本发明涉及式（Ⅰ）化合物、其制备以及其在制备虾青素和其它必需的虾青素前体方面的应用， The present invention relates to compounds of formula (Ⅰ), their preparation and their use in the preparation of astaxanthin and other necessary precursors of astaxanthin, and 其中R1为H或C1-C4-烷基;R2为C1-C4-烷基;及R3为可通过水解反应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团，优选为下列基团之一： Wherein R1 is H or C1-C4- alkyl; R2 is C1-C4- alkyl; and R3 is may be converted to ethers, silyl ether or a hydroxyl group by hydrolysis reaction of the aldehyde acetal protective group, preferably the following group One group: 式Ⅴ的C40-类胡萝卜素虾青素是鱼色素形成作用中所需要的染料， Ⅴ type of C40- carotenoid astaxanthin fish dye pigment formation in the desired effect,

从天然资源（例如藻或酵母类）中分离虾青素的可能性是有限的。 The possibility of separation of astaxanthin from natural sources (such as algae or yeast class) is limited. 因此人们一直试图通过合成的方法来制备虾青素。 So people have been trying to prepare astaxanthin by synthesis approach.

一种工业上可行的虾青素的合成方法被描述于EP5748和Helv.Chim.Acta 64（1981）2436中以及下列等等。 Synthesis on a commercially viable astaxanthin is described in EP5748 and Helv.Chim.Acta 64 (1981) 2436 and in the following, and so on. 其合成路线如下： The synthesis route is as follows:

在每一情况中所用的C9单元是2，2，4，6，6-五甲基-7，7α-二氢-2H，6H-1，3-苯并间二氧杂环戊烯-5-酮，它可由3，4-二羟基-2，6，6-三甲基-2-环己烯-1-酮与丙酮或2，2-二甲氧基丙烷反应来制备： C9 unit in each case used was 2,2,4,6,6-pentamethyl -7,7α- dihydro -2H, inter-6H-1,3- benzodioxol-5-ene - one, it may be 3,4-dihydroxy-2,6,6-trimethyl-2-cyclohexen-1-one with acetone or 2,2-dimethoxypropane is prepared by reacting: 在所述参考文献中提及的C6单元为具有被保护的OH基的下式3-甲基戊烯炔-1-醇： C6 cells mentioned in the references as having a protected OH group of the formula 3-methyl-penten-1-ol: 所提及的保护基除三烷基甲硅烷基外，还有叔丁基和-C（CH3）2-O-CH3基团。 In addition to protecting groups mentioned trialkylsilyl group, there are t-butyl and -C (CH3) 2-O-CH3 groups. 此外，EP5748还提及作为C6单元的下式3-甲基戊烯炔-3-醇的三烷基甲硅烷基醚： In addition, EP5748 also referred to as a unit of the following formula C6 3-methyl-penten-yn-3-ol trialkylsilyl ether: 没有给出该3-甲基戊烯炔-3-醇醚与C9单元的反应的实验实例。 Did not give the 3-methyl-pentene-yn-3 Experimental Example ethers react with C9 cells. 该合成中的关键步骤是借助于有机金属反应将C9单元键合到C5单元上。 The key step of the synthesis reaction by means of an organometallic C9 unit bonded to the C5 unit. 或者用格利雅试剂[在四氢呋喃（THF）中]或者用丁基锂溶液将乙炔去质子化。 Or with a Grignard reagent [tetrahydrofuran (THF) in] with butyl lithium solution or deprotonated acetylene. 格利雅试剂变体和丁基锂变体在Helv.Chim.Acta 64（1981）2439中进行了系统地比较，明确优选的是丁基锂变体。 Grignard reagent variants and butyllithium variants were systematically comparing Helv.Chim.Acta 64 (1981) 2439, and specifically preferred are butyl lithium variants. 在此情况中偶联产物的产率为理论值的85.6%。 In this case, 85.6% yield of theory coupling product.

经在无机酸介质中处理可以从该偶联产物中除掉所有保护基团，形成6-羟基-3-（3-甲基-5-羟基-3-戊烯-1-基炔基）-2，4，4-三甲基-2-环己烯酮。 Treated can remove all protecting groups from the coupling product in an inorganic acid medium to form a 6-hydroxy-3- (3-methyl-5-hydroxy-3-penten-1-yl-ynyl) - 2,4,4-trimethyl-2-cyclohexenone. 可以这样制备：用锌粉和乙酸在CH2Cl2中还原三键，随后使其与HBr反应，然后再与三苯膦反应，所得C15-三苯基鏻盐可与2，7-二甲基-2，4，6-辛三烯二醛反应制得虾青素。 Can be prepared by: reduction with zinc dust and acetic acid in CH2Cl2 triple bond, and then reacted with HBr, and then reacted with triphenylphosphine, resulting C15- triphenyl phosphonium salt with 2,7-dimethyl-2 , 4,6 cyclooctatriene two aldehyde reaction of astaxanthin.

所述方法本来是非常好的，只是具有必须使用丁基锂的缺点，丁基锂是非常昂贵的，易燃并且不易进行工业处理。 The method would have been very good, but has the disadvantage must use butyl lithium, butyl lithium is very expensive, and are not easily flammable industrial processing. 此外，丁基锂一般以在己烷中的溶液的形式存在，所以在反应后必须处理有机溶剂的混合物。 In addition, generally in the form of butyl lithium in hexane solution exists, so must be treated after the reaction mixture of the organic solvent.

使用格利雅试剂在工业上也不是非常有利的，这是因为处理低沸点烷基卤化物存在一定困难并且在制备格利雅试剂（在反应的开始阶段）中可能遇到某些技术问题。 Grignard reagent used in the industry is not very advantageous, because there are certain difficulties in the processing of low-boiling alkyl halides and Grignard reagent (at the beginning stage of the reaction) may encounter some technical problems.

本发明的一个目的是改进已知的虾青素的合成方法，以避免先有技术在将C9单元键合到C6单元上时的缺点。 An object of the present invention is to improve the known method of synthesizing astaxanthin, in order to avoid the prior art when the C9 units bonded to C6 unit disadvantages.

我们已发现，这个目的可如下达到：当C6单元是式Ⅱ的3-甲基戊烯炔-3-醇的衍生物时， We have found that this object can be reached as follows: When 3-methyl-penten-yn-3-ol derivatives of the formula C6 Ⅱ unit when 其中R3为可经水解反应转化的羟基的醚、甲硅烷基醚或醛缩醇保护基团，特别是下列基团之一： Wherein R3 may be an ether, silyl ether or aldehyde hydrolysis reaction conversion of an acetal hydroxyl protecting group, especially one of the following groups:

在工业上简单得多的条件下，即在有机溶剂中在替代丁基锂或格利雅试剂的氨基化锂的存在下，将C9单元键合到适宜的C6单元上。 Under the much simpler in industrial conditions, i.e., in an organic solvent in the presence of butyllithium or alternative Grignard reagent lithium amide, and the C9 units bonded to a suitable cell C6. 该反应导致形成式Ⅰ化合物，该化合物在文献中未见描述过。 This reaction results in the formation of the compound of formula Ⅰ, the compound described in the literature no.

该反应的平稳性是特别惊人的，因为当具有1位的醚基团的下式C6单元用作起始原料时， The reaction stability is particularly amazing, because when having an ether group of the formula C6 cells used as starting materials, 在甲基叔丁基醚中它与C9单元的反应是察觉不到的。 In methyl tert-butyl ether reaction with C9 cells imperceptible.

因此本发明还涉及制备式Ⅰ化合物的方法， The invention therefore also relates to a process for preparing compounds of formula Ⅰ,

其中R1为H或C1-C4-烷基;R2为C1-C4-烷基;及R3为可通过水解反应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团;该方法包含使式Ⅱ的链烯炔烃与式Ⅲ的环己烯酮在惰性溶剂中在氨基化锂的存在下发生反应， Wherein R1 is H or C1-C4- alkyl; R2 is C1-C4- alkyl; and R3 is may be converted to ethers, silyl ether or a hydroxyl group by hydrolysis reaction of an aldehyde acetal protecting group; which process comprises reacting Formula Ⅱ alkenyl alkynes of formula Ⅲ cyclohexenone reacts in the presence of lithium amide in an inert solvent, 其中R1和R2具有上述意义。 Wherein R1 and R2 have the above meaning.

优选的C9单元为其中R1为H或甲基且R2为甲基的式Ⅲ环己烯酮类化合物。 Preferred C9 unit in which R1 is H or methyl and R2 is methyl the compound of formula Ⅲ cyclohexenone class. 其中R1＝H且R2＝甲基的式Ⅲ环己烯酮在文献中未见描述过。 Wherein R1 = H and R2 = methyl cyclohexenone of formula Ⅲ no described in the literature. 该化合物可通过使3，4-二羟基-2，6，6-三甲基-2-环己烯-1-酮与乙烯基乙基醚反应来制备。 This compound may be prepared by reacting 3,4-dihydroxy-2,6,6-trimethyl-2-cyclohexen-1-one is reacted with vinyl ethyl ether. 该C9单元与其中R3为-O-CH（CH3）-O-CH2-CH3的式Ⅱ的链烯炔烃的反应在工业上和经济上是特别优越的，因为这二个单元是用相同来源的保护基团即用乙烯基乙基醚来制备的。 The C9 reaction unit and wherein R3 is -O-CH (CH3) Ⅱ of formula -O-CH2-CH3 alkenyl alkynes in industrially and economically particularly advantageous, because these two elements are designated by the same source i.e., the protecting groups using vinyl ethyl ether prepared. 该链烯炔烃公开于J.Org.Chem.47（1982）2130-2134中。 The alkenyl alkynes J.Org.Chem.47 (1982) 2130-2134 discloses in. 按照上述引用文献，在鸡油菌黄质的合成中，用丁基锂使其被金属取代，然后键合到2，6，6-三甲基-2-环己烯酮上。 According to the above cited references, in canthaxanthin synthesis, with butyl lithium metal substituted it is then bonded to the 2,6,6-trimethyl-2-cyclohexenone.

适于式Ⅱ的链烯炔烃类的保护基团是那些可通过水解反应相对容易地转化为羟基的保护基团。 Suitable for type Ⅱ alkenyl alkynes protecting groups are those that can be relatively easily converted by a hydrolytic reaction of a hydroxyl-protecting group. 可以提及的实例为醚基团，例如 Examples which may be mentioned an ether group, e.g. 、甲硅烷基醚基团例如-O-Si（CH3）3或醛缩醇基团例如下列各式的α-烷氧基烷基醚基团：-O-CH2-O-CH3， Silyl ether groups such as -O-Si (CH3) 3, or an acetal alcohol groups for example the following kinds of α- alkoxyalkyl ether group: -O-CH2-O-CH3, 和适宜的吡喃基醚基团，例如四氢吡喃基氧基和4-甲基-5，6-二氢-2H-吡喃基氧基。 Suitable pyran and ether groups, e.g., tetrahydropyranyl group and 4-methyl-5,6-dihydro -2H- pyran-yloxy.

特别优越地是使用其中R3为下式四氢吡喃基氧基的式Ⅱ的链烯炔烃类， Is particularly advantageous to use wherein R3 is an alkenyl alkynes formula tetrahydropyranyloxy Ⅱ of Formula, 或使用其中R3为下式的α-乙氧基乙氧基的式Ⅱ的链烯炔烃类。 Alkenyl or alkynyl wherein R3 is a hydrocarbon of the formula α- ethoxyethoxy of Formula Ⅱ.

式Ⅱ的链烯炔烃类的使用量基于式Ⅲ的C9单元一般过量0至100mol%，优选50至75mol%。 The amount of formula Ⅱ alkenyl alkynes C9 based on unit of the general formula Ⅲ excess of 0 to 100mol%, preferably 50 to 75mol%.

适宜于本发明方法的惰性溶剂一般为对氨基化锂呈惰性的溶剂。 The method of the present invention is suitable for the inert solvent is generally inert to lithium amide solvent. 有利的是使用含醚的溶剂，例如二烷基醚类、四氢呋喃或二噁烷，特别是与水不混溶的甲基叔丁基醚。 Advantageous to use a solvent containing an ether, for example dialkyl ethers, tetrahydrofuran or dioxane, in particular with a water-immiscible methyl tert-butyl ether.

氨基化锂的用量基于式Ⅱ的链烯炔烃一般为1.0至1.05，优选约1.02当量。 Based on the amount of lithium amide of formula Ⅱ alkenyl alkynes is generally from 1.0 to 1.05, preferably about 1.02 equivalents.

所述方法一般按下述方式进行实施：将固体氨基化锂悬浮于惰性溶剂中，并向该悬浮液中慢慢加入式Ⅱ的链烯炔烃，后者被氨基化锂去质子化;将式Ⅲ的C9单元加入到所得链烯炔锂的悬浮液中;在反应继续进行数小时后，加入水以进行水解反应，如果用甲基叔丁基醚作为溶剂，则所需式Ⅰ产物存在于上层有机相中，这极大地简化了该方法的工业实施;通过蒸馏除去溶剂和任何过量C6单元可以约95%的产率分离出式Ⅰ产物;所蒸馏出的C6单元可以容易地返送回该合成过程中。 The method is generally implemented in the following manner: The solid lithium amide was suspended in an inert solvent, to the suspension was slowly added Ⅱ formula alkenyl alkynes, which is deprotonated lithium amide; the Ⅲ of formula C9 unit added to the resulting alkenyl alkynyl lithium suspension; After the reaction continued for several hours, water was added to conduct hydrolysis reaction, if the methyl tert-butyl ether as a solvent, the presence of the desired product of formula Ⅰ in the upper organic phase, which greatly simplifies the industrial implementation of the method; removal of solvent and any excess C6 unit may yield of about 95% of the product was isolated by distillation of formula Ⅰ; being distilled C6 units can be easily sent back The synthesis process.

令人惊奇的是，可以在惰性有机溶剂中有利地进行式Ⅲ的环己烯酮与式Ⅱ的链烯炔烃的反应，因为在先有技术中，例如当使用氨基化锂时，必须在-40℃并在液氨中使下式的6-氧代异佛尔酮与链烯炔烃反应（参见Helv.Chim.Acta 65（1982）No.89，958-967，尤其是960），这在工业上是非常复杂和昂贵的。 Surprisingly, it is possible to carry out the reaction of formula Ⅲ cyclohexenone of Formula Ⅱ alkenyl alkynes advantageously in an inert organic solvent, because the prior art, for example when using lithium amide, must -40 ℃ and isophorone alkenyl alkynes reacted with (see Helv.Chim.Acta 65 (1982) No.89,958-967, especially 960) in liquid ammonia manipulation of formula 6-oxo, This is the industry is very complex and expensive.

所述键合反应的温度一般为室温至所述溶剂的沸点。 The bonding reaction temperature is generally from room temperature to the boiling point of the solvent.

在含水的酸性介质中从本发明式Ⅰ化合物中消除保护基团可以实际上定量的产率得到式Ⅵ的6-羟基-3-（3-羟基-3-甲基-4-戊烯-1-基炔基）-4，4，6-三甲基-2-环己烯-1-酮。 Elimination of protecting groups from the compounds of the present invention of formula Ⅰ in aqueous acidic medium can be virtually quantitative yield formula Ⅵ 6-hydroxy-3- (3-hydroxy-3-methyl-4-pentene-1 - yl-ynyl) -4,4,6- trimethyl-2-cyclohexen-1-one.

式Ⅵ的炔二醇在Helv.Chim.Acta 65（1982）671以及下列等等中所公开的方法中是已知的，其中尽管键合时使用了丁基锂，但其产率只有56.2%，式Ⅵ的炔二醇可用锌粉和乙酸在氯代烃（例如二氯甲烷）中或在其它惰性有机溶剂例如甲基叔丁基醚或甲苯中或者在冰醋酸中还原为式Ⅳ的C15-二醇。 Ⅵ acetylenic diol of formula in Helv.Chim.Acta 65 (1982) 671, and a method disclosed in the following and the like are known, although bonding is used wherein the butyl lithium, but the yield is only 56.2% formula Ⅵ acetylenic diol available zinc dust and acetic acid in a chlorinated hydrocarbon (e.g. dichloromethane) or, for example methyl t-butyl ether or toluene or reduced to the formula Ⅳ in other inert organic solvents in glacial acetic acid C15 - diol.

用锌/乙酸还原式Ⅵ的炔二醇在文献中未见描述过。 With zinc / acetic acid reduction formula Ⅵ acetylenic diol described in the literature no.

优选使用大约20%浓度的式Ⅵ的炔二醇在二氯甲烷/冰醋酸中的溶液，所用二氯甲烷/冰醋酸的比例为约1∶2至1∶2.5。 Preferably using about 20% strength solution of formula Ⅵ acetylenic diol in dichloromethane / glacial acetic acid, the use of methylene chloride / glacial acetic acid in a ratio of from about 1:2 to 2.5. 每摩尔起始原料适宜使用的锌量为约1-3克原子，优选约1.3至1.5克原子。 The amount of zinc per mole of the starting material used is suitably about 1 to 3 gram atoms, preferably from about 1.3 to 1.5 g atoms. 该氢化反应的温度为-20℃至室温，优选约0℃。 The hydrogenation reaction temperature is -20 ℃ to room temperature, preferably about 0 ℃.

以这种方法获得的式Ⅳ的C15-二醇可随后被转化为虾青素，有利地是按Helv.Chim.Acta 64（1981）2419-2446中所描述的方法进行。 C15- diol Ⅳ of formula obtained in this way can then be converted to astaxanthin, advantageously by Helv.Chim.Acta 64 (1981) 2419-2446 described the method performed. 我们还发现由式Ⅵ的炔二醇出发合成虾青素还无需中间分离式Ⅳ的C15-二醇和由其制得的式Ⅶ的C15-溴化物，或由其制备的式Ⅷ的C15-三苯基鏻盐，即实际上以“一罐煮”的反应方式进行。 We have also found by the formula Ⅵ acetylenic diol starting synthetic astaxanthin also without an intermediate separate Ⅳ of C15- diol and made therefrom formula Ⅶ of C15- bromide, or prepared therefrom formula Ⅷ of C15- three phenyl phosphonium salts, i.e., substantially in the "one-pot cooking" the reaction method. 与先有技术合成虾青素的方法相比，这进一步提供了更大的优点。 Compared with the prior art method of synthesis of astaxanthin, which further provides even greater advantages.

因此本发明还涉及一种非常优越的制备式Ⅴ的虾青素的总方法，该方法包含：A.在惰性溶剂中在氨基化锂存在下使式Ⅱ的链烯炔烃与式Ⅲ的环己烯酮反应， The invention therefore also relates to a very advantageous method of preparing formula Ⅴ total astaxanthin, the method comprising:. A in an inert solvent in the presence of lithium amide with the alkyne of formula alkenyl Ⅲ Ⅱ the ring of formula cyclohexenone reaction, 其中R3为可通过水解反应转化为羟基的醚、甲硅烷基醚或醛缩醇保护基团， Wherein R3 may be converted to ethers by hydrolysis reaction of a hydroxyl group, silyl ether or acetal protective group,

其中R1为H或C1-C4-烷基，R2为C1-C4-烷基; Wherein R1 is H or C1-C4- alkyl, R2 is C1-C4- alkyl;

B.在含水的酸性介质中除掉所得式Ⅰ化合物中的保护基团; B. The resulting compound of formula Ⅰ remove the protecting group in an aqueous acidic medium;

C.在二氯甲烷/乙酸中用锌粉还原所得的式Ⅵ的炔二醇; C. in dichloromethane / acetic acid with zinc dust, reducing the resulting formula Ⅵ acetylenic diol;

D.使所得式Ⅳ的C15-二醇与盐酸或氢溴酸反应; D. The resulting type Ⅳ of C15- diol with hydrochloric or hydrobromic acid;

E.使所得式Ⅶ的C15-卤化物与三苯膦反应; E. The resulting halide of formula Ⅶ of C15- reacted with triphenylphosphine;

其中X为Cl或Br，和 Wherein X is Cl or Br, and

F.使所得式Ⅷ的三苯基鏻盐与2，7-二甲基-2，4，6-辛三烯二醛进行Wittig反应，得到虾青素。 F. The resulting triphenyl phosphonium salt of formula Ⅷ and 2,7-dimethyl-2,4,6-octatriene dialdehyde Wittig reaction to give astaxanthin.

其中X为Cl或Br。 Wherein X is Cl or Br.

实施例1a.C9单元的制备将170g（1.0mol）晶状的3，4-二羟基-2，6，6-三甲基-2-环己烯-1-酮悬浮于500ml二氯甲烷中。 Preparation Example 1a.C9 unit will 170g (1.0mol) of crystalline 3,4-dihydroxy-2,6,6-trimethyl-2-cyclohexen-1-one was suspended in 500ml of dichloromethane . 首先向该悬浮液中加入500mg（2.9mmol）对甲苯磺酸，然后在室温（RT）下在2小时（h）的时间内加入144g（2.0mol）乙烯基乙基醚。 First To the suspension was added 500mg (2.9mmol) of p-toluenesulfonic acid, and then in 2 hours (h) time added 144g (2.0mol) vinyl ethyl ether at room temperature (RT) under. 然后将混合物在室温下搅拌4h，然后加入100ml 5%浓度的氢氧化钠溶液。 The mixture was then stirred for 4h at room temperature, followed by addition of 100ml 5% sodium hydroxide solution. 分出下面的有机相，水相用100ml二氯甲烷萃取一次，合并有机相，用200ml水洗涤，并在旋转蒸发仪上浓缩。 The organic phase was separated below the aqueous phase was extracted once with 100ml of dichloromethane, and the combined organic phase was washed with 200ml of water and concentrated on a rotary evaporator. 残余物在极大地减压（油泵）的条件下干燥，得到2，4，6，6-四甲基-7，7a-二氢-6H-苯并[1，3]间二氧杂环戊烯-5-酮，为黄色油状物，用薄层色谱法（TLC）检测其为纯的，用气相色谱法（GC）检测其几乎为纯的。 The residue was greatly under reduced pressure (oil pump) is dried, to give 2,4,6,6- tetramethyl--7,7a- dihydro -6H- benzo [1,3] dioxol en-5-one, as a yellow oil which was purified by thin layer chromatography (TLC) is detected as a pure, nearly pure detected by gas chromatography (GC).

粗产物通过蒸馏法（在90℃/0.1毫巴）纯化。 The crude product was purified by distillation (at 90 ℃ / 0.1 mbar) and purified.

产量为185g，相应于理论值的94.4%。 The yield was 185g, corresponding to 94.4% of the theoretical value.

b.式Ⅰ的C15单元的制备将118g（5.13mol）固体氨基化锂加入到2.0升甲基叔丁基醚（MTB）中，并将该无色悬浮液在+50℃搅拌30分钟（min）。 b. Preparation of Formula Ⅰ C15 unit will 118g (5.13mol) was added solid lithium amide to 2.0 l of methyl tert-butyl ether (MTB) are added and the colorless suspension was stirred for 30 minutes (min at + 50 ℃ ). 然后在30分钟时间内加入840g（5.0mol）3-（1-乙氧基乙氧基）-3-甲基-1-戊烯-4-炔，并将混合物在+50℃搅拌2小时。 Was then added over a 30 minute period 840g (5.0mol) 3- (1- ethoxyethoxy) -3-methyl-4-yn-1-pentene, and the mixture was stirred at + 50 ℃ 2 hours. 将其冷却至+25至30℃，然后在15分钟时间内加入558g（2.85mol）实施例1a的C9单元。 It was cooled to +25 to 30 ℃, then added over a 15 minute period 558g (2.85mol) Example C9 unit 1a. 将反应混合物在室温下搅拌1.5小时，然后在15分钟内将其加入到另一含有1.5升水的容器中。 The reaction mixture was stirred for 1.5 hours at room temperature, and then over 15 minutes and added to another vessel containing 1.5 liters of water. 将各相搅拌10分钟。 The phases were stirred for 10 minutes. 分出水相（下层）。 The aqueous phase (lower layer). 有机相用水洗涤三次，每次用500ml，并在+50℃浴中在减压至150毫巴的条件下于旋转蒸发仪中浓缩。 The organic phase was washed with water three times and concentrated under reduced pressure to 150 mbar in a rotary evaporator in a bath at + 50 ℃ with 500ml, and.

蒸发后残余物重1435g。 After evaporation residue weight 1435g.

通过Sambay蒸馏法（夹套温度为110℃，2-3毫巴，沸点为40-45℃）除去过量的3-（1-乙氧基乙氧基）-3-甲基-1-戊烯-4-炔。 By Sambay distillation (jacket temperature 110 ℃, 2-3 mbar, a boiling point of 40-45 ℃) to remove excess of 3- (1-ethoxyethoxy) -3-methyl-1-pentene 4-yn.

Sambay排出物：1023g 5-[3-（1-乙氧基乙氧基）-3-甲基戊-4-烯-1-基炔基]-2，4，6，6-四甲基-5，6，7，7a-四氢苯并[1.3]间二氧杂环戊烯-5-醇，纯度为95%。 Sambay effluent: 1023g 5- [3- (1- ethoxyethoxy) -3-methyl-pent-4-en-1-yl-ynyl] -2,4,6,6- tetramethyl - 5,6,7,7a- tetrahydro-benzo [1.3] dioxol-5-ol, 95% purity.

c.6-羟基-3-（3-羟基-3-甲基-4-戊烯-1-基炔基）-2，4，4-三甲基-2-环己烯-1-酮（Ⅵ）的制备将603g（1.65mol）在1b中得到的式Ⅰ的叔醇（Sambay排出物）溶于1400ml CH2Cl2中，向其中加入500ml水，然后加入250ml 30%浓度的H2SO4，并将混合物在室温搅拌过夜。 c.6- hydroxy-3- (3-hydroxy-3-methyl-4-penten-1-ynyl) -2,4,4-trimethyl-2-cyclohexen-1-one ( Ⅵ) A mixture of 603g (1.65mol) obtained in 1b Ⅰ the tertiary alcohol of formula (Sambay effluent) was dissolved in 1400ml CH2Cl2, to which was added 500ml of water, followed by addition of 250ml 30% concentration of H2SO4, and the mixture was stirred at room temperature overnight. 分出有机相（下层）并用500ml 5%浓度的NaHCO3溶液和500ml水各洗涤一次。 The separated organic phase (lower layer) and 500ml 5% NaHCO3 solution and the concentration of each washed once with 500ml of water.

在旋转蒸发仪中浓缩有机相，在极大减压的条件下干燥油状残余物。 The organic phase was concentrated in a rotary evaporator, under greatly reduced pressure and dried oily residue.

重量：408g 6-羟基-3-（3-羟基-3-甲基-4-戊烯-1-基炔基）-2，4，4-三甲基-2-环己烯-1-酮，相应于定量的粗产率。 Weight: 408g 6- hydroxy-3- (3-hydroxy-3-methyl-4-penten-1-ynyl) -2,4,4-trimethyl-2-cyclohexen-1-one corresponding to a quantitative crude yield.

d.式Ⅷ的三苯基鏻盐的制备将248g（1mol）在实施例1c中制备的式Ⅵ的炔二醇粗品溶于1000ml二氯甲烷中。 Preparation of d. Ⅷ the formula triphenyl phosphonium salt of 248g (1mol) prepared in Example 1c Formula Ⅵ acetylenic diol was dissolved in 1000ml of dichloromethane. 冷却至0℃后，加入180g（3.0mol）乙酸。 After cooling to 0 ℃, was added 180g (3.0mol) of acetic acid. 然后在0℃以15分钟间隔分批加入11g锌粉（总共加入88g锌，相当于1.35克原子）。 And then at 15 minute intervals 0 ℃ 11g zinc dust was added portionwise (total 88g of zinc was added, equivalent to 1.35 g atom). 在最后一批锌加入之后，将混合物在0℃搅拌45分钟。 After the last batch of zinc was added, and the mixture was stirred at 0 ℃ 45 minutes. 滤出所得乙酸锌，滤饼用二氯甲烷洗涤二次，每次用250ml。 The resulting zinc acetate was filtered off, the filter cake was washed with dichloromethane twice with 250ml. 在0℃在15分钟时间内向滤液中加入258g 47%浓度的HBr（1.50 mol HBr）的水溶液，并然后将混合物在0℃搅拌20分钟，然后加入900ml水，分出有机相（下层）。 The filtrate was added at 0 ℃ within 15 minutes in 258g 47% concentration of HBr (1.50 mol HBr) aqueous solution, and then the mixture was stirred at 0 ℃ 20 minutes and then 900ml of water, the separated organic phase (lower layer). 水相用150ml二氯甲烷洗涤一次。 The aqueous phase was washed once with 150ml of dichloromethane. 合并有机相，并与900ml水混合。 The combined organic phase was mixed with 900ml of water. 加入47g固体NaHCO3，然后将各相搅拌几分钟。 Add 47g solid NaHCO3, stirred for several minutes and then the phases. 分出下层的那一相，用900ml水洗涤，并加入8ml 1，2-环氧丁烷。 That the separation of the lower phase was washed with 900ml water and add 8ml 1,2- butylene oxide. 在冷却至≤+10℃的同时，在约15分钟时间内，分批加入262g（1.0mol）固体三苯膦，并在约30分钟时间内使混合物达到室温，再加入8ml 1，2-环氧丁烷。 After cooling to ≤ + 10 ℃, while in about 15 minutes, was added portionwise 262g (1.0mol) of solid triphenylphosphine, and the mixture was brought to room temperature over about 30 minutes, then add 8ml 1,2- ring Oxygen butane.

然后，在大气压力下，蒸掉二氯甲烷，同时加入MTB直至沸点达到+55℃为止。 Then, at atmospheric pressure, dichloromethane was distilled off while adding MTB + 55 ℃ until the boiling point reached so far.

将三苯基鏻盐悬浮液冷却至室温，在室温下搅拌30分钟后抽滤。 The triphenylphosphonium salt suspension was cooled to room temperature, stirred for 30 minutes at room temperature, suction filtered. 滤饼用MTB洗涤二次，每次用800ml，在N2气流下干燥过夜。 The filter cake was washed with MTB twice with 800ml, dried under N2 stream overnight.

重量：419g（理论值的73%）。 Weight: 419g (73% of theory).

实施例2由式Ⅵ的炔二醇出发不分离式Ⅷ的三苯基鏻盐进行虾青素的制备将100g式Ⅵ的炔二醇粗品（GC检测其纯度为约86%）溶于400ml二氯甲烷中。 Example 2 Preparation of acetylene glycol represented by the formula Ⅵ starting Ⅷ not separate the triphenyl phosphonium salt of astaxanthin 100g of acetylenic diol of formula Ⅵ crude (GC detection of about 86% purity) was dissolved in 400ml two methyl chloride. 冷却至0℃后，加入72g乙酸。 After cooling to 0 ℃, 72g of acetic acid was added. 在0℃下，以15分钟时间间隔分批加入4.4g锌粉（总共加入35.2g锌）。 At 0 ℃, at 15 minute intervals was added portionwise 4.4g of zinc powder (35.2g zinc was added in total). 在加完最后一批锌后，将混合物在0℃搅拌45分钟。 After the addition was complete the last batch of zinc, and the mixture was stirred at 0 ℃ 45 minutes. 滤掉所得乙酸锌，滤饼用二氯甲烷洗涤两次，每次用70ml。 The resulting zinc acetate was filtered off, the filter cake was washed twice with methylene chloride, each time with 70ml. 滤液用水洗涤两次，每次用300ml，在0℃下在30分钟时间内逐滴加入到104g 47%浓度的HBr水溶液中。 The filtrate was washed twice, each time with 300ml, at 0 ℃ wise over 30 minutes dropwise added to 104g 47% concentration in an aqueous solution of HBr. 将混合物在0℃搅拌30分钟，加入360ml水，分出有机相。 The mixture was stirred at 0 ℃ 30 minutes, add 360ml of water, the organic phase separated. 水相用50ml二氯甲烷萃取一次。 The aqueous phase was extracted once with 50ml of dichloromethane. 合并有机相，并与360ml水混合。 The combined organic phase was mixed with 360ml water. 加入47g固体NaHCO3，然后将各相在一起短暂地搅拌。 Add 47g of solid NaHCO3, the phases were then briefly stirred together. 分出下层的那相，用360ml水洗涤，加入3ml 1，2-环氧丁烷。 That the lower phase was separated, washed with 360ml of water, was added 3ml 1,2- butylene oxide. 在冷却至≤+10℃的同时，加入105g三苯鏻，并将混合物在室温下搅拌18小时。 After cooling to ≤ + 10 ℃ while adding 105g triphenyl phosphonium, and the mixture was stirred at room temperature for 18 hours. 然后加入22.8g（0.139mol）C10-二醛2，7-二甲基-2，4，6-辛三烯二醛，将混合物冷却至0℃，并在0℃下加入57.5g 30%浓度的甲醇钠的甲醇溶液。 Was then added 22.8g (0.139mol) C10- dialdehyde 2,7-dimethyl-2,4,6-octatriene dialdehyde, the mixture was cooled to 0 ℃, and 57.5g 30% concentration was added at 0 ℃ solution of sodium methoxide in methanol. 将混合物在0℃搅拌3小时，然后加入500ml水。 The mixture was stirred for 3 hours at 0 ℃, 500ml of water was then added. 分出有机相，水相用二氯甲烷萃取两次，每次用100ml。 The organic phase was separated, the aqueous phase was extracted with dichloromethane twice with 100ml. 合并有机相，用400ml水洗涤一次。 The combined organic phases were washed once with 400ml water. 在大气压力下，蒸出二氯甲烷，同时加入甲醇直至沸点为+65℃。 At atmospheric pressure, methylene chloride was distilled off, and methanol was added until a boiling point of + 65 ℃. 将悬浮液回流15小时，然后冷却至0℃。 The suspension was refluxed for 15 hours, then cooled to 0 ℃. 滤出所得晶体，用甲醇和庚烷洗涤，然后溶于500ml二氯甲烷中。 The resulting crystals were filtered off, washed with methanol and heptane, and then dissolved in 500ml of dichloromethane. 按如上所述用甲醇再次置换溶剂。 As described above substituted with methanol solvent again. 干燥滤饼得到63g（理论值的76.0%）虾青素，HPLC测定纯度为98.2%。 The cake was dried to give 63g (theoretical value of 76.0%) astaxanthin, HPLC purity of 98.2% was measured.