朴-4′-胡萝卜醛 0.2％实施例16藏花酸二乙酯的制备在2.5升装有机械搅拌器，温度计滴液漏斗和氮气化器的四颈烧瓶中，将16.45克(100毫摩尔)的2,7-二甲基-2,4,6-辛三烯-1,8-二醛和93.5克(220毫摩尔)的[3-乙氧基羰基-丁-2-烯基]三苯基鏻氯化物悬浮在750毫升的无水乙醇中。 According to the analysis results of high-pressure liquid chromatography or gas chromatography, the composition of the product for a full :( -E) - Park Red yeast aldehyde 96.8% (Z) - Park Red yeast aldehyde 0.9% residual aldehyde β- apo-4'-carrot 0.2 Preparation Example 16 Diethyl% Crocein embodiment in 2.5 liters equipped with a mechanical stirrer, a thermometer a dropping funnel and a nitrogen of the four-necked flask, 16.45 g (100 mmol) of 2,7-dimethyl -2,4,6-octatriene-1,8-dialdehyde, and 93.5 g (220 mmol) of [3-ethoxycarbonyl - 2-enyl] triphenylphosphonium chloride was suspended in 750 ml of absolute ethanol. 在室温和激烈搅拌下滴加220毫升(220毫摩尔)乙醇钠溶液(1.0M在乙醇中)。 Was added dropwise 220 ml (220 mmol) of sodium ethoxide solution was stirred at room temperature and intense (1.0M in ethanol). 反应混合物在室温和通入氮气下搅拌约12小时。 The reaction mixture was stirred for about 12 hours at room temperature and purged with nitrogen.

得到的红色悬浮液用约2毫升浓醋酸处理。 The resulting red suspension was treated with about 2 ml of concentrated acetic acid. 然后，用100-110℃下的油浴由反应物中蒸出320毫升乙醇，再加入400毫升的低离子水。 Then, using an oil bath at 100-110 ℃ under distill from the reactor was 320 ml of ethanol was added 400 ml of low ionic water. 悬浮液在回流下(内部温度82℃)再搅拌10小时，然后在冰浴中(内部温度3-4℃)再搅拌2小时。 The suspension was stirred for 10 hours under reflux (internal temperature 82 ℃), then stirred in an ice bath (internal temperature 3-4 ℃) 2 hours. 用玻璃吸滤漏斗分离沉淀，用冰冷的含水乙醇(在水中60％)洗涤。 Glass funnel precipitate was isolated by suction filtration, (60% in water) was washed with ice-cold aqueous ethanol. 在50℃和喷水真空下干燥约16小时，得到34克红色、半晶体有些胶粘状的藏花酸二乙酯，(粗产品理论收率为88.5％)。 Water at 50 ℃ and dried under vacuum for about 16 hours, to give 34 g of red, semicrystalline somewhat tacky Crocein diethyl (theoretical yield of crude product was 88.5%).

以上的粗产品悬浮在175毫升的含水乙醇(在水中60％)中，在110℃，21bar(2.1KPa)压力和氮气通入下进行了10小时的异构化反应。 The above crude product was suspended in 175 ml of aqueous ethanol (60% in water), and at 110 ℃, 21bar (2.1KPa) pressure and nitrogen was passed through for 10 hours under an isomerization reaction. 晶体产物在喷水真空下吸滤分出，和以前一样地用含水乙醇洗涤。 Crystalline product was separated by suction filtration under water vacuum, and previously washed with aqueous ethanol in the same manner. 在50℃和喷水真空下干燥16小时后，得到31.1克红色结晶，熔点为208-209℃的藏花酸二乙酯。 At 50 ℃ and water and dried under vacuum for 16 hours to obtain 31.1 g of red crystals, mp 208-209 ℃ Crocein diethyl ester of.

理论收率为80.9％；HPLC:90.4％(全-E)异构体；UV(E11):3052cm-1(在433nm最大)。 Theoretical yield was 80.9%; HPLC: 90.4% (full -E) isomer; UV (E11): 3052cm-1 (at 433nm maximum).

实施例17双阿朴-4,4′-胡萝卜二醛的制备为了制备[7-甲酰基-3,7-二甲基-辛-2,4,6-三烯基]三苯基鏻氯化物，将45.06克(0.099摩尔)的这种盐加入装有搅拌器，温度计，冷凝器，自动计量器和氩气发生器并通入氩气的2.5升四颈磺化烧瓶中。 Preparation of carrot dialdehyde apomorphine 4,4 17 pairs Example To prepare [7- formyl-3,7-dimethyl - octyl-2,4,6-triene-yl] triphenylphosphonium chlorine compound, the 45.06 g (0.099 mole) of this salt was added equipped with a stirrer, a thermometer, a condenser, and an argon automatic meter generator and purging with argon of 2.5 l four-necked sulfonation flask. 然后烧瓶中的物质悬浮在190毫升甲醇中，悬浮液在室温下搅拌，用12.94毫升(0.1188摩尔)原甲酸甲酯处理。 Then the flask were suspended in 190 ml of methanol, the suspension was stirred at room temperature with 12.94 ml (0.1188 mol) of methyl orthoformate processing. 加入1.86毫升的4.59％的对-甲苯磺酸在甲醇中的溶液之后，混合物在室温下搅拌。 Was added 1.86 ml of 4.59% of - toluenesulfonic acid in methanol is then added and the mixture was stirred at room temperature. 反应溶液呈棕-橙色。 The reaction solution was brown - orange. 反应结束后，溶液用0.210毫升的29.37％甲醇钠溶液(含0.0014摩尔碱)中和。 After completion of the reaction, the solution was treated with 0.210 ml of 29.37% sodium methoxide solution (containing 0.0014 moles of base) neutralization.

缩醛作用以后，为了进行维悌希反应，将2.39克(0.045摩尔)的2,7-二甲基-2,4,6-辛三烯-1,8-二醛和600毫升的异丙醇在室温下加至以上的反应溶液中。 After acetalization, in order to carry out the Wittig reaction, 2.39 g (0.045 mole) of 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde, and 600 ml of isopropyl alcohol at room temperature was added to the above reaction solution. 得到一种橙色的悬浮液。 To give an orange suspension. 20.03毫升的29.37％的甲醇钠溶液(含0.0495的碱)在室温下和30分钟内加至悬浮液中。 20.03 ml of 29.37% sodium methoxide solution (containing the alkali 0.0495) at room temperature and added over 30 minutes to the suspension. 温度因此而升至约27℃，悬浮液的颜色转成暗棕色。 So while the temperature rose to about 27 ℃, the color of the suspension turned into a dark brown. 反应混合物在室温下继续反应1.5小时。 The reaction mixture was allowed to react at room temperature for 1.5 hours. 得到的乙缩醛用395毫升的0.5N的硫酸在30分钟内进行脱缩醛反应。 The resulting acetal with 395 ml of 0.5N sulfuric acid deprotection of the acetal reaction is completed in 30 minutes. 为了中和，在搅拌下加入395毫升的0.5N氢氧化钠的水溶液。 For neutralization, the aqueous solution was added under stirring 395 ml of 0.5N sodium hydroxide. 搅拌约90分钟后，吸滤此棕色晶体淤浆，滤饼依顺序用异丙醇和去离子水洗涤。 After stirring for about 90 minutes, this brown crystals suction filtration, slurry, cake was washed in sequence with isopropanol and deionized water. 得到的黑-棕色晶体在50℃和20-30mbar(2-3KPa)下在真空干燥箱中干燥16小时。 The resulting black - brown crystals (2-3KPa) was dried 16 hours in a vacuum oven at 50 ℃ and 20-30mbar. 这样就得到了重量收率大于99％的19.26克黑棕色晶体的双阿朴-4.4′-胡萝卜二醛。 This was more than double the yield of 99% by weight of 19.26 grams of black-brown crystals of apomorphine -4.4'- carrot dialdehyde. 粗产物的组成根据高压液体色谱的分析含约72％(全E)异构体和约19％(Z)异构体。 Analysis of the crude product according to the composition containing the high-pressure liquid chromatography of from about 72% (all-E) isomer and about 19% (Z) isomer.

实施例18β-阿朴-8′-胡萝卜酸乙酯的制备18.83克(91.3％；0.04565摩尔)β-阿朴-10′-胡萝卜醛加至-500毫升装搅拌器，温度计，冷凝器，滴液漏斗和氩气化器的四颈磺化烧瓶中。 Example 18β- Preparation of ethyl -apo-8'carrot 18.83 g (91.3%; 0.04565 mole) β- apo -10'- carrot aldehyde was added to -500 mL stirrer, a thermometer, a condenser, a dropping funnel and argon gasifier four-necked sulfonation flask. 24.16克(0.0545摩尔)(1-乙氧基羰基乙基)三苯基鏻的溴化物和85毫升乙醇在搅拌下加至烧瓶中。 24.16 g (0.0545 mol) of (1-ethoxycarbonyl-ethyl) triphenylphosphonium bromide and 85 ml of ethanol was added under stirring to the flask. 74.0克甲醇钠在乙醇中的溶液(含碱0.054摩尔)在30分钟内加至生成红色，易于搅动的悬浮液中。 74.0 g sodium methoxide solution in ethanol (0.054 mole alkali) was added over 30 minutes to form a red, easy stirring suspension. 加入时，温度由20升至26℃，悬浮液变得粘稠了。 When added, the temperature rose from 20 26 ℃, the suspension becomes thick. 在50℃下继续反应90分钟，反应混合物又变稀了。 Continue for 90 minutes at 50 ℃, the reaction mixture was also thinning the. 用2毫升醋酸处理后用冰浴冷至17℃。 After treatment with 2 ml of acetic acid in an ice bath to cool to 17 ℃.

得到的晶体吸滤出来，在0℃下分两次，每次用50毫升乙醇洗涤。 The resulting crystals out suction filtration, twice at 0 ℃, washed with ethanol 50 ml. 在45℃和20-30mbar(2-3KPa)压力下晶体在真空干燥器中干燥后，得到16.6克暗红色晶体。 At 45 ℃ and 20-30mbar (2-3KPa) crystal under a pressure in a vacuum dryer and dried to give 16.6 g of dark red crystals. 以β-阿朴-10′-胡萝卜醛为基础，这相当于72.1％收率。 Carrots with β- apo -10'- aldehyde-based, which is equivalent to 72.1% yield. 根据高压液体色谱的分离结果，此粗产品中的(全E)β-阿朴-8′-胡萝卜酸乙基酯的含量为90％。 According to the results of high pressure liquid chromatography separation, (all E) content of β- apo-8'carrot acid ethyl ester, the crude product was 90%.

实施例19园红酵母素的制备10.0克(0.024摩尔)β-阿朴-8′-胡萝卜醛悬浮在一个1.5升装有搅拌器，温度计，回流冷凝器和氩气发生器的四颈磺化烧瓶内130毫升的异丙醇中。 Preparation Example 19 Park Rhodotorula Pigment 10.0 g (0.024 moles) β- apo-8'carrot aldehyde was suspended in a 1.5 l equipped with a stirrer, a four-necked sulfonation thermometer, reflux condenser, and an argon gas generator the flask 130 ml of isopropanol. 悬浮液加热至回流温度(在100℃的油浴中约83℃)。 Suspension was heated to reflux temperature (in an oil bath at 100 ℃ for about 83 ℃). 14.04克(0.0276摩尔)[7-乙氧基羰基-3,7-二四基-2,4,6-庚三烯基]三苯基鏻氯化物溶在80毫升异丙醇中并转移至一个100毫升哈密顿注射器中。 14.04 g (0.0276 mol) [7-ethoxycarbonyl-3,7 twenty-four yl 2,4,6-trienyl] triphenylphosphonium chloride was dissolved in 80 ml of isopropanol and transferred to a a 100 ml Hamilton syringe. 然后8.56克(0.0276摩尔)乙醇钠在乙醇中的溶液吸入到20毫升的哈密顿注射器中。 Then 8.56 g (0.0276 mole) of sodium ethoxide in ethanol was drawn into 20 ml of Hamilton syringe. 9毫升鏻盐溶液(总量的10％)在回流温度下加至已预先制好的β-阿朴-8′-胡萝卜醛的悬浮液中。 9 ml phosphonium salt solution (10% of the total) at reflux temperature is added to the already preformed β- apo-8'carrot aldehyde suspension. 然后，剩余的鏻盐溶液在100分钟内加入，同时将乙醇钠溶液在约2小时内加入。 Then, the remaining phosphonium salt solution was added over 100 minutes, while the sodium ethoxide solution was added over about 2 hours. 加料结束后混合物在回流温度下继续搅拌30分钟。 Mixture was stirred at reflux temperature for 30 minutes after addition was complete.

然后，混合物的内部温度冷至60℃，加入150毫升异丙醇。 Then, the internal temperature of the mixture was cooled to 60 ℃, added 150 ml of isopropanol. 为了皂化生成的中间物园红酵母乙基酯，加入3.75克(0.0568摩尔)溶于12.8毫升去离子水中的氢氧化钾。 In order to generate the intermediate saponification Park Rhodotorula ethyl ester, was added 3.75 g (0.0568 mol) was dissolved in 12.8 ml of deionized water of potassium hydroxide. 反应混合物再次加热至回流温度(80℃)，使其反应2小时。 The reaction mixture was heated again to reflux temperature (80 ℃), allowed to react for 2 hours. 在皂化过程中，悬浮液的粘度会变化，因此搅拌速度需要适当的调整。 In the saponification process, viscosity of the suspension vary, the stirring speed therefore require appropriate adjustment.

皂化结束后，加入127毫升1N硫酸，混合物在内部温度为80℃下搅拌1小时。 After saponification, was added 127 ml 1N sulfuric acid, and the mixture was stirred at an internal temperature at 80 ℃ 1 hour. 再加入570毫升异丙醇后，反应混合物在81.5℃的内温下搅拌17小时，然后悬浮液用冰/水浴冷却至20℃。 After addition of 570 ml of isopropanol, the reaction mixture was stirred at an inner temperature of 81.5 ℃ of 17 hours, then the suspension with an ice / water bath was cooled to 20 ℃. 得到的紫色晶体吸滤分离，依次用异丙醇和去离子水洗涤。 The resulting purple crystals isolated by suction filtration, successively washed with isopropanol and deionized water.

得到了31.6克水湿的粗园红酵母素。 Obtained 31.6 g crude wet garden Red Yeast.

为了精制水湿的粗园红酵母素，可以将其按顺序在水和丙酮中浸煮：粗园红酵母素在1升装有搅拌器，温度计，回流冷凝器和氩气发生器的烧瓶中悬浮在600毫升的去离子水中。 Red Yeast for refining crude wet garden can be sequentially immersed in boiling water and acetone: Red Yeast crude park in one liter equipped with a stirrer, thermometer, reflux condenser and argon gas generator flask was suspended in 600 ml of deionized water. 用120℃的油浴将悬浮液加热至回流温度(99℃)，并在此温度下搅拌2小时。 In an oil bath at 120 ℃ of the suspension was heated to reflux temperature (99 ℃), and stirred at this temperature for 2 hours. 然后用冰/水浴将悬浮液冷却至20℃，吸滤出晶体。 Then with an ice / water bath and the suspension was cooled to 20 ℃, the crystals filtered off with suction. 所得晶体用去离子水和丙酮洗涤，得到了21.7克丙酮浸湿的园红酵母素。 The resulting crystals were washed with deionized water and acetone and 21.7 g of acetone-soaked garden Red Yeast. 为了进一步精制，丙酮浸湿的园红酵母素悬浮在1.5升装有搅拌器，温度计，回流冷凝器和氩气发生器的磺化烧瓶中600毫升的丙酮中。 For further purification, acetone soaked garden Rhodotorula pigment was suspended in 1.5 liters equipped with a stirrer, a thermometer sulfonation flask, reflux condenser, and an argon gas generator in 600 ml of acetone. 用80℃的油浴把悬浮液加热至回流温度(57℃)，并在此温度下搅拌2小时。 With an oil bath at 80 ℃ The suspension was heated to reflux temperature (57 ℃), and stirred at this temperature for 2 hours. 然后，混合物用冰/水浴冷却至20℃。 Then, the mixture with an ice / water bath was cooled to 20 ℃. 晶体用吸滤法滤出，用丙酮洗涤。 Crystals were filtered off by suction filtration, washed with acetone. 得到11.44克(以β-阿朴-8′-胡萝卜醛为基础的收率为84.4％)紫色晶体的园红酵母素，根据高压液体色谱的分析结果，其中(全-E)-园红酵母素的含量达到99.7％。 Obtain 11.44 g (with β- apo-8'-based carrot aldehyde yield 84.4%) Park Red Yeast purple crystals, according to the results of high-pressure liquid chromatography analysis, which (full -E) - Park Red Yeast pigment content of 99.7%.

实施例20β-阿朴-8′-胡萝卜酸乙酯的制备35.16克β-阿朴-12′-胡萝卜醛和54.24.克[(E)-3-乙氧基羰基-丁-2-烯基]三苯基鏻氯化物悬浮在200毫升异丙醇中。 EXAMPLE 20β- preparation apo-8'carrot 35.16 g of ethyl β- apo -12'- carrot aldehyde and 54.24 g [(E) -3- ethoxycarbonyl - 2-enyl ] triphenylphosphonium chloride was suspended in 200 ml of isopropanol. 悬浮液加温至约30℃。 The suspension was heated to about 30 ℃. 在15分钟内加入总量为6.46克的固体甲醇钠并用15毫升异丙醇冲洗。 Solid sodium was added over 15 minutes a total amount of 6.46 g of methanol and treated with 15 ml of isopropanol rinse. 在2小时内加热至50℃反应完成。 Was heated over 2 hours to 50 ℃ completion of the reaction. 然后，加入215毫升水，混合物用硫酸中和，在回流条件下，异构化进行了14小时。 Then, 215 ml of water was added, the mixture was neutralized with sulfuric acid, under reflux conditions, isomerization was 14 hours. 混合物在温热时过滤，用含水异丙醇洗涤，在45℃和减压(20mbar,2KPa)下干燥。 The mixture was filtered while warm, and washed with aqueous isopropanol, at 45 ℃ and under reduced pressure (20mbar, 2KPa) and dried. 得到了43.88克晶体β-阿朴-8′-胡萝卜酸乙酯。 Crystal got 43.88 g of ethyl β- apo-8'carrots. 以β-阿朴-12′-胡萝卜醛计，收率为95.3％。 To β- apo -12'- carrot aldehyde The yield was 95.3%. β-阿朴-8′-胡萝卜酸乙酯的所有异构物结晶物的含量达98％。 content of the apo-8'-β- carrot all isomers of ethyl crystals up to 98%.

实施例21链孢霉黄素乙酯β-阿朴-4′-胡萝卜酸乙酯的制备17.58克β-阿朴-12′-胡萝卜醛和30.53克[7-乙氧基羰基-3,7-二甲基]2,4,6-庚三烯基]三苯基鏻氯化物在一通氩气的烧瓶中悬浮在400毫升乙醇中。 17.58 g β- apo -12'- carrot aldehyde and 30.53 g [7-ethoxycarbonyl-3,7-PREPARATION 21 Neurospora crassa flavin β- apo-4'-ethyl acetate implementation carrot methyl] hept-2,4,6-triene-yl] triphenylphosphonium chloride in a flask in an argon gas was suspended in 400 ml of ethanol. 在0-10℃和搅拌下，5分钟内加入23.69毫升的18.1％乙醇钠在乙醇中的溶液。 At 0-10 ℃ and stirring within 5 minutes was added 23.69 ml of 18.1% ethanol solution of sodium in ethanol. 然后，反应先在15℃下进行30分钟又在25-30℃下进行90分钟。 Then, the first reaction is carried out for 30 minutes at 15 ℃ and carried out at 25-30 ℃ 90 minutes.

得到的悬浮液用2.5毫升1％的硫酸处理，然后在回流温度(浴温95℃，内部温度76℃)下煮沸17小时。 The resulting suspension was treated with 2.5 ml of 1% sulfuric acid, and then boiled under reflux temperature (bath temperature 95 ℃, the internal temperature of 76 ℃) 17 hours.

冷却生成的暗红色悬浮液，吸滤分出晶体物，六次每次用40毫升乙醇/水(1∶1)在50℃下，两次每次用40毫升乙醇在25℃下洗涤。 Cooling the resulting dark red suspension, the crystal was separated by suction filtration, six times each at 50 ℃, twice washed with 40 ml each of ethanol at 25 ℃ treated with 40 ml of ethanol / water (1/1). 紫-红色的晶体在真空干燥箱中在45℃和20-30mbar(2-3KPa)压力下干燥约16小时。 Purple - red crystals (2-3KPa) was dried for about 16 hours in a vacuum oven at 45 ℃ and 20-30mbar pressure.

用这种方式得到了21.2克链孢霉黄素乙酯，以β-阿朴-12′-胡萝卜醛计收率为80.3％。 In this way was 21.2 grams of ethyl flavin Neurospora crassa to β- apo -12'- carrot yield of 80.3% formaldehyde meter.

晶体中(全E)链孢霉黄素乙酯的含量达99.8％。 Crystals (all E) content of ethyl Neurospora crassa flavin 99.8%.