4，4'-二酮基类胡萝卜素的制备 Preparation of 4,4-diketo-carotenoids

本发明涉及对称的、末端环取代的多烯的新制备方法，尤其是鸡油菌黄质、虾青素等类型的类胡萝卜素及对应的2，2'-二去甲类胡萝卜素(一般称之为4，4'-二酮基类胡萝卜素)，是通过缩醛化的多烯二醛与环状二烯醇醚进行的酸催化的缩合反应来制备的。 The present invention relates to a symmetrical end ring-substituted polyenes new preparation methods, especially canthaxanthin, astaxanthin and other types of carotenoids and the corresponding 2,2'-carotene to the CPI (general 4,4'-diketo-called carotenoids), the condensation reaction is acid-catalyzed acetalization of polyene by dialdehyde and cyclic diene ethers prepared performed.

路易斯酸催化的α，β-不饱和醚(醛烯醚)的加成反应生成缩醛，长期以来是已知的，可追溯到Muller-Cunradi与Pieroh的成果(见美国专利2165962)。 Lewis acid-catalyzed α, β- unsaturated ethers (aldehyde enol ether) is an addition reaction of acetals, has long been known, can be traced back results Muller-Cunradi and Pieroh (see U.S. Patent No. 2,165,962). Hoaglin与Hirsch(《美国化学会会志》71，3468及以下相关页(1949))对该反应进行了进一步研究，并将其可能的应用范围扩大到β-胡萝卜素、番红花酸二醛、番茄红素以及β-阿朴类胡萝卜素的合成上，Isler等人在二十世纪五十年代同样也做到了这些(《瑞士化学学报》39，249及以下相关页和463及以下相关页(1956)，出处同上，42，854及以下相关页(1959)以及美国专利2827481和2827482)。 Hoaglin and Hirsch ("American Chemical Society" and the following related pages 71,3468 (1949)) the reaction was further studied, and to expand its range of possible applications to β- carotene, saffron, di-aldehyde on the synthesis of lycopene and carotenoids β- apomorphine, Isler et al., 1950 also did these ("Helvetica Chimica Acta," 39,249 and the following related pages and 463 and the following related pages (1956), ibid., 42,854, and the following related pages (1959) and US Patent 2,827,481 and 2,827,482). 后来，Mukaiyama(《应用化学》89，858及以下相关页(1977)和《有机反应》28，203及以下相关页(1982))利用易获得的三甲硅烷基烯醇醚，又对该反应进行了延伸。 Later, trimethylsilyl enol ether Mukaiyama ("Applied Chemistry" and the following related 89,858 (1977) and "Organic Reactions" 28,203 and the following related pages (1982)) the use of readily available, and the reaction was carried out the extension.

还有，在脂族与脂环族酮的烯醇醚的情况下，不只是烷基烯醇醚，甲硅烷基烯醇醚也与缩醛反应得到β-烷氧基酮，由于醇的裂解，得到对应的消去产物(《化学快报》1974，16及以下相关页《美国化学会会志》102，3248及以下相关页(1980)，《化学快报》1987，1051及以下相关页以及出处同上，1975，569及以下相关页)。 Further, in the case of aliphatic and alicyclic ketone enol ethers, enol ethers not only an alkyl group, a silyl enol ether and acetal obtained also β- alkoxy ketone, due to cleavage of the alcohol to obtain the corresponding elimination product ("Chemical Letters" 1974,16 and the following related pages "American Chemical Society" and the following related pages 102,3248 (1980), "Chemistry Letters" 1987,1051 and the following related pages, and ibid. , 1975,569 and the following related pages).

Nazarov与Krasnaya(J.Gen.Chem.USSR 28，2477及以下相关页(1958))和Makin(《纯化学与应用化学》47，173及以下相关页(1976)，J.Gen.Chem.USSR 31，3096及以下相关页(1961)和32，3112及以下相关页(1962))报道了第一种路易斯酸催化的1-烷氧基-1，3-二烯(二烯醇醚)与α，β-不饱和缩醛的缩合反应。 Nazarov and Krasnaya (J.Gen.Chem.USSR 28,2477 and the following related pages (1958)) and Makin ("Pure and Applied Chemistry" 47,173 and the following related pages (1976), J.Gen.Chem.USSR 31,3096 and these related pages (1961) and 32,3112 and these related pages (1962)) reported the first Lewis acid-catalyzed 1-alkoxy-1,3-diene (diene ether) and α, β- unsaturated acetal condensation reaction. 这里，就所能看到的而言，缩醛与二烯醇醚的偶合仅发生在其γ-位，生成链延长的α，β-不饱和缩醛，不过，所生成的产物竞争前者缩醛与进一步的二烯醇醚反应生成进一步的链延长的α，β-不饱和缩醛等(调聚物的生成；又见Chemla等，《法国化学会通报》130，200及以下相关页(1993))。 Here, it can be seen, the coupling of the acetal with a diene ether γ- occurs only in its position, generate chain extension of α, β- unsaturated acetals, however, the resulting product was reduced competition former Further reaction of an aldehyde with a diene ether generate further chain extension of α, β- unsaturated acetal (generated telomer; see also Chemla et al., "Bulletin Chemical Society of France" 130,200 and below the relevant page ( 1993)). 已经发现对该反应来说，这样一种缩合是不能为合成目的所利用的，尤其是对阿朴类胡萝卜素醛而言(Isler等，Adv.Org.Chem.4，115及以下相关页(1963))。 It has been found for the reaction, such a condensation is not utilized for the purpose of synthesis, especially for the purposes of apo carotenoids aldehyde (Isler, etc., Adv.Org.Chem.4,115 and below the relevant page ( 1963)).

不只是1-烷氧基-1，3-二烯，在路易斯酸催化剂的存在下，三甲硅烷氧基二烯(CH2＝CH-CH＝CH-OSi(CH3)3类型)也能与α，β-不饱和缩醛缩合，这一点已由Mukaiyama等公开在《化学快报》1975，319及以下相关页中。 Not just the 1-alkoxy-1,3-diene, in the presence of a Lewis acid catalyst, trimethylsiloxy-diene (CH2 = CH-CH = CH-OSi (CH3) 3 type) also with α, β- unsaturated acetal condensation Mukaiyama, etc. This has been disclosed in "Chemistry Letters" 1975,319 and the following related pages. 在该偶合反应中，看来该攻击也仅发生在二烯系的末端(γ)碳原子上(“γ-攻击”；Mukaiyama等，《日本化学会通报》50，1161及以下相关页(1977)和日本特许公报(公开)36645/1977/《化学文摘》87，201825t，(1977))。 In the coupling reaction, it appears that the attacks only happen at the end of the diene (γ) on the carbon atom ("γ- attack"; Mukaiyama et al., "Chemical Society of Japan Bulletin" and the following related 50,1161 (1977 ) and Japanese Patent Publication (Kokai) 36645/1977 / "Chemical Abstracts" 87,201825t, (1977)). 与1-烷氧基-1，3-二烯的反应生成α，β-不饱和缩醛，相形之下，在三甲硅烷氧基二烯与缩醛反应的情况下，所生成的醛不与二烯进行进一步的反应(没有调聚物生成)。 The reaction with the 1-alkoxy-1,3-diene generating α, β- unsaturated acetals, in contrast, in the case of trimethylsiloxy diene and an acetal reaction, the aldehyde is not generated and further reaction of the diene (no telomer generation). 因此，仅需少量的溴化锌和其他多种路易斯酸作为催化剂(Fleming等《四面体快报》1979，3209及以下相关页和Chimia 34，265及以下相关页(1980)以及Brownbridge《合成》1983，85及以下相关页)。 Therefore, only a small amount of zinc bromide and many other Lewis acid as a catalyst (Fleming and other "Tetrahedron Letters" 1979,3209 and the following related pages and Chimia 34,265 and the following related pages (1980) and Brownbridge "synthetic" 1983 85 and the following related pages). 利用该方法，Mukaiyama等能够合成维生素A(公开36645/1977，《化学快报》1975，1201及以下相关页和《日本化学会通报》51，2077及以下相关页(1978))，Rhone-Poulenc的工作人员也开发出合成类胡萝卜素和维生素A的新途径(DOS 2701489和AECSocietede Chimie Organique et Biologique No.7824350)。 Using this method, Mukaiyama, etc. can synthesize vitamin A (open 36645/1977, "Chemistry Letters" 1975,1201 and the following related pages and "Chemical Society of Japan Bulletin" and the following related pages 51,2077 (1978)), Rhone-Poulenc's new ways of staff also developed a synthesis of carotenoids and vitamin A (DOS 2701489 and AECSocietede Chimie Organique et Biologique No.7824350).

在Nazarov与Krasnaya、Makin以及Chemla等人成果的基础上，如果所需...CH＝CH-CH(O烷基1)-CH2-CH＝CH-CH(O烷基1)(O烷基2)类型的主要产物收率能够增加、并且能够抑制调聚物的生成的话，上述路易斯酸催化的二烯醇醚与α，β-不饱和缩醛的缩合反应将是一种非常重要的获得阿朴胡萝卜素醛和双阿朴胡萝卜素醛的方法。 On the basis of Nazarov and Krasnaya, Makin and Chemla et al., On the results, if desired ... CH = CH-CH (O-alkyl 1) -CH2-CH = CH-CH (O-alkyl 1) (O-alkyl The main product yields 2) type can be increased, and can inhibit the formation of telomer words, the above-described Lewis acid-catalyzed diene ethers and α, β- unsaturated acetal condensation reaction is a very important to obtain apo-carotene aldehyde and aldehyde method of double-apo-carotene. 于是，从该主要产物的缩醛基C(O烷基1)(O烷基2)的水解和烷基1OH的消去，能够得到所需...CH＝CH-CH＝CH-CH＝CH-CHO类型的多烯醛(欧洲专利公开说明书(EP)0816334 A1)。 Thus, the major product from the acetal group C (O-alkyl 1) (O-alkyl 2) alkyl 1OH hydrolysis and elimination, it is possible to obtain the desired ... CH = CH-CH = CH-CH = CH -CHO type of polyene aldehydes (European Patent Publication (EP) 0816334 A1).

...CH＝CH-CH＝C(O烷基/三甲硅烷基)-CH2-烷基类型的酮二烯醇醚与醛、缩醛、正酯和其他亲电子试剂反应，得到...E-CH2-CH＝CH-CO-CH2-烷基(E代表一种亲电子反应物)类型的α，β-不饱和酮，这样的例子是已知的(《四面体快报》22，705及以下相关页和2833及以下相关页(1981)，出处同上，27，2703及以下相关页(1986)，出处同上，29，685及以下相关页(1988)以及《化学报告》123，1571及以下相关页(1990))。 ... CH = CH-CH = C (O-alkyl / trimethylsilyl) -CH2- alkyl ether type diene ketones with aldehydes, acetals, ortho esters, and other electrophilic reagent, to give ... E-CH2-CH = CH-CO-CH2- group (E represents an electrophilic reactant) type of α, β- unsaturated ketones, such examples are known ("Tetrahedron Letters" 22,705 and the following related pages and 2833 and the following related pages (1981), ibid., and the following related 27,2703 (1986), ibid., 29,685, and the following related pages (1988) and "Chemical Report" 123,1571 and the following related pages (1990)). 该反应的用途似乎多少是有限的，这倒不是由于其反应性的缘故，而是因为上述酮二烯醇醚是难以获得的，其中特别是在其制备中不得不考虑区域选择性问题(生成所不需要的...CH2-CH＝CH-C(O-烷基/三甲硅烷基)＝CH-烷基类型的区域异构体)。 The purpose of this reaction appears to be a limited number, This is not due to their reactivity sake, but because of the above-diene ether ketone is difficult to obtain, in particular, have to consider the area where the selectivity issue in its preparation (generated The undesired ... CH2-CH = CH-C (O- alkyl / trimethylsilyl) = CH- alkyl type regioisomer).

基于上述二烯醇醚缩合反应，最近，A.Ruttimann研究出一种新的、经济的阿朴胡萝卜素醛和双阿朴胡萝卜素醛合成法(EP 0816334 A1)，该方法的优点在于，在催化条件下，也就是利用一种路易斯酸催化剂，完成CC连接。 Based on the above-mentioned diene-ether condensation reaction, recently, A.Ruttimann developed a new, economical and apo-carotenal double apo-carotene aldehyde synthesis (EP 0816334 A1), the advantages of this method is that, in under catalytic conditions, that is, using a Lewis acid catalyst, complete CC connection. 而且，在该方法中也不需要含磷或含硫试剂。 Further, in this method does not require phosphorus or sulfur-containing reagent.

现已找到一种新的方法，用来合成鸡油菌黄质、虾青素、对应的2，2'-二去甲类胡萝卜素和结构上相似的对称的具有两个末端环的类胡萝卜素(4，4'-二酮基类胡萝卜素)。 Has now found a new method for the synthesis of canthaxanthin, astaxanthin, the corresponding 2,2'-carotene and structurally similar to the CPI symmetrical ring has two ends of carotenoid Su (4,4-diketo-carotenoids). 这种新的合成法同样是基于一种催化的二烯醇醚缩合反应的，也避免了含磷与含硫试剂的使用，但要以非常精细和令人惊讶的方式使用一种环状化合物参与反应，该化合物不仅具有末端环的主要性质，而且具有缩合反应所需的二烯醇醚基团。 This new synthesis also is based on a diene ether catalyzed condensation reaction, but also to avoid the use of phosphorus-containing and sulfur-containing reagents, but a very fine and surprising use of a cyclic compound participate in the reaction, the compound not only has the main properties of the end ring, and having the desired condensation reaction diene ether groups.

本发明的目的是从多烯二缩醛开始制备上述对称的类胡萝卜素，同时尽可能避免上述本领域中存在的缺点，并取代迄今为此目的而使用的Wittig、Horner或Julia反应。 Object of the present invention is from carotenoid polyene diacetal begin preparation of the above symmetrical, as far as possible to avoid the disadvantages present in the above-described in the art, and a substituted Wittig hitherto used for this purpose, Horner or Julia reaction. 按照本发明，在一种适当催化剂、即路易斯酸或布忍司特酸的存在下，使一种多烯二缩醛与一种环状二烯醇醚反应，所得缩合产物水解后，在与两个环键合的主要共轭烃链的两端进行碱或酸诱发的醇消去反应，以得到所需对称的、末端环取代的、完全共轭的多烯，藉此达到本发明目的。 According to the present invention, in a suitable catalyst, i.e. the Lewis acid or cloth tolerance zafirlukast presence of an acid, reacting a polyene diacetal ether with a cyclic diene reaction, the resulting hydrolyzate after condensation, with two ring bonded at both ends of the main hydrocarbon chain conjugated alkali or acid induced alcohol elimination reaction, to give the desired symmetrical, ring-substituted end, a completely conjugated polyene, thereby achieve the object of the present invention. 不仅环状二烯醇醚与多烯二缩醛的反应是新的，而且出乎意料的是，该反应是由缩醛排他地攻击二烯醇醚的γ-位来完成的。 Not only ether and cyclic diene polyene diacetal reaction is new, and surprisingly, the reaction is attacked by an acetal exclusively diene ether γ- bits to complete. 通过在水解后进行的碱或酸诱发的链烷醇消去反应，无需含磷或含硫试剂即可生成两个共轭的CC双键，这与本领域中迄今所通常使用的方法相反。 By alkaline or acid hydrolysis after induced alkanol elimination reaction without phosphorus or sulfur-containing agent to generate two conjugated CC double bond, which is opposite to the method in the art so far generally used.

因此，本发明涉及通式I Accordingly, the present invention relates to the general formula I

的对称的、末端环取代的多烯的制备方法，其中R1代表氢或羟基，m代表0或1，n代表0、1或2，该方法包括：在一种路易斯酸或布忍司特酸的存在下，使通式II的多烯二(O，O-二烷基缩醛) Symmetrical, polyene preparation terminal ring-substituted, wherein R1 represents hydrogen or hydroxy, m represents 0 or 1, n represents 0, 1 or 2, the method comprising: a Lewis acid or cloth tolerance Sterling acid in the presence, of the general formula II polyene di (O, O- dialkyl acetal)

其中R2代表C1-6烷基，n含义同上，与通式III的环状二烯醇醚反应， Wherein R2 represents C1-6 alkyl, n meanings as defined above, with a cyclic diene ether of the general formula III The reaction,

其中R3代表氢，R4代表C1-4烷氧基，或者R3与R4共同代表一个被取代或不取代的亚甲二氧基-OC(R5)(R6)-O-，其中R5与R6彼此独立代表氢、C1-4烷基或苯基，m含义同上，在酸性条件下水解该反应产物，然后在碱性或酸性条件下，从由此得到的通式IV化合物中裂解掉链烷醇R2OH， Wherein R3 represents hydrogen, R4 represents C1-4 alkoxy, or R3 and R4 together represent a substituted or non-substituted methylenedioxy -OC (R5) (R6) -O-, wherein R5 and R6 independently of each other represents hydrogen, C1-4 alkyl or phenyl, m meanings as defined above, under acidic conditions, hydrolysis of the reaction product, and then under basic or acidic conditions, cleaved from the compound of formula IV thus obtained in the off alkanol R2OH ,

其中R1代表氢或羟基，这分别取决于式III中的R3与R4是代表氢或C1-4烷氧基，还是共同代表被取代或不取代的亚甲二氧基，R2、m和n含义同上。 Wherein R1 represents hydrogen or hydroxy, depending on whether the formula III R3 and R4 represent hydrogen or C1-4 alkoxy, or together represent a substituted or non-substituted methylenedioxy group, R2, m and n have the meaning Ibid.

在本发明范围内，术语“C1-4烷基”或“C1-6烷基”分别包含直链和支链基团，例如甲基、乙基、异丁基和己基。 Within the scope of the present invention, the term "C1-4 alkyl" or "C1-6 alkyl group", respectively, comprising straight chain and branched chain groups, such as methyl, ethyl, isobutyl and hexyl. 该含义也适用于烷氧基“C1-4烷氧基”的烷基部分。 This also applies to the meaning of alkoxy "C1-4 alkoxy" alkyl moiety.

在式III的环状二烯醇醚的情况下，考虑存在一种取代的环戊烯的情形(m代表0，则使式III特定地代表式IIIa In the case of cyclic diene ether of formula III, taking into account the presence of a substituted cyclopentene case (m represents 0, then the formula III represent a particular formula IIIa

或一种取代的环己烯的情形(m代表1，在这种情况下，使式III特定地代表式IIIb Or a substituted cyclohexene case (m represents one, in this case, of formula III represent a particular formula IIIb

从这种意义上来说，不言而喻，式I与式IV化合物所具有的末端环状基团(环)对应为下式基团 In this sense, it being understood that the compounds of formula I and formula IV has the terminal cyclic group (ring) corresponding to a group of formula

其中*表示各自的连接位置。 Wherein each * represents the connection position.

除非另有相反的特意说明，在本发明范围内所公开的多烯和环状二烯醇醚的结构式均包含了同分异构形式，例如旋光活性和顺式/反式或E/Z异构体，以及它们的混合物。 Unless otherwise specifically described the contrary, structural formula and cyclic diene polyene alcohol within the scope of the present invention are disclosed containing isomeric forms, e.g., optically active cis / trans or E / Z isomers thereof, and mixtures thereof. 关于E/Z异构现象，一般来说优选按照本发明方法制得的式I产物和式II多烯二(O，O-二烷基缩醛)的全E异构体。 On the E / Z isomerism, generally preferably full E-isomer was prepared according to the present invention is obtained by the product of formula I and formula II polyene di (O, O- dialkyl acetal) of.

在按照本发明方法的第一个过程步骤中，也就是在酸性条件下的多烯二(O，O-二烷基缩醛)与环状二烯醇醚的反应中，前者化合物排他地攻击环状二烯醇醚的γ-位。 In the method according to the present invention, the first process step, i.e. under acidic conditions of polyene di (O, O- dialkyl acetal) is reacted with cyclic diene ether, the former compound exclusively attack γ- bit cyclic diene ether. 如果所用的式III环状二烯醇醚中R3代表氢、R4代表C1-4烷氧基，那么将得到通式V化合物为第一个过程步骤的中间产物 If used in a cyclic diene ether of formula III wherein R3 represents hydrogen, R4 represents C1-4 alkoxy, then the resulting compound of formula V Intermediates of the first process step

另一种情况下，即所用的式III环状二烯醇醚中R3与R4共同代表被取代或不取代的亚甲二氧基，那么将得到通式VI化合物为第一个过程步骤的中间产物 In another case, i.e. with a cyclic diene ether of formula III where R3 and R4 together represent a substituted or non-substituted methylenedioxy group, then the compound of general formula VI first intermediate process steps product

第一个过程步骤习惯上是在一种路易斯酸或布忍司特酸的存在下，使式II的多烯二(O，O-二烷基缩醛)与式III的环状二烯醇醚在一种有机溶剂中反应，反应温度在约-50℃至约+60℃范围内(例如约-25℃至约+60℃)，优选在约-30℃至室温的范围内(例如从约0℃至约室温)。 The first step of the process is in the habit of a Lewis acid or cloth tolerance zafirlukast the presence of acid, of formula II polyene di (O, O- dialkyl acetal) of formula III with a cyclic diene ether in an organic solvent, the reaction temperature is in the range of from about -50 ℃ to about + 60 ℃ (e.g., from about -25 ℃ to about + 60 ℃), preferably in the range of about -30 ℃ to room temperature range (e.g., from about 0 ℃ to about room temperature). 一般来说，适用的有机溶剂为极性或非极性非质子传递溶剂。 In general, suitable organic solvent polar or non-polar solvent is passed aprotic. 这样的溶剂例如低级卤代脂肪烃，例如二氯甲烷和氯仿；低级脂肪醚和环醚，例如二乙醚、叔丁基甲基醚和四氢呋喃；低级脂肪腈，例如乙腈；低级脂肪酯，例如乙酸乙酯；以及芳香烃，例如甲苯。 Such a solvent such as a lower halogenated aliphatic hydrocarbons, such as methylene chloride and chloroform; lower aliphatic and cyclic ethers, such as diethyl ether, tert-butyl methyl ether and tetrahydrofuran; lower aliphatic nitriles, such as acetonitrile; lower aliphatic esters, such as ethyl acetate ; and aromatic hydrocarbons such as toluene. 优选的溶剂是乙腈，并可选择性地与上述其它溶剂结合使用，尤其是乙酸乙酯或二氯甲烷。 The preferred solvent is acetonitrile, and optionally in combination with other solvents described above, especially ethyl acetate or dichloromethane. 如果使用的是乙腈与乙酸乙酯或二氯甲烷的混合物，那么乙腈与乙酸乙酯或二氯甲烷的体积比优选约为1∶1至4∶1，特别是约为4∶1。 If using a mixture of acetonitrile with ethyl acetate or dichloromethane, then the volume of acetonitrile with ethyl acetate or methylene chloride is preferably about 1:1 to 4:1, especially about 4:1. 可用的路易斯酸的例子是氯化锌、氯化锌二醚合物、溴化锌、二(三氟甲磺酸)锌、四氯化钛、四氯化锡、三氟化硼醚合物以及氯化铁(III)；可用的布忍司特酸的例子是对甲苯磺酸、甲磺酸、三氟甲磺酸、硫酸以及三氟乙酸。 Available Lewis acids are zinc chloride, zinc di etherate, zinc bromide, bis (trifluoromethanesulfonate) zinc, titanium tetrachloride, tin tetrachloride, boron trifluoride etherate and ferric chloride (III); cloth tolerance zafirlukast Examples of useful acids are p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid and trifluoroacetic acid. 一般来说，路易斯酸是优选的，尤其是锌盐、三氟化硼醚合物和氯化铁(III)。 In general, Lewis acids are preferred, especially zinc salts, boron trifluoride etherate and iron chloride (III). 一般来说，催化剂的用量是催化量(低于化学计算量)，常规用量约为0.5至30摩尔百分比，以多烯二(O，O-二烷基缩醛)的用量计，优选的摩尔百分比优选在大约5％和10％之间。 In general, the amount of catalyst used is a catalytic amount (less than the stoichiometric amount), a conventional amount of about 0.5 to 30 mole percent, with a polyene di (O, O- dialkyl acetal) used terms, preferred molar percentage is preferably between about 5% and 10%. 进一步地，每当量多烯二(O，O-二烷基缩醛)习惯上使用约为2.1至4当量、优选约为2.2至2.6当量的环状二烯醇醚。 Further, whenever the amount of polyene di (O, O- dialkyl acetal) using about 2.1 to 4 equivalents, preferably about 2.2 to 2.6 equivalents of cyclic diene ether customary. 而且，反应习惯上在常压下进行，一般来说，压力不是决定性的。 Moreover, the reaction is carried out under normal pressure customary, in general, the pressure is not critical.

式V或式VI的中间体通常频繁地与不同而近似的中间体共同沉淀出来，可以在反应混合物冷却到(例如)约-10℃至-20℃、并过滤后分离这些中间体。 Intermediates of formula V or formula VI are usually frequently with different approximate common intermediate precipitated, the reaction mixture may be cooled to (e.g.) about -10 ℃ to -20 ℃, and filtered to separate these intermediates. 随后，用酸水溶液将中间体水解为对应的式IV化合物。 Subsequently, an aqueous solution with an acid compound corresponding to the intermediate of formula IV hydrolysis.

如果不进行分离和随后的水解，也可以直接在反应混合物中进行水解。 Without being isolated and subsequent hydrolysis, the hydrolysis may be carried out directly in the reaction mixture. 此时，向反应混合物中加入一种酸，优选为稍微稀释的乙酸水溶液，例如乙酸∶水的体积比约为9∶1，混合物随后通常在约0℃至50℃的温度范围内搅拌一定时间，例如大约30分钟至2小时。 At this time, the reaction mixture was added to an acid, preferably slightly dilute aqueous acetic acid, such as acetic acid: water volume ratio of about 9:1, the mixture was then stirred for a certain time is usually in a temperature range from about 0 ℃ to 50 ℃ of , e.g., about 30 minutes to 2 hours. 除了乙酸以外，为了在一定程度上促进水解反应，还可以使用催化量的对甲苯磺酸，例如约1-2摩尔百分比，以多烯二(O，O-二烷基缩醛)的用量计。 In addition to acetic acid, to some extent, promote the hydrolysis reaction, can also be used a catalytic amount of p-toluenesulfonic acid, e.g., about 1-2 mole percent to polyene di (O, O- dialkyl acetal) in an amount meter . 与式V或VI的中间体产物的单独水解相比，直接在反应混合物中进行水解是优选的。 Compared with the formula V or VI alone hydrolysis intermediate product, the hydrolysis is preferably carried out directly in the reaction mixture.

式IV的产物可以从反应混合物中分离，并且如果需要的话，用本身已知的方法纯化。 The product of formula IV can be isolated from the reaction mixture, and if desired, purified by methods known per se. 典型的方法是将混合物与水合并，全部用一种水不混溶的有机溶剂萃取，例如一种低级烷、二烷基醚或脂肪酯，分别例如己烷、叔丁基甲基醚或乙酸乙酯，有机相用水和/或碳酸氢钠溶液和/或饱和氯化钠水溶液洗涤，干燥并浓缩。 A typical approach is to merge the mixture with water, organic solvent extraction with an all water immiscible, e.g., a lower alkyl, dialkyl ether or aliphatic ester, respectively, such as hexane, tert-butyl methyl ether or ethyl acetate , organic phase was washed with water and / or sodium bicarbonate solution and / or saturated aqueous sodium chloride solution, dried and concentrated. 然后，如果需要的话，可以进一步纯化所分离的、并且至少在某种程度上洗涤过的粗产物，例如通过柱色谱法，例如使用诸如己烷、乙酸乙酯、甲苯或其混合物等洗脱液，或者通过(重)结晶法，例如从一种醇中，例如甲醇或乙醇。 Then, if desired, be further purified by separation, and at least to some extent washed crude product, e.g., by column chromatography, for example using an eluent such as hexane, ethyl acetate, toluene or mixtures thereof , or by (re) crystallization, e.g., from an alcohol, such as methanol or ethanol.

至于最后一个过程步骤，即链烷醇R2OH从式IV化合物上的裂解、链烷醇从β-烷氧基醛或δ-烷氧基-α，β-不饱和醛上的消去、同时生成对应的α，β-不饱和醛，是专业文献中已知的，可以在各种条件下进行。 As a final process step, i.e. cleavage of the alkanol R2OH from the compound of formula IV on the alkanol from β- alkoxy aldehyde or δ- alkoxy -α, β- unsaturated aldehydes on the erasing, while generating corresponding The α, β- unsaturated aldehydes, are known in the professional literature, can be carried out under various conditions. 例如，在已知的碱诱发的消去反应领域中，1，8-二氮杂双环[5.4.0]十一碳-7-烯是非常常用的碱，其用量约为2至4当量，以醛的用量计。 For example, in the elimination reaction of the known base-induced, and 1,8-diazabicyclo [5.4.0] undec-7-ene are very common base, in an amount of about 2-4 equivalents, Total amount of aldehyde. 这样的条件用在已知的类胡萝卜素的制备(特别参见《日本化学会通报》50，1161及以下相关页(1977)，出处同上，51，2077及以下相关页(1978)，《化学快报》1975，1201及以下相关页和German Offenlegungsschrift 2701489)和维生素A的制备(特别参见《化学快报》1975，1201及以下相关页)中。 Such a condition known carotenoids was prepared in (see especially "Chemical Society of Japan Bulletin" and the following related 50,1161 (1977), ibid., 51,2077 and the following related pages (1978), "Chemistry Letters "1975,1201 following related pages and German Offenlegungsschrift 2701489) and the preparation and vitamin A (see especially" Chemistry Letters "1975,1201 and the following related pages) in. 作为酸诱发的链烷醇裂解的例子，可再次参考《日本化学会通报》50，1161及以下相关页(1977)和J.Gen.Chem.USSR 30，3875及以下相关页(1960)，其中使用对甲苯磺酸或85％磷酸作为酸催化剂。 As examples of the acid-induced alkanol cleavage, may refer to "inform the Chemical Society of Japan," and the following related pages again 50,1161 (1977) and J.Gen.Chem.USSR 30,3875 and the following related pages (1960), which p-toluenesulfonic acid or 85% phosphoric acid as the acid catalyst. 尤其是在类胡萝卜素的制备中，为该裂解反应使用乙酸钠/乙酸的缓冲系统(Helv.Chem.Acta.39，249及以下相关页和463及以下相关页(1956)和美国专利2827481和2827482)。 Especially in the preparation of the carotenoid, for the cleavage reaction using sodium acetate / acetic acid buffer system (Helv.Chem.Acta.39,249 and below the relevant page and associated pages 463 and following (1956) and U.S. Patent No. 2,827,481 and 2827482). 在对应的烷氧基酮(β-烷氧基酮或δ-烷氧基-α，β-不饱和酮)的情况下，链烷醇的裂解一般来说也是非常成功的：这方面见《合成》1986，1004及以下相关页或《有机化学杂志》49，3604及以下相关页(1984)。 In the corresponding alkoxy ketones (β- alkoxy ketones or δ- alkoxy -α, β- unsaturated ketone), the cleavage of the alkanol in general is very successful: in this regard, see " synthesis "1986,1004 and the following related pages or" Journal of Organic Chemistry, "and the following related 49,3604 (1984). 有鉴于此和其他有关文献，本领域的技术人员为成功完成按照本发明的过程的最后一步找出反应条件，将是没有困难的。 In view of this and other relevant literature, skilled personnel for the successful completion of the reaction conditions, in accordance with the final step in the process to find out the present invention will be no difficulty.

而且，链烷醇R2OH(每当量式IV化合物为2当量)的裂解也可以用几当量的碱来完成，以一当量式IV化合物计。 Moreover, alkanol R2OH (Whenever the compound of formula IV to 2 equivalents) of cleavage can also be accomplished several equivalents of base to one equivalent of the compound of formula IV meter. 于是在这种情况下，最后一个过程步骤习惯上是在一种碱的存在下，随着链烷醇R2OH的裂解，将溶于一种适当的有机溶剂中的式IV化合物转化为对应的式I多烯。 So in this case, the last step of a process customary in the presence of a base, with the cleavage of the alkanol R2OH, dissolved in a suitable organic solvent of a compound of formula IV is converted to the corresponding formula I polyene. 一般来说，适当的有机溶剂是质子溶剂或非质子传递溶剂或其混合物，例如醇类，例如乙醇和异丙醇，和醇混合物；或芳香烃，例如甲苯。 In general, suitable organic solvent is a protic solvent or aprotic solvent or mixtures thereof, for example, alcohols, such as ethanol and isopropanol, and alcohol mixtures; or an aromatic hydrocarbon such as toluene. 碱可以是无机碱或有机碱，一般来说宜为强碱，尤其是那些碱金属醇化物，它们是更强的碱，例如乙醇钠。 The base may be an inorganic or organic base, in general is preferably a strong base, especially those alkali metal alcoholates which are stronger bases, such as sodium ethoxide. 正如上文所指出的那样，习惯上每当量式IV化合物使用两当量的碱，优选约为2.5至8当量。 As noted above, as is customary whenever the amount of a compound of formula IV using two equivalents of base, preferably about 2.5 to 8 equivalents.

因此，如果碱金属醇化物作为碱来使用的话，则预先制备醇钠的链烷醇溶液，或者从金属钠和链烷醇新近制备。 Therefore, if the alkali metal alcoholate as the base to be used, then the previously prepared solution of sodium alkoxide in an alkanol, or freshly prepared from metallic sodium and the alkanol. 醇钠的醇溶液与式IV化合物在(相同的)链烷醇中的溶液或混悬液(也优选为预先制备)的混合顺序可以是随意的。 Alcoholic solution of the sodium alkoxide with the compound of formula IV in the (same) alkanol in the solution or suspension (also preferably pre-prepared) mixing order can be random. 反应混合物然后一边加热一边搅拌，宜在约60℃至140℃的温度范围内进行，优选在约为80℃至100℃的温度下。 The reaction mixture was then stirred while heating, preferably in a temperature range from about 60 ℃ to 140 ℃ carried out, preferably at a temperature of about 80 ℃ to 100 ℃ of. 根据溶剂沸点的不同，反应习惯上在常压下进行，或者在轻度过压下进行(为了达到所需温度)，一般来说，压力不是决定性的。 Depending on the boiling point of the solvent, the reaction is carried out under normal pressure habit, or slight overpressure (in order to achieve the desired temperature), in general, the pressure is not critical. 在这些条件下，正常的裂解反应在几小时后结束，尤其是在大约5至10小时后结束。 Under these conditions, the normal cleavage reaction ended after a few hours, especially from about 5 to 10 hours after the end.

在酸诱发的链烷醇裂解的情况下，一般来说，适用的酸是无机强酸，例如氢氯酸、氢溴酸、氢碘酸、硫酸和高氯酸，和磺酸类，例如甲磺酸、三氟甲磺酸和对甲苯磺酸。 In the case of acid-induced alkanol cleavage, in general, suitable acids are inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and perchloric acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid. 无机酸可以是含水的，水的浓度因酸而异，约为10至50％。 Inorganic acids may be aqueous, water concentration varies by an acid, about 10-50%. 氢氯酸(尤其约为10至37％)、氢溴酸(尤其约为25至30％)或氢碘酸(例如47％)是最适用的。 Hydrochloric acid (especially about 10-37%), hydrobromic acid (especially about 25-30%) or hydriodic acid (e.g. 47%) is the most suitable. 在此情况下，仅需要使用催化量的酸即可，即，每当量式IV化合物最多用1当量，优选约为0.1至1当量。 In this case, only the need to use a catalytic amount of an acid, i.e., whenever the maximum amount of a compound of formula IV with 1 equivalents, preferably about 0.1 to 1 equivalent. 而且，酸诱发的链烷醇裂解在一种对式IV化合物具有良好溶解度的溶剂中进行(所谓的“均相裂解”)，或者在一种不是这种情况的溶剂中进行，也就是说，在该溶剂中，式IV化合物呈另一种混悬液的形式(非均相裂解)。 Furthermore, the acid-induced cleavage of the alkanol solvent in a compound of formula IV have good solubility performed (so-called "homogeneous cleavage"), or in a solvent is not the case of a, that is, in the solvent, the compound of formula IV with as another form of suspension (heterogeneous cleavage). 不过在两种情况下，酸催化剂都不必完全溶解。 In both cases, however, do not have to completely dissolve the acid catalyst. 适用于均相裂解的溶剂尤其是卤代脂肪烃，例如二氯甲烷、氯仿和1，2-二氯乙烷，和芳香烃，例如苯和甲苯。 Applicable to homogeneous cleavage solvents especially halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform and 1,2-dichloroethane, and aromatic hydrocarbons, such as benzene and toluene. 适用于非均相裂解的溶剂(分散介质)是低级脂肪腈、酮和羧酸，分别例如乙腈、丙酮和乙酸，优选为乙腈和丙酮。 The solvent (dispersion medium) applicable to the heterogeneous cleavage are lower aliphatic nitriles, ketones and carboxylic acids, respectively, such as acetonitrile, acetone, and acetic acid, preferably acetonitrile and acetone. 在两种情况下，链烷醇裂解习惯上在约-20℃至+50℃的温度范围内进行的，优选在约0℃至室温的范围内。 In both cases, the alkanol cleavage diet in a temperature range from about -20 ℃ to + 50 ℃ carried out, preferably at room temperature to about 0 ℃ range. 每种情况中的反应时间与反应温度无关，可达几小时，正常的裂解反应最晚在约5小时后结束。 In each case the reaction time and the reaction is independent of temperature, up to a few hours, a normal cleavage reaction after about 5 hours later than the end.

酸诱发的链烷醇裂解比碱诱发的链烷醇裂解更适用于虾青素的制备，也就是R1代表羟基且m和n都代表1的式I化合物。 Acid induced cleavage of the alkanol ratio of alkali-induced cleavage of the alkanol is more suitable for the preparation of astaxanthin, i.e. R1 represents a hydroxyl group and m and n represent the compounds of formula I 1.

单独进行水解和链烷醇裂解的另一种选择是，这两个过程步骤可以合并为一个过程步骤进行，无需进行式IV化合物的分离，并使用一种多少更强的酸，尤其是一种无机酸，例如含水的氢氯酸。 Another option separate hydrolysis and cleavage of the alkanol is that the two process steps can be combined into a single process step, without separation of the compound of formula IV, and uses a much stronger acid, in particular a inorganic acids, such as aqueous hydrochloric acid.

与所选择的最后一个过程步骤程序无关，产物可以用本身已知的方法从反应混合物中分离，通常是将反应混合物冷却，习惯上冷却至室温或甚至约0℃，可选地加入水并过滤。 The last step of the process regardless of the procedure selected, the product may be isolated by methods known per se from the reaction mixture, usually the reaction mixture was cooled to room temperature and cooled on customary or even about 0 ℃, optionally water was added and filtered . 分离后，产物可以用(例如)水和/或含水乙醇洗涤，最后如果需要的话，在减压下干燥。 After separation, the product can be used (for example) water and / or aqueous ethanol, and finally, if desired, dried under reduced pressure. 如果需要的话，可以进一步使用诸如柱色谱法和重结晶法，以得到更纯净的产物。 If desired, may be further used, such as column chromatography and recrystallization, to obtain a more pure product. 如果需要将产物中存在的Z异构体异构化为对应的E异构体，在分离和纯化过程中可以包括相关的中间步骤；该步骤包括冷却后立即加入一种醇或含水醇，例如含水异丙醇，将混合物加热到约80℃至100℃，随即再次将混合物冷却，滤出固体并干燥。 If desired the product present in the corresponding Z-isomer is isomerized to the E isomer, in the separation and purification process may comprise the intermediate step associated; This step comprises adding an alcohol or aqueous alcohol immediately after cooling, e.g. aqueous isopropanol, and the mixture was heated to about 80 ℃ to 100 ℃, then the mixture was cooled, the solid was filtered off again and dried. 饱和的低级烃也可以考虑用作溶剂，例如庚烷。 Saturated lower hydrocarbons may also be considered as a solvent, such as heptane. 一般来说，E异构体的溶解度比对应的Z异构体低，因此经常产生大量沉淀。 In general, the solubility of the E-isomer is lower than the corresponding Z-isomer, it is often a large amount of precipitate. 而且如上所述，式I产物的全E异构体一般来说是优选的。 As noted above, all-E isomer of the product of formula I is generally preferred.

在如上定义的按照本发明的过程中，R2优选代表甲基，R3优选代表氢，R4优选代表异丁氧基，或者R3与R4优选共同代表亚甲二氧基(R5＝R6＝氢)，n优选代表1。 As defined above in the process according to the invention, R2 preferably represents methyl group, R3 preferably represents hydrogen, R4 preferably represents isobutoxy group, or R3 and R4 together represent preferably a methylenedioxy group (R5 = R6 = hydrogen), n preferably represents 1.

一部分按照本发明过程所得到的浸提物是已知的，其他产物可以按照本身已知的方法从在一定程度上是已知的前体物质制得。 Part of the process according to the present invention is obtained extracts is known, the other can be obtained from the product to some extent are known precursors prepared according to methods known per se.

因此，例如，新颖的式II的多烯二(O，O-二烷基缩醛)用一种已知的通用方法可以简单地制得，即，在催化量的一种有机酸或路易斯酸的存在下，分别例如对甲苯磺酸或氯化锌，使对应的式VII多烯二醛 Thus, for example, the novel formula II polyene di (O, O- dialkyl acetal) by a known general method can be easily prepared, i.e., in a catalytic amount of an organic acid or a Lewis acid in the presence of, respectively, e.g., p-toluenesulfonic acid or zinc chloride, so that the corresponding polyene dialdehyde of formula VII

与三烷基原甲酸酯反应，特别是在分别对应的C1-6链烷醇中进行，例如在甲醇中与O，O-二甲基乙缩醛反应(例如参见Organikum，Organisch-chemisches Grundpraktikum第6版，p.377及以下相关页(1963))。 Trialkyl orthoformate is reacted with, particularly in the corresponding C1-6 alkanol, e.g. methanol, and O, O- dimethyl acetal reaction (see Organikum, Organisch-chemisches Grundpraktikum 6th ed., p.377 and following the relevant page (1963)). 反应在一定程度上是在混悬液中进行的，也就是将分别的多烯二醛悬浮在链烷醇或链烷醇/二氯甲烷混合物中，然后习惯上向该混悬液中加入约四摩尔当量的三烷基原甲酸酯，随后加入痕量的酸催化剂，例如对甲苯磺酸。 The reaction is carried out to some extent in suspension, that is, respectively the polyene dialdehyde was suspended in alkanol or alkanol / methylene chloride mixture, and then added to the suspension to about the customary four molar equivalents of a trialkyl orthoformate, followed by addition of a trace amount of an acid catalyst, such as p-toluenesulfonic acid. 在此过程中，二醛缓慢溶解，同时，所生成的式II的多烯二(O，O-二烷基缩醛)缓慢结晶出来。 In this process, two aldehyde dissolves slowly, at the same time, the resulting formula II polyene two (O, O- dialkyl acetal) slowly crystallized out. 反应习惯上在约0℃至40℃的温度范围内进行，通常进行30分钟至约4小时。 The reaction is customary in a temperature range from about 0 ℃ to 40 ℃ performed, usually 30 minutes to about 4 hours. 进一步参考欧洲专利公开说明书252389和391033以及J.Mol.Cat.79，117及以下相关页(1993)，它们阐述了一般已知的缩醛化方法。 With further reference to European Patent Publication 252 389 and 391 033 and J.Mol.Cat.79,117 and these related pages (1993), which describes a method generally known acetalization.

下面将要讨论的式VII多烯二醛，或者是已知的，尤其是见于有关类胡萝卜素的专业文献中，或者是新颖的，也可以按照本身已知的方法制备。 Of formula VII as will be discussed polyene dialdehyde, are either known, especially found in specialized literature on carotenoids, or are novel, can be prepared according to methods known per se. 例如，由文献可知，2，7-二甲基-2，4，6-辛三烯-1，8-二醛(所谓的“C10-二醛”)与C5-或C10-维蒂希醛进行两重反应，得到不同链长的二醛。 For example, known from the literature, 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde (so-called "C10- dialdehyde") and C5- or C10- Wittig aldehyde The reaction carried out twofold, to give different chain lengths dialdehyde. 出版于Birkhauser Basel and stuttgast，1971的教科书《类胡萝卜素》，尤其在VI和XII章给出了很多关于已知二醛的制备和产生的有用的信息。 Published in Birkhauser Basel and stuttgast, 1971 textbook "carotenoids", especially in Chapter VI and XII are given a lot of preparation on the known dialdehydes and useful information generated.

式III的环状二烯醇醚是新颖的，代表了本发明进一步方面的内容。 Cyclic diene ether of formula III are novel and represent a further aspect of the present invention.

其中R3代表氢、R4代表C1-4烷氧基、m代表0的环状二烯醇醚可以按照下列反应流程1进行制备，原料为已知的2-甲基-1，3-环戊二酮： Wherein R3 represents hydrogen, R4 represents C1-4 alkoxy group, m represents 0 may be a cyclic diene ethers prepared according to the following reaction scheme, starting materials are known 2-methyl-1,3-cyclopentadiene ketone:

反应流程1 Reaction Scheme 1

其中R4代表甲氧基或异丁氧基的式X化合物是已知的，可以按照Rosenberger等人的方法进行制备(《有机化学杂志》47，2134及以下相关页(1982))，原料为商业上可得到的式VIII的2-甲基-1，3-环戊二酮/1-羟基-2-甲基环戊-3-酮，分别与甲醇或异丁醇进行酸催化的醚化反应，生成对应的式IX化合物，随后在低温下，例如约-70℃，与甲基碘和二异丙基锂胺进行双甲基化反应。 Wherein R4 represents methoxy or isobutoxy group of compounds of formula X are known, can be prepared ("Journal of Organic Chemistry" and the following related pages 47,2134 (1982)) according to Rosenberger et al. Method, the raw material for the commercial the formula VIII obtained 2-methyl-1,3-cyclopentadione / 1-hydroxy-2-methyl-cyclopentyl-3-one, respectively, with methanol or isobutanol acid catalyzed etherification reaction of to give the corresponding compound of formula IX, then at a low temperature, e.g., about -70 ℃, with methyl iodide and diisopropyl amine, lithium bis methylation reaction. 对第一个过程步骤VIII→IX来说，对甲苯磺酸/甲苯是尤为适合的酸催化剂/溶剂组合，四氢呋喃优选用作第二个过程步骤的溶剂。 The first step of the process VIII → IX, the acid catalyst p-toluenesulfonic acid / toluene is particularly suitable / solvent combination, tetrahydrofuran is preferably used as the second step of the process solvent. 其中R4代表甲氧基或异丁氧基以外的C1-4烷氧基的其他式X化合物可以用相似方法制备。 Other compounds of formula X wherein R4 represents methoxy or isobutoxy group other than C1-4 alkoxy may be prepared by a similar method.

按照Peterson烯化反应(《有机化学杂志》33，780及以下相关页(1968))，然后使式X的酮基烯醇醚与三甲硅烷基甲基锂(宜由三甲硅烷基甲基氯和金属锂在戊烷中制得)在戊烷中反应，随后加入水，得到晶体形式的式XI化合物。 According to Peterson olefination ("Journal of Organic Chemistry" and the following related pages 33,780 (1968)), and then the ketone group and trimethylsilyl enol ether of formula X is methyl lithium (preferably by trimethylsilyl chloride and prepared lithium in pentane) reaction in pentane, followed by addition of water to give a crystalline form of a compound of formula XI. 随后，用氢化钾作为碱、在四氢呋喃溶剂中、在低于室温的温度下，例如在约0℃至15℃的温度范围内，直接将式XI化合物转化为所需的式IIIa环状二烯醇醚。 Subsequently, potassium hydride as a base, in a tetrahydrofuran solvent, at temperatures below room temperature, for example in a temperature range from about 0 ℃ to 15 ℃ directly the compound of formula XI is converted to the desired cyclic diene of formula IIIa ether. 在此过程中，将在过程步骤X→XI中用作溶剂的戊烷蒸馏，并用最后一个过程步骤XI→IIIa的溶剂(四氢呋喃)代替，直至沸点达到约62℃(四氢呋喃的沸点为66℃)。 In this process, will be used in the process step X → XI in pentane solvent was distilled and replaced with the last process step XI → IIIa solvent (tetrahydrofuran), until it reaches a boiling point of about 62 ℃ (boiling point of THF is 66 ℃) . 没有必要分离作为中间体产生的式XI化合物：通过溶剂置换和热处理，该化合物分解为所需的式IIIa环状二烯醇醚和三甲硅链烷醇的锂盐。 There is no need to isolate the compound of formula XI as intermediates produced: by solvent replacement and heat treatment, decomposition of the lithium salt of the compound of formula IIIa desired trimethylsilyl ethers and cyclic dienes alkanol.

加入水后，由此得到的二烯醇醚宜用一种适当的溶剂萃取，尤其是一种低级烷，例如戊烷或己烷，或用一种低级脂肪醚萃取，例如二乙醚，其后在高真空下蒸馏，进行纯化。 After addition of water, thereby obtaining a diene ether is appropriate to a suitable extraction solvent, especially a lower alkyl, such as pentane or hexane, or a lower aliphatic ether extracts, such as diethyl ether, followed by distillation under high vacuum, and purified.

其中R3代表氢、R4代表C1-4烷氧基、m代表1的式III环状二烯醇醚可以按照下列反应流程2制备： Wherein R3 represents hydrogen, R4 represents C1-4 alkoxy group, m represents one of the cyclic diene ethers of formula III can be prepared according to the following reaction scheme 2:

反应流程2 Reaction Scheme 2

其中R4代表甲氧基、乙氧基或异丁氧基的式XIII化合物是已知的(分别见《四面体快报》37，1015及以下相关页(1996)和EP31875)，可以按照Rosenberger等人的方法进行制备(《有机化学杂志》47，2134(1982))，原料为异丁酸甲酯和乙基乙烯基酮(通过Robinson成环反应)，随后使所得式XII的1-羟基环己-3-酮与对应的链烷醇进行酸催化的醚化反应，得到对应的式XIII化合物。 Wherein R4 represents methoxy, ethoxy or isobutoxy group of compounds of formula XIII are known (see "Tetrahedron Letters" 37,1015 and these related pages (1996), and EP31875, respectively), can follow Rosenberger et al. Preparation method ("Journal of Organic Chemistry," 47,2134 (1982)), the raw material for methyl isobutyrate and ethyl vinyl ketone (by Robinson annulation), then the resulting Formula XII 1- hydroxy-cyclohexyl 3-one with the corresponding alkanol acid catalyzed etherification reaction to give the corresponding compound of formula XIII. 对最后一个过程步骤XII→XIII来说，甲磺酸或对甲苯磺酸尤其适合用作酸催化剂，低级烷、例如己烷，或芳香烃、例如苯或甲苯，尤其适合用作溶剂。 The last step of a process for XII → XIII, methanesulfonic acid or p-toluenesulfonic acid is particularly suitable for use as a catalyst, lower alkoxy, such as hexane, or aromatic hydrocarbons, such as benzene or toluene, particularly suitable as the solvent. 其中R4代表甲氧基、乙氧基或异丁氧基以外的C1-4烷氧基的其他式XIII化合物可以用相似方法制备。 Other compounds of formula XIII wherein R4 represents methoxy, ethoxy or isobutoxy group other than C1-4 alkoxy may be prepared in a similar manner.

制备所需的式IIIb环状二烯醇醚的第三个和最后一个过程步骤与制备对应的5环化合物所需的过程步骤X→XI和过程步骤XI→IIIa可以是相似的(按照Peterson烯化反应，《有机化学杂志》33，780及以下相关页(1980))。 Required for preparing the desired cyclic diene ether of the formula IIIb the third and final step of a process for preparing the 5 ring compound corresponding to the process step X → XI XI → IIIa and process steps may be similar (according to Peterson ene reaction, "Journal of Organic Chemistry," and the following related pages 33,780 (1980)). 尽管式XIV化合物可以通过结晶法分离和纯化，不过它是非常不稳定的，尤其是纯晶体形式；在空气中易于重排为式XV化合物 Although the compounds of formula XIV may be isolated and purified by crystallization, but it is very volatile, particularly pure crystalline form; easy rearrangement of a compound of Formula XV in air

因此，式XIV化合物在结晶和适于在高真空下并充以惰气、例如氩的条件下干燥后，必须尽可能迅速地用在下一个(最后一个)过程步骤中。 Thus, the crystalline compound of formula XIV under high vacuum and adapted and filled with an inert gas, such as argon after drying under the conditions to be as quickly as possible with the next (and final) step in the process. 最后一个过程步骤宜在氢化钾碱的存在下、在四氢呋喃溶剂中进行，反应温度在约0℃至15℃的范围内。 The last step of the process preferably in the presence of a base potassium hydride, in tetrahydrofuran solvent, and the reaction temperature in the range from about 0 ℃ to 15 ℃ of.

加入水后，由此得到的二烯醇醚宜用一种适当的溶剂萃取，尤其是一种低级烷，例如戊烷或己烷，或用一种低级脂肪醚萃取，例如二乙醚，其后在高真空下蒸馏，进行纯化。 After addition of water, thereby obtaining a diene ether is appropriate to a suitable extraction solvent, especially a lower alkyl, such as pentane or hexane, or a lower aliphatic ether extracts, such as diethyl ether, followed by distillation under high vacuum, and purified.

高效进行式IIb环状二烯醇醚的制备方法是，在约0℃至-10℃的温度下，使式XIII化合物与三甲硅烷基甲基锂在戊烷中反应，其后用四氢呋喃代替戊烷，直至达到四氢呋喃的沸点；因此这是一种一罐反应(one-potreaction)。 Preparation with high efficiency cyclic diene of formula IIb ether is at a temperature of from about 0 ℃ to -10 ℃ of the compound of formula XIII with trimethylsilyl methyl lithium in pentane reaction, subsequently with tetrahydrofuran instead pentyl alkoxy, until it reaches the boiling point of tetrahydrofuran; therefore it is a can of the reaction (one-potreaction). 正如上述式IIIa环状烯醇醚的制备方法，所得式XIV中间体因此分解为所需的式IIIb环状烯醇醚和三甲硅烷醇的锂盐。 As the preparation method of the cyclic enol ether of formula IIIa, the resulting intermediate of formula XIV thus decompose the lithium salt of formula IIIb desired cyclic trimethylsilyl enol ether and alcohol. 不过应当避免在四氢呋喃中加热的时间过长，因为在主要为碱性的条件下，所得环状烯醇醚能部分异构化为对应的式XVI环己二烯 However, it should be avoided in tetrahydrofuran heated too long, because in mainly alkaline conditions, resulting cyclic enol ether can be partially isomerized to the corresponding Formula XVI cyclohexadiene

最后，其中R3与R4共同代表一个可选被取代的亚甲二氧基-OC(R5)(R6)-O-的式III环状二烯醇醚可以按照下列反应流程3进行制备，原料分别为已知的1，5-二羟基-2，4，4-三甲基环戊-1-烯-3-酮或1，6-二羟基-2，4，4-三甲基环已-1-烯-3-酮：反应流程3 Finally, where R3 and R4 together represent an optionally substituted methylenedioxy -OC (R5) (R6) -O- cyclic diene ether of formula III according to the following reaction scheme 3 can be prepared, starting material, respectively known 1,5-dihydroxy-2,4,4-trimethyl-1-ene-3-one or 1,6-dihydroxy-2,4,4-trimethyl cyclohexanone - 1- en-3-one: Reaction Scheme 3

用一种本身已知的方法，将式XVII化合物与一种酮R5COR6或其二甲基缩醛进行缩醛化反应，得到对应的式XVIII化合物(见《瑞士化学学报》64，2436及以下相关页(1981)和EP 0085158 A2)。 In a manner known per se, the compound of formula XVII with a ketone R5COR6 dimethyl acetal or acetal, to give the corresponding compound of formula XVIII (see "Helvetica Chimica Acta" 64,2436 and these related (1981) and EP 0085158 A2). 如果所用的酮或二甲基缩醛是丙酮或其二甲基缩醛，在此情况下，由此得到的式XVIII化合物是已知的，其中R5与R6都代表甲基，m代表0或1。 If the ketone used is acetone or dimethyl acetal or dimethyl acetal, in this case, the compound of formula XVIII thus obtained are known, wherein R5 and R6 represent methyl, m represents 0 or 1. 不过，优选使用甲醛或甲醛二甲基缩醛作为缩醛化试剂，则大量得到R5与R6都代表氢的XVIII化合物。 However, it is preferred to use formaldehyde or formaldehyde dimethyl acetal as the acetalization reagent, the large quantities R5 and R6 all represent hydrogen XVIII compound. 下面两个过程步骤XVIII→XIX和XIX→IIIc可以分别按照类似于反应流程1或2的过程步骤X→XI与XI→IIIa或XIII→XIV与XIV→IIIb的方法进行。 The following two process steps XVIII → XIX and XIX → IIIc may be respectively a manner similar to Reaction Scheme X → XI and XI → IIIa or XIII → XIV and XIV → IIIb method procedure 1 or 2 steps. 该过程优选的产物是4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环，也就是R5与R6都代表氢且m代表1的式IIIc化合物。 Preferred product of the process is 4,6,6-trimethyl--5,6,7,7a- tetrahydro-5-methylene-1,3-benzo-dioxolane, that is, R5 and R6 are represents hydrogen and m stands for a compound of formula IIIc 1.

不仅式III的环状二烯醇醚，而且式IV、V和VI的中间体都是新颖的，同样代表了本发明的进一步方面内容。 Not only the cyclic diene ether of formula III and formula IV, V and VI are novel intermediates, also represents a further aspect of the present invention.

按照本发明方法的终产物、即对称的、末端环取代的通式I多烯在极大程度上属于类胡萝卜素领域，可以用相应的方法加以利用，例如作为着色剂或色素，用于食品、蛋黄、体被(尤其是皮肤、腿和嘴)和/或家禽的皮下脂肪、鱼和有外壳的动物等的肉和/或体被(尤其是皮肤、鳞和贝壳)。 The final product according to the method of the present invention, i.e. symmetric, the end of the ring-substituted polyene of formula I belong to a large extent on the carotenoids in the field, can be used with the appropriate methods, for example as a colorant or pigment, used in food , egg yolk, body is meat (especially skin, legs and mouth), and / or subcutaneous fat of poultry, fish and other animals, and with a housing and / or body is (especially skin, scales and shells). 例如，虾青素是适用于鲑鱼着色的主要色素。 For example, the pigment astaxanthin is mainly applied to salmon colored. 可以按照本身已知的方法实现该用途，例如欧洲专利申请No.630578所述。 The purpose can be achieved by methods known per se, for example, in European Patent Application No.630578.

根据下列实施例对本发明进行举例说明：A.多烯二(O，O-二烷基缩醛)(式II化合物)的制备实施例18，8'-二阿朴胡萝卜素醛二甲基缩醛(番红花酸二醛二甲基缩醛)在带有磁搅拌器和氩气化装置的500ml圆底烧瓶中，将15g(50.1mmol)番红花酸二醛(根据HPLC结果，纯度≥99％)和30g(141mmol)三甲基原甲酸酯悬浮在50ml二氯甲烷和40ml甲醇中。 The following examples illustrate the present invention in accordance with:. A polyene di (O, O- dialkyl acetal) (compound of formula II) of Preparation Example 18,8'- di apo carotenal dimethyl ketal aldehyde (saffron diethyl dimethyl acetal) in a 500ml round bottom flask equipped with a magnetic stirrer and argon gasification means, a 15g (50.1mmol) di saffron aldehyde (based on HPLC results, purity ≥99%) and 30g (141mmol) trimethyl orthoformate was suspended in 50ml of dichloromethane and 40ml of methanol. 在室温下，一边搅拌一边向其中加入60mg对甲苯磺酸一水合物。 At room temperature with stirring was added thereto 60mg p-toluenesulfonic acid monohydrate. 所存在的晶体在约2-3分钟内溶解，再过5分钟后有黄色沉淀生成。 The presence of crystals was dissolved in about 2-3 minutes, after further 5 minutes a yellow precipitate formed. 搅拌约40分钟后，滴加250ml甲醇，随后是0.3ml三乙胺。 After stirring for about 40 minutes, a solution of 250ml of methanol, followed by 0.3ml of triethylamine. 随后在减压(350-400mbar/35-40kPa)、30℃下，在30分钟内蒸馏除去约50ml溶剂，即二氯甲烷。 Then under reduced pressure (350-400mbar / 35-40kPa), at 30 ℃, within 30 minutes the solvent was removed by distillation of about 50ml, i.e., dichloromethane. 然后将残余物用冰浴冷却至0℃，滤出，用-10℃甲醇洗涤，在高真空、室温下干燥。 The residue was then cooled with an ice bath to 0 ℃, filtered off, washed with methanol -10 ℃, in high vacuum, and dried at room temperature. 得到17.8g番红花酸二醛二甲基缩醛，为橙黄色晶体。 Saffron get 17.8g di dimethyl acetal, as orange crystals. 从50ml热二氯甲烷中重结晶，一边搅拌一边向其中滴加260ml甲醇，随后冷却至0℃，过滤，用10℃甲醇洗涤，在室温、高真空下干燥后，得到17.02g(产率87％)番红花酸二醛二甲基缩醛，为橙黄色晶体，熔点138℃，根据HPLC结果，含量＞99％；UV(己烷/2％二氯甲烷)：456nm(logE＝4.63)，423nm(logE＝5.02)，398nm(logE＝4.90)，378nm(logE＝4.63)；1H-NMR(C6D6，400MHz)：1.83(s，6H)，1.87(s，6H)，3.18(s，12H)，4.59(s，2H)，6.25-6.7(m，10H，烯H)；微量分析：计算值：C74.19％ H9.34％实测值：C74.1％ H9.32％实施例28，8'-二阿朴胡萝卜素醛二乙基缩醛(番红花酸二醛二乙基缩醛)在室温下，在带有磁搅拌器和氩气化装置的250ml圆底烧瓶中，将10.0g番红花酸二醛(根据HPLC结果，纯度≥99％)悬浮在30ml二氯甲烷和70ml乙醇中。 Recrystallized from 50ml hot methylene chloride, while stirring 260ml of methanol was added dropwise thereto, followed by cooling to 0 ℃, filtered, washed with 10 ℃ methanol, and dried at room temperature in high vacuum to give 17.02g (yield 87 %) Saffron di dimethyl acetal as an orange-yellow crystals, melting point 138 ℃, based on HPLC results, content of> 99%; UV (hexane / 2% methylene chloride): 456nm (logE = 4.63) , 423nm (logE = 5.02), 398nm (logE = 4.90), 378nm (logE = 4.63); 1H-NMR (C6D6,400MHz): 1.83 (s, 6H), 1.87 (s, 6H), 3.18 (s, 12H ), 4.59 (s, 2H), 6.25-6.7 (m, 10H, alkylene H); microanalysis: Calcd: C74.19% H9.34% Found: C74.1% H9.32% Example 28, 8'-apo-carotenal di diethyl acetal (saffron diethyl diethylacetal) at room temperature, in a 250ml round bottom flask equipped with a magnetic stirrer and argon gasification means, a 10.0g saffron di aldehyde (based on HPLC results, purity ≥99%) were suspended in 30ml of dichloromethane and 70ml ethanol. 在室温下，一边搅拌一边向其中加入22g(140mmol)三乙基原甲酸酯和50mg对甲苯磺酸一水合物。 At room temperature with stirring was added thereto 22g (140mmol) of triethyl orthoformate and 50mg of p-toluenesulfonic acid monohydrate. 所存在的晶体在约10-15分钟内溶解，形成暗绿色溶液。 The presence of crystals was dissolved in about 10-15 minutes to form a dark green solution. 在室温下再搅拌15分钟后，混合物用0.5ml三乙胺中和，随后在减压(200-120mbar/20-12kPa)下除去二氯甲烷。 After stirring at room temperature for 15 minutes, the mixture was neutralized with 0.5ml of triethylamine, then under reduced pressure (200-120mbar / 20-12kPa) dichloromethane removed. 因此分离到橙色晶体。 Thus isolated orange crystals. 下面再加入30ml乙醇，混合物冷却至0℃，滤出晶体，用-10℃乙醇洗涤。 The following was added 30ml of ethanol, the mixture was cooled to 0 ℃, crystals were filtered off, washed with -10 ℃ ethanol. 在高真空、室温下干燥后，得到11.23g番红花酸二醛二乙基缩醛，为微细的橙色粉末，熔点128-129℃。 After high vacuum dry at room temperature to afford 11.23g of diethyl saffron aldehyde diethyl acetal as an orange fine powder, melting at 128-129 ℃. 从0℃的二氯甲烷/乙醇中重结晶，得到10.4g(产率68％)番红花酸二醛二乙基缩醛，为微细的橙黄色晶体，熔点130-130.5℃，根据HPLC结果，含量为97.5％；UV(环己烷/3％二氯甲烷)：462nm(logE＝5.11)，434nm(logE＝5.10)，411nm(logE＝4.88)；质谱：444(M+，80)；1H-NMR(C6D6，400MHz)：1.26(t，J＝7Hz，6H)，1.94和2.04(2s，均为3H)，3.50和3.70(2m，均为2H)，4.90(s，1H)，6.4-6.8(5烯H)；微量分析：计算值：C75.63％ H9.97％实测值：C75.44％ H9.86％B.环状二烯醇醚(式III化合物)的制备实施例31-异丁氧基-2，4，4-三甲基-3-外亚甲基环戊烯(式III中R3代表氢，R4代表异丁氧基，m代表0)(i)1-异丁氧基-2，4，4-三甲基环戊烯-3-酮的制备为了制备二异丙基锂胺的四氢呋喃溶液(“LDA溶液”)，在氩气下，向470ml(750mmol)丁基锂的1.6M己烷溶液与390ml四氢呋喃的混合物中滴加117ml(830mmol)二异丙胺，滴加在30分钟内完成，并使温度缓慢降至-15℃。 From 0 ℃ methylene chloride / ethanol and recrystallized to give 10.4g (68% yield) of saffron diethyl diethylacetal, as fine orange crystals, mp 130-130.5 ℃, according to the results of HPLC in an amount of 97.5%; UV (cyclohexane / 3% dichloromethane): 462nm (logE = 5.11), 434nm (logE = 5.10), 411nm (logE = 4.88); Mass spectrum: 444 (M +, 80); 1H -NMR (C6D6,400MHz): 1.26 (t, J = 7Hz, 6H), 1.94 and 2.04 (2s, both 3H), 3.50 and 3.70 (2m, both 2H), 4.90 (s, 1H), 6.4- 6.8 (5-ene-H); microanalysis: Calcd: C75.63% H9.97% Found: C75.44% H9.86% B Preparation of cyclic diene ether (compound of Formula III) of Example 31. - isobutoxy-2,4,4-trimethyl-3-exo-methylene cyclopentene (formula III wherein R3 represents hydrogen, R4 representative isobutoxy, m for 0) (i) 1- iso Preparation of 2,4,4-trimethyl-butoxy-cyclopenten-3-one To a tetrahydrofuran solution of lithium diisopropyl amine ("LDA solution") was prepared under argon, 470ml (750mmol) 1.6M solution of butyllithium in hexane and the mixture of 390ml of tetrahydrofuran was added dropwise 117ml (830mmol) of diisopropylamine was added dropwise over 30 minutes to complete, and the temperature was gradually reduced to -15 ℃.

将430ml(约330mmol)上述LDA溶液置于带有机械搅拌器、温度计500ml滴液漏斗和氩气化装置的1.5升磺化烧瓶中。 The 430ml (about 330mmol) above LDA solution was placed with a mechanical stirrer, a thermometer and a dropping funnel 500ml argon gasification means of 1.5 l sulfonation flask. 向其中滴加55g(327mmol)1-异丁氧基-2-甲基环戊烯-3-酮。 To this was added dropwise 55g (327mmol) 1- isobutoxy-2-methyl-cyclopentene-3-one. 反应混合物然后在-70℃下搅拌20分钟，随后用20.3ml(46.3g，326mmol)甲基碘缓慢处理，使温度升至室温。 The reaction mixture was then stirred at -70 ℃ 20 minutes, followed by 20.3ml (46.3g, 326mmol) methyl iodide slow processing, the temperature was raised to room temperature. 在室温下搅拌15分钟后，再将混合物冷却至-70℃，再滴加300ml(230mmol)上述LDA溶液，然后是14.1ml(32.1g，226mmol)甲基碘。 Stirred at room temperature for 15 minutes, the mixture was cooled to -70 ℃, and then added dropwise 300ml (230mmol) above LDA solution, followed by 14.1ml (32.1g, 226mmol) of methyl iodide. 使混合物温度再升至室温，该程序用下列试剂重复三次：128ml(98mmol)LDA溶液和6.1ml(14g，100mmol)甲基碘、86ml(66mmol)LDA溶液和4.0ml(9g，65mmol)甲基碘以及42ml(32mmol)LDA溶液和2.0ml(4.5g，32mmol)甲基碘。 Temperature of the mixture was raised to room temperature again, the program is repeated three times using the following reagents: 128ml (98mmol) LDA solution and 6.1ml (14g, 100mmol) of methyl iodide, 86ml (66mmol) LDA solution and 4.0ml (9g, 65mmol) methyl iodine and 42ml (32mmol) LDA solution and 2.0ml (4.5g, 32mmol) of methyl iodide. 其后将反应混合物在室温下搅拌一小时。 Next, the reaction mixture was stirred at room temperature for one hour.

为了进行逐步反应，先向其中缓慢滴加100ml水，然后是500ml二乙醚，分离含水相，有机相用约500ml饱和氯化钠溶液洗涤。 In order to carry out the reaction stepwise, 先向 100ml of water was slowly added dropwise, followed by 500ml diethyl ether, the aqueous phase was separated, washed with about 500ml organic phase was washed with saturated sodium chloride solution. 随后有机相经无水硫酸钠干燥，在35℃、减压下浓缩。 The organic phase is then dried over anhydrous sodium sulfate, and concentrated under 35 ℃, under reduced pressure. 得到65g粗的1-异丁氧基-2，4，4-三甲基环戊烯-3-酮，为无色的油。 To give 65g of crude 1-isobutoxy-2,4,4-trimethyl-cyclopentene-3-one, as a colorless oil.

从49g(291mmol)1-异丁氧基-2-甲基环戊烯-3-酮开始，以完全相似的方法重复该甲基化反应。 From 49g (291mmol) 1- isobutoxy-2-methyl-cyclopentene-3-one begins to repeat a similar manner to complete the methylation reaction. 以这种方法进一步得到49g粗的1-异丁氧基-2，4，4-三甲基环戊烯-3-酮。 In this way further 49g of crude 1- isobutoxy-2,4,4-trimethyl-cyclopentene-3-one.

通过在短Vigreux柱上蒸馏，对这两批粗产物(共114g)进行纯化(沸点约83℃/0.4mbar(40MPa))。 In short Vigreux column by distillation, for these two groups of the crude product (total 114g) and purified (boiling point of about 83 ℃ / 0.4mbar (40MPa)). 得到85g产物，部分固化为玻璃形式。 Get 85g product, partially cured glass form. 将产物溶于500ml戊烷，在冰箱(-25℃)中从该溶液中结晶。 The product was dissolved in 500ml of pentane, crystallized from the solution in the refrigerator (-25 ℃) in. 过滤后，晶体在室温、真空(14mmHg)下干燥，得到79.6g(产率66％)1-异丁氧基-2，4，4-三甲基环戊烯-3-酮，为雪白色小片，熔点63℃。 After filtration, the crystals were dried at room temperature under vacuum (14mmHg), to give 79.6g (66% yield) of 1-isobutoxy-2,4,4-trimethyl-cyclopentene-3-one, as a snow white small pieces, mp 63 ℃. 根据气相色谱(GC)结果，所需产物的含量为100％。 According to gas chromatographic (GC) results, the content of the desired product as 100%.

(ii)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环戊烯的制备将170ml三甲硅烷基甲基锂(约140mmol)的约0.8M戊烷溶液(制备方法是，将3.3g(0.48mol)锂粉的140ml戊烷溶液与24.7g(0.2mol)氯甲基三甲硅烷在40℃(回流温度)下加热约16小时，在氩气下用压力吸滤器过滤，用20ml戊烷清洗；根据滴定结果，每种情况的产率均为80-85％：见《有机金属化学杂志》9，165-168(1967))置于带有机械搅拌器、温度计、滴液漏斗和氩气化装置的500ml四颈磺化烧瓶中。 (Ii) 1- isobutoxy-2,4,4-trimethyl-3 Preparation of exo-methylene cyclopentene will 170ml trimethylsilyl methyl lithium (about 140mmol) of from about 0.8M pentane solution (Preparation method will 140ml pentane solution 3.3g (0.48mol) of lithium powder and 24.7g (0.2mol) chloro methyl trimethoxy silane was heated at 40 ℃ (reflux temperature) for about 16 hours, under argon pressure Nutsche filtration, washing with 20ml pentane; according to titration results, the yield of 80-85% in each case are: see "Journal of Organometallic Chemistry" 9,165-168 (1967)) is placed with a mechanical stirrer , 500ml four-necked sulfonation flask with a thermometer, a dropping funnel and argon gasification means. 在-20℃下，向其中滴加23g(112mol)1-异丁氧基-2，4，4-三甲基环戊烯-3-酮(根据GC结果，纯度为96％)的50ml四氢呋喃溶液。 At -20 ℃, to which was added dropwise 23g (112mol) 1- isobutoxy-2,4,4-trimethyl-cyclopentene-3-one (according to GC result, 96% pure) in 50ml of tetrahydrofuran solution. 然后，使混合物温度升至室温，安装Vigreux柱，蒸馏除去溶剂(戊烷)，连续加入四氢呋喃(最终至300mol)，直至液上温度达到62℃。 Then, the temperature of the mixture was raised to room temperature, installation Vigreux column, distilling off the solvent (pentane), continuously added tetrahydrofuran (eventually to 300mol), until the liquid temperature reached 62 ℃. 然后，将混合物冷却至0℃，滴加150ml水。 Then, the mixture was cooled to 0 ℃, 150ml of water was added dropwise. 用戊烷萃取，有机相用饱和碳酸钠溶液和氯化钠溶液洗涤后，经无水硫酸钠干燥，过滤，在35℃、减压下浓缩。 Extracted with pentane, washed with saturated sodium carbonate solution and the organic phase was washed with sodium chloride solution and dried over anhydrous sodium sulfate, filtered, and concentrated at 35 ℃, under reduced pressure. 通过短Vigreux柱蒸馏(沸点49-55℃/0.40-0.45mbar(40-45Pa))，得到17.24g(产率78％)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环戊烯，为无色的油，根据GC结果，含量为99.4％。 Distillation through a short Vigreux column (b.p. 49-55 ℃ / 0.40-0.45mbar (40-45Pa)), to give 17.24g (78% yield) of 1-methyl-3-isobutoxy-2,4,4 - exo-methylene cyclopentene, as a colorless oil, according to the results of GC content of 99.4%. 1H-NMR(250MHz，d6-DMSO)：特别是4.37(d，J～3Hz，2H，烯H)，3.65(d，J～7Hz，2H，-O-CH2-CH)；IR(膜)：1659，1619cm-1；质谱：194(M+，65％)。 1H-NMR (250MHz, d6-DMSO): in particular, 4.37 (d, J ~ 3Hz, 2H, alkenyl H), 3.65 (d, J ~ 7Hz, 2H, -O-CH2-CH); IR (film): 1659,1619cm-1; Mass spectrum: 194 (M +, 65%).

微量分析：计算值：C80.35％ H11.41％实测值：C80.47％ H11.32％实施例41-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯(式III中R3代表氢，R4代表异丁氧基，m代表1；两步法)(i)1-异丁氧基-2，4，4-三甲基-3-羟基-3-三甲硅烷基甲基环己烷的制备将450ml三甲硅烷基甲基锂(约360mmol/1.3当量)的0.8M戊烷溶液(从7.1g(1mol)锂粉、51g(0.41mol)氯甲基三甲硅烷和350ml戊烷按照类似于实施例3(ii)/《有机金属化学杂志》9，165-168(1967)所述的方法制备)置于带有磁搅拌器、温度计、滴液漏斗和氩气化装置的750ml四颈磺化烧瓶中。 Microanalysis: Calcd: C80.35% H11.41% Found: C80.47% H11.32% Example 41- isobutoxy-2,4,4-trimethyl-3 exomethylene cyclohexene (Formula III wherein R3 represents hydrogen, R4 representative isobutoxy, m equals 1; two-step method) (i) 1- isobutoxy-2,4,4-trimethyl-3-hydroxy - Preparation of 3-trimethylsilyl methylcyclohexane will 450ml trimethylsilyl methyl lithium (about 360mmol / 1.3 eq) of 0.8M solution in pentane (from 7.1g (1mol) of lithium powder, 51g (0.41mol) chloroformate trimethoxy silane and 350ml pentane in analogy to Example 3 (ii) / "Journal of Organometallic Chemistry" 9,165-168 (1967) prepared as described) is placed in a magnetic stirrer, a thermometer, a dropping funnel with an embodiment 750ml four-necked sulfonating flask and argon gasification means. 在约-20℃下，在约一小时内，向该溶液中滴加60g(0.278mol)1-异丁氧基-2，4，4-三甲基环己烯-3-酮(根据GC结果，纯度为9.75％)，引发轻微的放热反应。 At about -20 ℃, in about one hour, this solution was added dropwise 60g (0.278mol) 1- isobutoxy-2,4,4-trimethyl-cyclohexen-3-one (according to GC As a result, a purity of 9.75%), caused a slight exothermic reaction. 加入完成后，混合物在0℃冰浴中搅拌一小时，直至根据GC结果，浸提物不再存在。 After addition was complete, the mixture was stirred for one hour at 0 ℃ ice bath, until the results according to GC, extracts longer exists.

下面，通过滴液漏斗缓慢加入100ml水。 Next, the dropping funnel was slowly added 100ml of water. 其后，分离含水相，用总共为100ml的戊烷萃取两次，每次50ml。 Thereafter, the separated aqueous phase was extracted twice with a total of 100ml of pentane, each 50ml. 合并了的有机相用100ml饱和氯化钠溶液洗涤，用无水硫酸钠干燥，在减压下浓缩。 The combined organic phases were washed with 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 一边在50℃下搅拌约一小时，一边从125ml戊烷中结晶，吸滤，在高真空、室温下干燥约18小时后，得到75g(产率90％)1-异丁氧基-2，4，4-三甲基-3-羟基-3-三甲硅烷基甲基环己烷，为白色晶体，熔点约50℃；1H-NMR(250MHz，CDCl3)：特别是0.12(s，9H，Si(CH3)3)，1.80(t，J＝7Hz，2-CH2)，1.86(s，2H，-CH2-Si)，2.47(t，J＝7Hz，3-CH2)。 Under stirring at 50 ℃ for about one hour, while crystallized from 125ml of pentane, suction filtered, after under high vacuum, dried at room temperature for about 18 hours to give 75g (yield 90%) of 1- isobutoxy -2, 4,4-trimethyl-3-hydroxy-3-trimethylsilyl methyl cyclohexane, as white crystals melting at about 50 ℃; 1H-NMR (250MHz, CDCl3): in particular, 0.12 (s, 9H, Si (CH3) 3), 1.80 (t, J = 7Hz, 2-CH2), 1.86 (s, 2H, -CH2-Si), 2.47 (t, J = 7Hz, 3-CH2).

该产物必须立即用在下一步中，因为它是非常不稳定的，易于重排为油状的式XV化合物(见一般性说明中的相应讨论)。 The product must be used immediately in the next step, because it is very volatile and easy rearrangement of a compound of formula XV as an oil (see the general description of the corresponding discussion).

(ii)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯的制备将60ml氢化钾的油悬液(约20％wt/vol.，含有约12g/0.3mol KH)置于带有机械搅拌器、温度计、滴液漏斗和氩气化装置的750ml四颈磺化烧瓶中。 (Ii) 1- isobutoxy-2,4,4-cyclohexene preparation trimethyl-3-exo-methylene will 60ml oil suspension of potassium hydride (about 20% wt / vol., Containing about 12g / 0.3mol KH) placed in 750ml four-necked sulfonation flask equipped with a mechanical stirrer, thermometer, dropping funnel and argon gasification means. 氢化钾用总共75ml的戊烷洗涤三次，每次25ml，每次洗涤后倾析掉溶剂，向其中加入200ml四氢呋喃。 Potassium hydride was washed three times with a total of 75ml of pentane, each 25ml, decanting after each wash off the solvent, 200ml of tetrahydrofuran was added thereto. 利用冰浴将混合物冷却至5℃，在不超过10℃的温度下，在约1小时内滴加上述75g(0.25mol)1-异丁氧基-2，4，4-三甲基-3-羟基-3-三甲硅烷基甲基环己烷的50ml四氢呋喃溶液。 The mixture was cooled in an ice bath to 5 ℃, at a temperature not exceeding 10 ℃, within about 1 hour dropwise added the above 75g (0.25mol) 1- isobutoxy-2,4,4-trimethyl -3 - hydroxy -3- 50ml tetrahydrofuran trimethylsilyl methylcyclohexane. 然后，混合物在15-20℃下搅拌1小时，再在室温下搅拌1小时(GC控制：约96％产物，不再有浸提物)。 Then, the mixture was stirred for 1 hour at 15-20 ℃, and then stirred at room temperature for 1 hour (GC control: about 96% of the product, no more extracts).

为了逐步完成反应，将混合物冷却至0℃，小心地滴加200ml水。 In order to gradually complete the reaction, the mixture was cooled to 0 ℃, careful dropwise addition of 200ml water. 分离出两相来，含水相用总共300ml的戊烷萃取三次，每次100ml。 To the two phases separated, the aqueous phase was extracted three times with a total of 300ml of pentane each time 100ml. 合并了的有机相用100ml饱和氯化钠溶液洗涤，用无水硫酸钠干燥，浓缩。 The combined organic phases were washed with 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. 将分离了的残余物再次溶于250ml戊烷，再次用无水硫酸钠干燥，过滤并在减压下浓缩。 The separated residue was again dissolved in 250ml of pentane, dried over anhydrous sodium sulfate again, filtered, and concentrated under reduced pressure. 得到58g粗的1-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯，为淡黄色液体。 To give 58g of crude 1-isobutoxy-2,4,4-trimethyl-3-exomethylene cyclohexene, as a pale yellow liquid. 在小的10cm Vigreux柱上以0.1mbar(10Pa)蒸馏，得到沸点约为55-60℃的51.2g(产率93％)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯，为无色的油，根据GC结果，所需产物含量为95％。 In small 10cm Vigreux column to 0.1mbar (10Pa) and evaporated to afford a boiling point of about 55-60 ℃ 51.2g (93% yield) of 1-methyl-3-isobutoxy-2,4,4 - exomethylene cyclohexene as a colorless oil, according to GC result, desired product content of 95%. 1H-NMR(C6D6，250MHz)：0.89(d，J＝7Hz，2xCH3)，1.12(s，2xCH3)，1.42(t，J＝7Hz，2-CH2)，1.80(七重峰，J＝7Hz，-CH-(CH3)2)，2.03(t，J～2Hz，5-CH3)，2.08(bt，J～7Hz，3-CH2)，3.28(d，J＝7Hz，O-CH2)，4.97(d，J＝10Hz，＝CH2)；IR(膜)：1643，1118cm-1；微量分析：计算值：C80.71％ H11.61％实测值：C80.64％ H12.01％实施例51-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯(一步法)将400ml三甲硅烷基甲基锂(约0.3mol/1.2当量)的0.76M戊烷溶液(从8.5g(1.2mol)锂粉、50g(0.4mol)氯甲基三甲硅烷和300ml戊烷按照类似于实施例3(ii)/《有机金属化学杂志》9，165-168(1967)所述的方法制备)置于带有机械搅拌器、温度计、带蒸馏头的20cm Vigreux柱和氩气化装置的750ml四颈磺化烧瓶中。 1H-NMR (C6D6,250MHz): 0.89 (d, J = 7Hz, 2xCH3), 1.12 (s, 2xCH3), 1.42 (t, J = 7Hz, 2-CH2), 1.80 (septet, J = 7Hz, - CH- (CH3) 2), 2.03 (t, J ~ 2Hz, 5-CH3), 2.08 (bt, J ~ 7Hz, 3-CH2), 3.28 (d, J = 7Hz, O-CH2), 4.97 (d , J = 10Hz, = CH2); IR (film): 1643,1118cm-1; microanalysis: Calcd: C80.71% H11.61% Found: C80.64% H12.01% Example 51- iso butoxy-2,4,4-trimethyl-3-exomethylene cyclohexene (one step) will 400ml trimethylsilyl methyl lithium (approximately 0.3mol / 1.2 eq) of 0.76M pentane solution ( From 8.5g (1.2mol) of lithium powder, 50g (0.4mol) chloromethyl trimethoxy silane and 300ml pentane in analogy to Example 3 (ii) / "Journal of Organometallic Chemistry" embodiment 9,165-168 (1967) the The production method) was placed in 750ml four-necked sulfonation flask equipped with a mechanical stirrer, a thermometer, 20cm Vigreux column with a distillation head and argon gasification means. 在约-20℃下，在30分钟内，向该溶液中滴加53g(0.25mol)1-异丁氧基-2，4，4-三甲基环己烯-3-酮(根据GC结果，纯度为97.5％)的100ml四氢呋喃溶液，引发轻微的放热反应。 At about -20 ℃, within 30 minutes, this solution was added dropwise 53g (0.25mol) 1- isobutoxy-2,4,4-trimethyl-cyclohexen-3-one (based on the results of GC 100ml tetrahydrofuran solution, 97.5% purity), triggering a slight exothermic reaction. 然后将混合物在0℃下搅拌1小时，随后通过Vigreux柱蒸馏除去约300ml戊烷，加入200ml四氢呋喃后，继续蒸馏，直至沸点达到约60℃(GC控制：约90％所需产物；浸提物和中间体不再存在)。 After the mixture was then stirred for 1 hour at 0 ℃, followed by removal of pentane by about 300ml Vigreux distillation column, 200ml of tetrahydrofuran was added, the distillation was continued until a boiling point of about 60 ℃ (GC control: about 90% of the desired product; extracts and intermediates longer exists).

然后，将混合物冷却至+5℃，小心地滴加200ml水，如前面的试验(实施例4(ii))对混合物进行逐步操作。 Then, the mixture was cooled to + 5 ℃, careful dropwise addition of 200ml of water, as in the previous test (Example 4 (ii)) and the mixture was gradually operate. 得到55g粗的1-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯，为淡棕色的油，在0.15mbar(15Pa)的高真空下通过10cm Vigreux柱进行蒸馏。 To give 55g of crude 1-isobutoxy-2,4,4-trimethyl-3-exomethylene cyclohexene, as a light brown oil, at 0.15mbar (15Pa) by 10cm Vigreux high vacuum column distillation. 在58-60℃的沸点下，得到39g(产率71％)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环己烯，为淡黄色液体。 At the boiling point of 58-60 ℃ to obtain 39g (yield 71%) of 1-isobutoxy-2,4,4-trimethyl-3-exomethylene cyclohexene, as a pale yellow liquid. 根据GC结果，含量为94％；光谱数据如实施例4(ii)。 According to the results of GC content of 94%; Spectroscopic data as in Example 4 (ii).

实施例62，2，4，6，6-五甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环(式III中R3与R4共同代表亚异丙二氧基，m代表1)(i)2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚的制备将约500ml三甲硅烷基甲基锂(约0.4mol/2.0当量)的约0.8M戊烷溶液(从5.2g(0.75mol)锂粉、62.5g(0.51mol)氯甲基三甲硅烷和250ml戊烷按照类似于实施例3(ii)/《有机金属化学杂志》9，165-168(1967)所述的方法制备)置于带有机械搅拌器、温度计、滴液漏斗和氩气化装置的1.5升四颈磺化烧瓶中。 Example 62,2,4,6,6- pentamethyl -5,6,7,7a- tetrahydro-5-methyl-1,3-benzo sub-dioxolane (formula III, R3 and R4 together represent isopropylidene dioxy, m for 1) (i) 2,2,4,6,6- pentamethyl -5,6,7,7a- tetrahydro-5-trimethylsilyl-methyl-1 , 3-Benzodioxol-5-phenol trimethylsilyl About 500ml of methyl lithium (approximately 0.4mol / 2.0 eq.) in about pentane 0.8M (from 5.2g (0.75mol) of lithium powder, 62.5g (0.51mol) chloromethyl trimethoxy silane and 250ml pentane in analogy to Example 3 (ii) / "Journal of Organometallic Chemistry" 9,165-168 (1967) prepared according to the method) was placed with a mechanical stirrer, thermometer, dropping funnel and argon gasification means of 1.5 l four-necked sulfonation flask. 在约-20℃下，在30分钟内，向该溶液中滴加42.0g(0.2mol)的2，2，4，6，6-五甲基-5，6，7，7a-四氢-1，3-苯并二氧戊环-5-酮的140ml四氢呋喃溶液。 At about -20 ℃, within 30 minutes, this solution was added dropwise 42.0g (0.2mol) of 2,2,4,6,6-pentamethyl--5,6,7,7a- tetrahydro - 1,3-dioxolane -5- 140ml tetrahydrofuran ketone. 其后，使反应混合物温度缓慢升至0℃，然后升至室温，在室温下搅拌30分钟。 Thereafter, the reaction mixture temperature was slowly raised to 0 ℃, then warmed to room temperature and stirred at room temperature for 30 minutes. 反应完全后，将混合物再次冷却至0℃，缓慢滴加200ml水。 After completion of the reaction, the mixture was cooled again to 0 ℃, 200ml of water was slowly added dropwise. 分离含水相，用总共200ml己烷萃取两次，每次100ml。 Separating the aqueous phase was extracted twice with a total of 200ml of hexane, each time 100ml. 有机相合并，用100ml饱和碳酸氢钠溶液和100ml饱和氯化钠溶液洗涤，经无水硫酸钠干燥，在40℃/30mbar(3kPa)下浓缩。 The organic phases were combined, washed with 100ml saturated sodium bicarbonate solution and 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated at 40 ℃ / 30mbar (3kPa) under. 得到59.6g粗的2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚，为无色潮湿的晶体。 To give 59.6g crude 2,2,4,6,6-pentamethyl--5,6,7,7a- tetrahydro-5-methyl-1,3-benzo-trimethylsilyl-dioxolane -5 - phenol as a colorless wet crystals. 从250ml戊烷中重结晶(在加热溶解、冷却至约-20℃后)，得到49.3g纯产物，为白色晶体，熔点95℃。 Recrystallized from pentane 250ml (in dissolved by heating, cooled to about -20 ℃), to give 49.3g of pure product as white crystals, mp 95 ℃. 从母液中可进一步得到3.7g晶体，熔点95℃，也就是说，最后制得53.0g(产率89％)2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚。 From the mother liquor was further 3.7g crystals, mp 95 ℃, that is to say, finally obtained 53.0g (yield 89%) of 2,2,4,6,6-pentamethyl--5,6,7,7a - tetrahydro-5-trimethylsilyl-1,3-benzodioxol-5-ol. 1H-NMR(250MHz，CDCl3)：特别是0.06(s，9H，Si(CH3)3)，0.98(s，6H，C(6)-(CH3)2)，1.40和1.42(2s，6H，C(2)-(CH3)2)，4.43(类三重峰，J～8Hz，CH-O)；质谱：281(M--OH，5％)，242(M+-异丁烯，100％)；微量分析：计算值：C64.38％ H10.13％实测值：C64.10％ H9.95％(ii)2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环的制备将23ml氢化钾的20％油悬液(含有约3.7g/92mmol KH)用移液管移入带有磁搅拌器和具有固定的氩气泡计数器的滴液漏斗的500ml圆底烧瓶中，用己烷洗涤三次，每次10ml。 1H-NMR (250MHz, CDCl3): in particular, 0.06 (s, 9H, Si (CH3) 3), 0.98 (s, 6H, C (6) - (CH3) 2), 1.40 and 1.42 (2s, 6H, C (2) - (CH3) 2), 4.43 (t like, J ~ 8Hz, CH-O); Mass spectrum: 281 (M - OH, 5%), 242 (M + - isobutylene, 100%); microanalysis : Calculated: C64.38% H10.13% Found: C64.10% H9.95% (ii) 2,2,4,6,6- pentamethyl-tetrahydro -5,6,7,7a- Preparation of methyl-1,3-dioxolan-benzodioxol -5- times the 23ml of 20% potassium hydride in oil suspension (containing about 3.7g / 92mmol KH) was pipetted into with a magnetic stirrer and having fixed argon bubble counter dropping funnel 500ml round bottom flask and washed with hexane three times 10ml. 然后，向其中加入120ml四氢呋喃，在室温下向其中滴加25.0g(83mmol)2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚的220ml四氢呋喃溶液，混合物在室温下搅拌30分钟(GC控制：浸提物不再存在)。 Then, 120ml of tetrahydrofuran was added thereto at room temperature was added dropwise 25.0g (83mmol) 2,2,4,6,6- pentamethyl-tetrahydro-5-trimethylsilyl -5,6,7,7a- methyl-1,3-benzo-dioxolane -5- 220ml tetrahydrofuran solution of phenol, and the mixture was stirred for 30 minutes (GC control: extracts longer exists) at room temperature. 然后，将混合物冷却至0℃，缓慢滴加50ml水。 Then, the mixture was cooled to 0 ℃, 50ml water was slowly added dropwise. 进行类似于(i)中的逐步操作，得到29.7g粗的2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环，为淡黄色的油。 Be similar to (i) the stepwise operation, to give 29.7g of crude 2,2,4,6,6-pentamethyl-tetrahydro-5-methylene-1,3 -5,6,7,7a- - benzo dioxolane as a light yellow oil. 在非常短的Vigreux柱上蒸馏，得到沸点为50℃/0.02mbar(2Pa)的15.6g(产率90％)纯产物，为无色的油。 In a very short Vigreux distillation column to obtain a boiling point of 50 ℃ / 0.02mbar (2Pa) of 15.6g (yield 90%) of pure product as a colorless oil. 1H-NMR(250MHz，CDCl3)：特别是1.12和1.23(2s，均为3H，C(6)-(CH3)2)，1.50和1.53(2s，均为3H，C(2)(CH3)2)，1.73(s，3H，C(4)-CH3)，4.55(m，1H，CH-O)，4.79(d，J＝6Hz，＝CH2)；IR(膜)：1693，1112cm-1；质谱：208(M+，40)，107(100)；微量分析：计算值：C74.96％ H9.68％实测值：C74.70％ H9.42％实施例74，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环(式III中R3与R4共同代表亚甲二氧基，m代表1)(i，a)4，6，6-三甲基-5，6，7，7a-四氢-1，3-苯并二氧戊环-5-酮的制备(使用甲醛二甲基缩醛)将85g(0.5mol)2，2，6-三甲基-4，5-二羟基环己-5-烯-1-酮的700ml乙酸乙酯溶液和210ml(2.4mol)甲醛二甲基缩醛置于2升圆底烧瓶中，加入5gAmberlyst15(H+型)。 1H-NMR (250MHz, CDCl3): 1.12 and particularly 1.23 (2s, both 3H, C (6) - (CH3) 2), 1.50 and 1.53 (2s, both 3H, C (2) (CH3) 2 ), 1.73 (s, 3H, C (4) -CH3), 4.55 (m, 1H, CH-O), 4.79 (d, J = 6Hz, = CH2); IR (film): 1693,1112cm-1; Mass spectrum: 208 (M +, 40), 107 (100); microanalysis: Calcd: C74.96% H9.68% Found: C74.70% H9.42% Example 74,6,6- trimethyl -5,6,7,7a- tetrahydro-5-methylene-1,3-benzo-dioxolane (formula III, R3 and R4 together represent a methylenedioxy group, m for 1) (i, Preparation of a) 4,6,6- trimethyl -5,6,7,7a- tetrahydro-1,3-benzodioxol-5-one (formaldehyde dimethyl acetal) to 85g (0.5mol) 2,2,6- trimethyl-4,5-dihydroxy-cyclohex-5-ene-1-one in 700ml of ethyl acetate solution and 210ml (2.4mol) into formaldehyde dimethyl acetal 2 l round-bottomed flask was added 5gAmberlyst15 (H + type). 然后，将带有冷凝器的索式提取器(500ml，装有3分子筛)安装在圆底烧瓶上。 Then, with a condenser Soxhlet extractor (500ml, equipped 3 molecular sieves) is mounted on the round bottom flask. 总共回流10小时后，从催化剂中滤出混合物，在35℃/62mbar(6.2kPa)下浓缩。 After a total reflux for 10 hours, the mixture was filtered off from the catalyst, concentrated at 35 ℃ / 62mbar (6.2kPa) under. 通过10cm填充柱蒸馏后，得到沸点为78-84℃/0.3-0.15mbar(30-15Pa)的77.5g(产率85％)油，经冷却固化。 After 10cm packed column by distillation to give a boiling point of 78-84 ℃ / 0.3-0.15mbar (30-15Pa) of 77.5g (yield 85%) of an oil, solidified by cooling. 将5g该产物从20ml不超过-20℃的戊烷中重结晶。 5g of the product was not more than -20 ℃ from 20ml recrystallized from pentane. 过滤并在高真空、室温下干燥后，得到4.50g 4，6，6-三甲基-5，6，7，7a-四氢-1，3-苯并二氧戊环-5-酮，为白色晶体，熔点55.5-57℃。 After filtration and high vacuum, room temperature and dried, to give 4.50g 4,6,6- trimethyl -5,6,7,7a- tetrahydro-1,3-benzodioxol-5-one, as white crystals, mp 55.5-57 ℃. IR(cm-1)：1690，1639；质谱：182(M+，30)，126(100)；1H-NMR(400MHz，CDCl3)：1.16，1.21(2s，均为3H)，1.73(s，3H)，1.91(t，J＝19Hz，1H)，2.27(q，J1＝19Hz，J2＝9Hz，1H)，4.6(m，1H)，5.32(s，1H)，5.61(s，1H)；微量分析：计算值：C65.92％ H7.74％实测值：C65.83％ H7.79％(i，b)4，6，6-三甲基-5，6，7，7a-四氢-1，3-苯并二氧戊环-5-酮的制备(利用仲甲醛)将10.0g(58mmol)2，2，6-三甲基-4，5-二羟基环己-5-烯-1-酮的100ml乙酸乙酯溶液和3.5g(116mmol)低聚甲醛置于250ml圆底烧瓶中，加入500mg Amberlyst15(H+型)。 IR (cm-1): 1690,1639; Mass spectrum: 182 (M +, 30), 126 (100); 1H-NMR (400MHz, CDCl3): 1.16,1.21 (2s, both 3H), 1.73 (s, 3H ), 1.91 (t, J = 19Hz, 1H), 2.27 (q, J1 = 19Hz, J2 = 9Hz, 1H), 4.6 (m, 1H), 5.32 (s, 1H), 5.61 (s, 1H); Trace Analysis: Calcd: C65.92% H7.74% Found: C65.83% H7.79% (i, b) 4,6,6- trimethyl -5,6,7,7a- tetrahydro - 1,3-dioxolan-5-one was prepared (using paraformaldehyde) will 10.0g (58mmol) 2,2,6- trimethyl-4,5-dihydroxy-cyclohex-5-ene - 1-one in 100ml of ethyl acetate solution and 3.5g (116mmol) of paraformaldehyde placed in 250ml round bottom flask, was added 500mg Amberlyst15 (H + type). 所生成的水然后用乙酸乙酯通过30cmVigreux柱连续地共沸蒸馏(回收比10∶1)。 The water produced was then extracted with ethyl continuously by azeotropic distillation column 30cmVigreux (recovery ratio 10:1). 2.5小时后，向烧瓶中加入50ml乙酸乙酯。 After 2.5 hours, 50ml of ethyl acetate was added to the flask. 再过一小时，根据薄层色谱法结果，反应结束。 Another one hour, according to the results of thin-layer chromatography, the reaction is complete. 为了进行逐步操作，将反应溶液过滤，在减压下浓缩。 To stepwise operation, the reaction solution was filtered, concentrated under reduced pressure. 在0.3mbar(30Pa)和100℃浴温下进行短路径(short path)蒸馏，得到9.8g(产率93％)油性蒸馏物，冷却后固化。 Carried out at 0.3mbar (30Pa) and a bath temperature of 100 ℃ short path (short path) distilled to give 9.8g (yield 93%) as an oily distillate, after cooled and solidified. 产物与按(i，a)所述的产物相同。 The product with the press (i, a) the product of the same.

(ii)4，6，6-三甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚的制备使24.7ml(20.6g，0.17mol)氯甲基三甲硅烷与2.92g(0.42mol)锂粉在150ml戊烷中反应(按照实施例3中所述的方法)。 Preparation of (ii) 4,6,6- trimethyl -5,6,7,7a- tetrahydro-5-trimethylsilyl-1,3-benzodioxol-5-ol causes 24.7 ml (20.6g, 0.17mol) chloromethyl trimethoxy silane and 2.92g (0.42mol) of lithium powder in 150ml pentane in reaction (according to the method described in Example 3). 将所得三甲硅烷基甲基锂(约0.14mol)的戊烷溶液在氩气化作用下置于500ml烧瓶中。 The resulting trimethylsilyl methyl lithium (about 0.14mol) in pentane solution placed under argon gasification 500ml flask. 在-20℃下，在约20分钟内，向其中加入20g(0.11mol)4，6，6-三甲基-5，6，7，7a-四氢-1，3-苯并二氧戊环-5-酮的25ml四氢呋喃溶液。 At -20 ℃, over about 20 minutes, to which was added 20g (0.11mol) 4,6,6- trimethyl-tetrahydro-1,3-benzodioxol -5,6,7,7a- 25ml tetrahydrofuran-5-one. 再过20分钟后，使混合物温度缓慢升至室温，然后冷却至0℃。 Another 20 minutes, the temperature of the mixture was slowly warmed to room temperature, then cooled to 0 ℃. 其后，向其中滴加90ml水。 Thereafter, 90ml of water was added dropwise thereto. 随后，在水分离器中分离水，用戊烷萃取两次，每次100ml。 Subsequently, the water separated in the water separator, and extracted with pentane twice, each time 100ml. 戊烷相连续用碳酸氢钠溶液和氯化钠溶液洗涤，经无水硫酸钠干燥，浓缩。 Pentane phase was washed successively with sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. 粗产物(31.9g)在60ml戊烷中结晶，冷却至-25℃。 The crude product (31.9g) was crystallized in 60ml pentane, cooled to -25 ℃. 滤出所得白色晶体，用少量-20℃戊烷洗涤，在高真空、室温下干燥。 The resulting white crystals were filtered off, washed with a small amount of -20 ℃ pentane and dried under high vacuum at room temperature. 得到30.5g(产率几乎为100％)4，6，6-三甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚，为白色晶体。 To give 30.5g (yield nearly 100%) 4,6,6-trimethyl--5,6,7,7a- tetrahydro-5-trimethylsilyl-1,3-benzo-dioxolane 5-ol as white crystals. 熔点63-64.5℃。 Melting point 63-64.5 ℃. IR(Nujol，cm-1)：3510(OH)；质谱：253(M+-OH，5)，214(M-C4H8)；1H-NMR(C6D6，400MHz)；特别是0.27(s，9H)，4.9(s，1H)，5.19(s，1H)。 IR (Nujol, cm-1): 3510 (OH); Mass spectrum: 253 (M + -OH, 5), 214 (M-C4H8); 1H-NMR (C6D6,400MHz); in particular, 0.27 (s, 9H), 4.9 (s, 1H), 5.19 (s, 1H).

微量分析：计算值：C62.18％ H9.16％实测值：C62.07％ H9.51％(iii)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环的制备将23ml(约1当量)氢化钾(油中20％)置于带有磁搅拌器、滴液漏斗和氩气化装置的750ml四颈磺化烧瓶中，用己烷洗涤三次，加入120ml四氢呋喃。 Microanalysis: Calcd: C62.18% H9.16% Found: C62.07% H9.51% (iii) 4,6,6- trimethyl -5,6,7,7a- tetrahydro -5 - methylene-1,3-benzo-dioxolane will 23ml (about 1 eq.) potassium hydride (20% in oil) was placed in 750ml with a magnetic stirrer, a dropping funnel and argon gasification means four-necked sulfonation flask, washed three times with hexane, was added 120ml of tetrahydrofuran. 在0℃下，向其中滴加30.4g(0.11mol)4，6，6-三甲基-5，6，7，7a-四氢-5-三甲硅烷基甲基-1，3-苯并二氧戊环-5-酚的200ml四氢呋喃溶液。 At 0 ℃, to which was added dropwise 30.4g (0.11mol) 4,6,6- trimethyl -5,6,7,7a- tetrahydro-5-trimethylsilyl-1,3-benzo dioxolane -5- 200ml tetrahydrofuran phenols. 随后，将混悬液在20-30℃下搅拌2小时。 Subsequently, the suspension was stirred at 20-30 ℃ 2 hours. 再次冷却至0℃，小心地滴加200ml水。 Cooled again to 0 ℃, careful dropwise addition of 200ml water. 随后，用己烷萃取三次，每次100ml，用饱和氯化钠溶液洗涤，经无水硫酸钠干燥，在减压下除去溶剂后，得到18.7g黄色的油，在减压下进行短路径蒸馏。 Then, extracted with hexane three times, each time 100ml, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to give 18.7g of a yellow oil, in a short path distillation under reduced pressure . 在77-85℃/0.75mbar(7.5kPa)下得到15.6g(产率74％)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环，为无色的油。 To give 15.6g at 77-85 ℃ / 0.75mbar (7.5kPa) under (yield 74%) 4,6,6-tetrahydro-5-methyl--5,6,7,7a- methine -1 , 3-benzo dioxolane, as a colorless oil. 根据GC结果，所需产物的含量为96％(面积％)。 According to GC result, the content of the desired product was 96% (area%). IR(膜，cm-1)：1697，1600；质谱：180(M+，50)，107(100)；1H-NMR(C6D6，400MHz)；特别是0.83和0.95(2s，均为3H)，1.78(bs，3H)，3.9(m，1H)，4.59(s，1H)，4.70(s，1H)，4.75(s，1H)，4.91(Ss，1H)。 IR (film, cm-1): 1697,1600; Mass spectrum: 180 (M +, 50), 107 (100); 1H-NMR (C6D6,400MHz); in particular 0.83 and 0.95 (2s, both 3H), 1.78 (bs, 3H), 3.9 (m, 1H), 4.59 (s, 1H), 4.70 (s, 1H), 4.75 (s, 1H), 4.91 (Ss, 1H).

微量分析：计算值：C73.30％ H8.95％实测值：C73.08％ H9.21％实施例84，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环(“直通法”)将从8.7g(1.25mol)锂粉和74ml(61.6g，0.5mol)氯甲基三甲硅烷在450ml戊烷中制得的三甲硅烷基甲基锂(约0.43mol)溶液置于带有磁搅拌器、滴液漏斗、冷凝器和氩气化装置的750ml四颈磺化烧瓶中。 Microanalysis: Calcd: C73.30% H8.95% Found: C73.08% H9.21% Example 84,6,6- three-tetrahydro-5-methyl--5,6,7,7a- methylene-1,3-benzo-dioxolane ("direct method") from 8.7g (1.25mol) of lithium powder and 74ml (61.6g, 0.5mol) prepared in chloromethyl trimethoxy silane 450ml pentane resulting trimethylsilyl methyl lithium (about 0.43mol) was placed with a magnetic stirrer, a dropping funnel, 750ml four-necked sulfonation flask condenser and argon gasification means. 在-20℃下，在30分钟内，向其中滴加60.0g(0.33mol)4，6，6-三甲基-5，6，7，7a-四氢-1，3-苯并二氧戊环-5-酮的75ml四氢呋喃溶液。 At -20 ℃, over 30 minutes, to which was added dropwise 60.0g (0.33mol) 4,6,6- trimethyl-tetrahydro-1,3-benzodioxol -5,6,7,7a- dioxolan-5-one 75ml tetrahydrofuran. 然后，使混合物温度缓慢升至室温，随后通过Vigreux柱在62℃沸点以下蒸馏除去戊烷。 Then, the temperature of the mixture was slowly raised to room temperature, then pentane was removed by distillation at 62 ℃ Vigreux column below the boiling point. 蒸馏除去的戊烷连续用500ml四氢呋喃代替。 Pentane was distilled off continuously replaced with 500ml of tetrahydrofuran. 最后，混合物在GC控制下加热回流12小时。 Finally, the mixture was heated under reflux for 12 hours GC control. 随后，冷却至0℃，滴加200ml水，发生相分离，含水相用戊烷萃取三次，每次100ml。 Subsequently, cooling to 0 ℃, 200ml of water was added dropwise, phase separation occurs, the aqueous phase was washed with pentane and extracted three times, each time 100ml. 全部有机相用150ml饱和碳酸氢钠溶液和氯化钠溶液洗涤，经无水硫酸钠干燥，过滤并浓缩。 All the organic phases were washed with 150ml saturated sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. 得到67.5g黄色的油，通过10cm填充柱蒸馏。 To give 67.5g of a yellow oil, was distilled through a 10cm packed column. 在沸点为38℃/0.04mbar(4Pa)下，得到49.0g(产率82％)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环，为无色的油。 In a boiling point of 38 ℃ / 0.04mbar (4Pa) under to give 49.0g (82% yield) 4,6,6-tetrahydro-5-methyl--5,6,7,7a- methine -1 , 3-benzo dioxolane, as a colorless oil. 产物的分析数据与实施例7的产物相同。 Analysis of data for the product of Example 7 in the same product.

C.对称的、末端环取代的多烯(式I化合物)的制备实施例92，2'-二去甲鸡油菌黄质(式I中R1代表氢，m代表0，n代表1；“直通法”II+III→[IV]→I)将3.4g(8.6mmol)番红花酸二醛二甲基缩醛和5.1g(25mmol)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环戊烯(根据GC结果，纯度为98％)的60ml乙腈溶液置于带有磁搅拌器的100ml圆底烧瓶中，加入400mg(1.8mmol，20mol％)无水溴化锌，反应混合物在50℃下搅拌16小时。 C. Preparation of symmetry, the end ring-substituted polyene (compound of formula I) Example 92,2'- di demethyl canthaxanthin (formula I wherein R1 represents hydrogen, m for 0, n equals 1; " straight Act "II + III → [IV] → I) to 3.4g (8.6mmol) saffron di dimethyl acetal and 5.1g (25mmol) 1- isobutoxy-2,4,4 trimethyl-3-exo-methylene cyclopentene (according to GC result, 98% purity) in 60ml of acetonitrile was placed in a 100ml round bottom flask equipped with a magnetic stirrer, was added 400mg (1.8mmol, 20mol%) Anhydrous zinc bromide, the reaction mixture was stirred at 50 ℃ 16 hours. 在这个反应阶段后，进行薄层色谱分析，使用甲苯与乙酸乙酯的9∶1混合物作为洗脱液，结果显示不仅还有番红花酸二醛二甲基缩醛存在(Rf＝约0.6)，而且也有式IV反应产物存在(Rf＝约0.3)。 After the reaction stage, thin layer chromatography, using 9:1 mixture of toluene and ethyl acetate as eluent, showed that not only there crocus presence of diethyl dimethyl acetal (Rf = about 0.6 ), but also the presence of the reaction product of formula IV (Rf = 0.3).

然后，向所得暗色溶液中加入30ml乙酸乙酯，反应混合物冷却至0℃，用5ml乙酸与水的9∶1混合物处理，进行最后的水解。 Then, to the resulting dark solution was added 30ml of ethyl acetate, the reaction mixture was cooled to 0 ℃, with 9:1 mixture of acetic acid and 5ml of water treatment, the final hydrolysis. 然后将混合物再在该温度下搅拌一小时。 The mixture was then stirred at this temperature for one hour.

为了完成反应，混合物用约300ml乙酸乙酯稀释，全部连续用水、饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，均用100ml。 To complete the reaction, the mixture was diluted with about 300ml of ethyl acetate, washed successively with water all, the solution was washed with saturated sodium bicarbonate and saturated sodium chloride solution, are made of 100ml. 有机相用无水硫酸钠干燥，在35℃、减压下浓缩。 The organic phase was dried over anhydrous sodium sulfate, and concentrated under 35 ℃, under reduced pressure. 得到6.8g粗的8，8'-二甲氧基-7，8，7'，8'-四氢-2，2'-二去甲鸡油菌黄质(式IV的相应化合物中，R2尤其代表甲基)，为粘性、红色的油。 Get 6.8g crude 8,8'- dimethoxy -7,8,7 ', 8'-tetrahydro-2,2' corresponding compounds norepinephrine canthaxanthin (Formula IV, R2 especially represents a methyl group) as a viscous, red oil.

将该油溶于50ml乙醇，溶液用5.7ml乙醇钠的1.6摩尔乙醇溶液(含有9mmol NaOC2H5)处理。 The oil was dissolved in 50ml of ethanol was treated with 1.6 molar sodium ethoxide ethanol solution 5.7ml (containing 9mmol NaOC2H5) processing. 反应混合物在80℃下搅拌2小时，然后冷却至0℃。 The reaction mixture was stirred for 2 hours at 80 ℃, then cooled to 0 ℃. 用吸滤法滤出分离的暗色晶体，在高真空、室温下干燥，得到3.7g粗的2，2'-二去甲鸡油菌黄质，为暗紫色晶体。 Dark crystals were filtered off by suction separation under high vacuum at room temperature and dried, to give 3.7g of crude 2,2'-demethyl canthaxanthin as a dark purple crystal. 将该晶体溶于75ml异丙醇，混合物在回流温度下加热16小时。 The crystals were dissolved in 75ml of isopropanol, the mixture was heated at reflux temperature for 16 hours. 随后从二氯甲烷/异丙醇(1∶1)中重结晶，在减压下除去大部分二氯甲烷。 Then recrystallized from dichloromethane / isopropanol (1/1), and most of the dichloromethane was removed under reduced pressure. 过滤后，洗涤并在室温、高真空下干燥，得到2.5g(产率54％，以式II的二缩醛计)2，2'-二去甲鸡油菌黄质，为暗紫色晶体，熔点223-224℃；UV(环己烷/2％二氯甲烷)：527nm(logE＝5.02)，494nm(logE＝5.13)，468nm(logE＝5.02)，319nm(logE＝4.45)；1H-NMR(400MHz，CDCl3)；特别是1.33(s，2x CH3)，1.90，2.00，2.03(3s，3x CH3)，2.35(s，3-CH2)；IR(KBr)：1685cm-1. After filtration, washed, and at room temperature, dried under high vacuum to give 2.5g (54% yield to the count diacetal of formula II) 2,2'-demethyl canthaxanthin as a dark purple crystals, m.p. 223-224 ℃; UV (cyclohexane / 2% methylene chloride): 527nm (logE = 5.02), 494nm (logE = 5.13), 468nm (logE = 5.02), 319nm (logE = 4.45); 1H-NMR ( 400MHz, CDCl3); in particular, 1.33 (s, 2x CH3), 1.90,2.00,2.03 (3s, 3x CH3), 2.35 (s, 3-CH2); IR (KBr): 1685cm-1.

质谱536(M+，100％). Mass spectrum 536 (M +, 100%).

实施例108，8'-二甲氧基-7，8，7'，8'-四氢-2，2'-二去甲鸡油菌黄质中间体(式IV中R1代表氢，R2代表甲基，m代表0，n代表1)的制备和分离将1.18g(3mmol)番红花酸二醛二甲基缩醛、1.76g(9mmol)1-异丁氧基-2，4，4-三甲基-3-外亚甲基环戊烯和135mg(0.6mmol，20mol％)无水溴化锌在25ml乙腈中的混合物置于带有磁搅拌器的50ml圆底烧瓶中，在40℃下搅拌18小时，随后在50℃下搅拌6小时，在此过程中如实施例9所述进行同样的薄层色谱控制。 -7,8,7 ', 8'-tetrahydro-2,2'-norepinephrine canthaxanthin intermediates (Formula IV R1 represents hydrogen, R2 representative 108,8'- dimethoxy Example methyl, m for 0, n equals 1) Preparation and Isolation of 1.18g (3mmol) saffron di dimethyl acetal, 1.76g (9mmol) 1- isobutoxy -2,4,4 - trimethyl-3-exo-methyl cyclopentene and 135mg (0.6mmol, 20mol%) mixture of anhydrous zinc bromide in 25ml of acetonitrile was placed in 50ml round bottom flask equipped with a magnetic stirrer, at 40 stirred at ℃ 18 hours, followed by stirring at 50 ℃ 6 hours, and during this process as described in Example 9. The same TLC control. 然后，将混合物冷却至0℃，加入2ml乙酸与水的9∶1混合物，然后加入10ml乙酸乙酯。 Then, the mixture was cooled to 0 ℃, 9:1 mixture was added 2ml of acetic acid and water, followed by addition of 10ml of ethyl acetate. 混合物在0℃下搅拌两小时后，进行通常的逐步操作(如实施例9所述)，然后在150g硅胶(0.04-0.063mm)上进行柱色谱法分析，用9∶1甲苯/乙酸乙酯作为洗脱液，再用50℃乙醇进行消化作用。 The mixture was stirred at 0 ℃ After two hours, a usual stepwise operation (as described in Example 9), and then subjected to column chromatography on 150g silica gel (0.04-0.063mm), and with the 9:1 toluene / ethyl acetate as eluent, then 50 ℃ ethanol digestion. 得到230mg(产率约13％)8，8'-二甲氧基-7，8，7'，8'-四氢-2，2'-二去甲鸡油菌黄质，为红色晶体，熔点163-164℃。 Obtain 230mg (yield about 13%) 8,8'- dimethoxy -7,8,7 ', 8'-tetrahydro-2,2'-norepinephrine canthaxanthin, red crystal, melting point of 163-164 ℃. 1H-NMR(CDCl3，400MHz)：特别是1.18，1.21(2s，12H，C(1)-(CH3)2，C(1')-(CH3)2)，2.29(s，4H，C(3)H2，C(3')H2)，2.45(dxd，J1＝14Hz，J2＝5Hz，2H，C(7)H，C(7')H)，2.69(dxd，J1＝14Hz，J2＝7Hz，2H，C(7)H，C(7')H)，3.13(s，6H，2xOCH3)，3.75(dxd，J1＝7Hz，J2＝5Hz，C(8)H，C(8')H)，6.05-6.7(m约10H，烯烃的H). 1H-NMR (CDCl3,400MHz): in particular, 1.18,1.21 (2s, 12H, C (1) - (CH3) 2, C (1 ') - (CH3) 2), 2.29 (s, 4H, C (3 ) H2, C (3 ') H2), 2.45 (dxd, J1 = 14Hz, J2 = 5Hz, 2H, C (7) H, C (7') H), 2.69 (dxd, J1 = 14Hz, J2 = 7Hz , 2H, C (7) H, C (7 ') H), 3.13 (s, 6H, 2xOCH3), 3.75 (dxd, J1 = 7Hz, J2 = 5Hz, C (8) H, C (8') H ), 6.05-6.7 (m about 10H, olefin H).

质谱：600.5(M+，25％). Mass spectrum: 600.5 (M +, 25%).

实施例11鸡油菌黄质(式I中R1代表氢，m和n都代表1)(i)3，4，3'，4'-四脱氢-7，8，7'，8'-四氢-4，4'-二异丁氧基-8，8'-二甲氧基-β，β'-胡萝卜素(式V中R2代表甲基，R4代表异丁氧基，m和n都代表1)的制备在带有磁搅拌器、温度计和氯化钙试管的50ml双颈烧瓶中，将1.7g(4.3mmol)番红花酸二醛二甲基缩醛悬浮在20ml乙腈与5ml乙酸乙酯中。 Example 11 canthaxanthin implementation (formula I wherein R1 represents hydrogen, m and n represent 1) (i) 3,4,3 ', 4'- Tetradehydro -7,8,7', 8' tetrahydro-4,4'-dimethoxy-isobutoxy -8,8'- -β, β'- carotene (formula V where R2 represents methyl, R4 representative isobutoxy, m and n Preparation represents 1) in with a magnetic stirrer, a thermometer and a calcium chloride tube 50ml two-necked flask, 1.7g (4.3mmol) saffron di dimethyl acetal were suspended in 20ml of acetonitrile and 5ml ethyl acetate. 在0-5℃下，加入2.7g(12.3mmol)1-异丁氧基-2，4，4'-三甲基-3-外亚甲基环己烯和120mg(20mol％)无水氯化锌。 At 0-5 ℃, was added 2.7g (12.3mmol) 1- isobutoxy-2,4,4'-trimethyl-3-exomethylene cyclohexene and 120mg (20mol%) in dry chlorine zinc. 短时间后，除去冰浴，将橙色混悬液在室温下搅拌约20小时。 After a short time, ice bath was removed and the orange suspension was stirred at room temperature for about 20 hours. 向所得柠檬黄色混悬液中加入0.5ml三乙胺，将混合物冷却至0℃，一小时后用吸滤法过滤。 To the resulting lemon-yellow suspension was added 0.5ml of triethylamine, the mixture was cooled to 0 ℃, after one hour was filtered by suction filtration. 在室温、高真空下减压干燥后，得到2.6g(产率约82％)标题名称的化合物，为淡黄色粉末，熔点155-156℃。 Dried under reduced pressure at room temperature, after high vacuum to afford compound 2.6g (yield about 82%) of the title name as a pale yellow powder, mp 155-156 ℃.

为了获得分析数据，将该产物回流两次，每次均在25ml丙酮中回流30分钟，然后冷却至-10℃，用吸滤法过滤。 To obtain analytical data, the product was refluxed twice, each time in 25ml of acetone was refluxed for 30 minutes, then cooled to -10 ℃, filtered by suction filtration. 在室温、高真空下干燥后，得到1.4g 3，4，3'，4'-四脱氢-7，8，7'，8'-四氢-4，4'-二异丁氧基-8，8'-二甲氧基-β，β-胡萝卜素，为淡黄色粉末，熔点166-173℃。 After drying at room temperature, high vacuum to give 1.4g 3,4,3 ', 4'- tetradehydro -7,8,7', 8'-tetrahydro-4,4'-di-isobutoxy - 8,8'- dimethoxy -β, β- carotene as a pale yellow powder, mp 166-173 ℃. UV(环己烷/2％氯仿)：430nm(logE＝5.16)，404nm(logE＝5.15)，383nm(logE＝4.93)，365nm(logE＝4.60；1H-NMR(C6D6，400MHz)：特别是0.89(d，J＝7Hz，12H，2xCH(CH3)2)，1.20(s，6H，C(1)-CH3，C(1')-CH3)，1.23(s，6H，C(1')-CH3，C(1')-CH3)，3.09(s，6H，2xOCH3)，3.33(d，J＝7Hz，4H，2xO-CH2-)，4.59(t，J-5Hz，2H，2xC(3)H)；IR(KBr)：no C＝O，1650，1089cm-1(COC)；质谱：740(M+，≤1％)，533.4(15％)，326.1(100％). UV (cyclohexane / 2% chloroform): 430nm (logE = 5.16), 404nm (logE = 5.15), 383nm (logE = 4.93), 365nm (logE = 4.60; 1H-NMR (C6D6,400MHz): in particular 0.89 (d, J = 7Hz, 12H, 2xCH (CH3) 2), 1.20 (s, 6H, C (1) -CH3, C (1 ') - CH3), 1.23 (s, 6H, C (1') - CH3, C (1 ') - CH3), 3.09 (s, 6H, 2xOCH3), 3.33 (d, J = 7Hz, 4H, 2xO-CH2 -), 4.59 (t, J-5Hz, 2H, 2xC (3) H); IR (KBr): no C = O, 1650,1089cm-1 (COC); Mass spectrum: 740 (M +, ≤1%), 533.4 (15%), 326.1 (100%).

(ii)7，8，7'，8'-四氢-8，8'-二甲氧基鸡油菌黄质(式IV中R1代表氢，R2代表甲基，m和n都代表1)的制备在带有磁搅拌器、温度计和氩气化装置的50ml双颈烧瓶中，将1.00g(1.35mmol)3，4，3'，4'-四脱氢-7，8，7'，8'-四氢-4，4'-二异丁氧基-8，8'-二甲氧基-β，β'-胡萝卜素(熔点166-173℃)悬浮在10ml甲醇中，用1ml的50％含水乙酸处理，然后是30mg对甲苯磺酸一水合物。 (Ii) 7,8,7 ', 8'- tetrahydro -8,8'- dimethoxy canthaxanthin (formula IV wherein R1 represents hydrogen, R2 represents a methyl group, m and n represents 1) prepared in 50ml two-necked flask equipped with a magnetic stirrer, thermometer and argon gasification means, a 1.00g (1.35mmol) 3,4,3 ', 4'- tetradehydro -7,8,7', 8'-tetrahydro-4,4'-dimethoxy-isobutoxy -8,8'- -β, β'- carotene (m.p. 166-173 ℃) was suspended in 10ml methanol and treated with 1ml of 50% aqueous acetic acid, followed by 30mg of p-toluenesulfonic acid monohydrate. 将混合物在35-40℃下搅拌3小时。 The mixture was stirred at 35-40 ℃ 3 hours. 下面，向其中加入2ml水，将混合物冷却至0℃并过滤。 Here, 2ml of water was added thereto, and the mixture was cooled to 0 ℃ and filtered. 在减压下干燥后，得到800mg(产率约94％)标题名称的化合物，为黄橙色粉末，熔点183-189℃。 After drying under reduced pressure to give the compound 800mg (yield about 94%) of the title name, is a yellow-orange powder, mp 183-189 ℃.

为了获得分析数据，将750mg所得产物在硅胶(0.04-0.063mm)上纯化，用二氯甲烷与二乙醚的9∶1混合物作为洗脱液。 To obtain analytical data, the resulting product on silica gel 750mg (0.04-0.063mm) eluting with 9:1 mixture of dichloromethane and diethyl ether as eluent. 将纯的部分浓缩，残余物在10ml甲醇中以回流温度消化2小时。 The pure fractions were concentrated and the residue in methanol (10ml) at reflux temperature to digest for 2 hours. 冷却后，过滤并在室温、高真空下干燥，得到370mg纯的7，8，7'，8'-四氢-8，8'-二甲氧基鸡油菌黄质，为淡黄色粉末，熔点200-203℃；根据HPLC结果，含量为96.5％(面积％)；UV(环己烷/3％氯仿)：429nm(logE＝5.14)，403nm(logE＝5.13)，382nm(logE＝4.90)，365nm(logE＝4.59)；1H-NMR(CDCl3)，400MHz)：特别是1.14(s＝6H，C(1)-CH3，C(1')-CH3)，1.19(s，6H，C(1)-CH3，C(1')-CH3)，2.40(dxd，J1＝14Hz，J2＝4Hz，2H，C(7)-H，C(7')-H)，2.65(dxd，J1＝14Hz，J2＝7Hz，2HC(7)H，C(7')H，2.50(t，J～7Hz，4H，C(3)H2.C(3')H2)，3，11(s，6H，2xOCH3)，3.70(dxd，J1＝14Hz，J2＝7Hz，2H，2xCH-OCH3)，6.0-6.7(m，10H，烯烃H)；IR(KBr)：1660cm-1(C＝O)；质谱：628.5(M+，20)，477.3(100). After cooling, at room temperature and filtered, dried under high vacuum to give 370mg pure 7,8,7 ', 8'-tetrahydro--8,8'- dimethoxy canthaxanthin as a pale yellow powder, mp 200-203 ℃; according to HPLC results, content of 96.5% (area%); UV (cyclohexane / 3% chloroform): 429nm (logE = 5.14), 403nm (logE = 5.13), 382nm (logE = 4.90) , 365nm (logE = 4.59); 1H-NMR (CDCl3), 400MHz): in particular, 1.14 (s = 6H, C (1) -CH3, C (1 ') - CH3), 1.19 (s, 6H, C ( 1) -CH3, C (1 ') - CH3), 2.40 (dxd, J1 = 14Hz, J2 = 4Hz, 2H, C (7) -H, C (7') - H), 2.65 (dxd, J1 = 14Hz, J2 = 7Hz, 2HC (7) H, C (7 ') H, 2.50 (t, J ~ 7Hz, 4H, C (3) H2.C (3') H2), 3,11 (s, 6H , 2xOCH3), 3.70 (dxd, J1 = 14Hz, J2 = 7Hz, 2H, 2xCH-OCH3), 6.0-6.7 (m, 10H, olefin H); IR (KBr): 1660cm-1 (C = O); Mass spectrum : 628.5 (M +, 20), 477.3 (100).

微量分析：计算值：C79.62％ H9.63％ (with0.26％H2O)实测值：C79.43％ H9.63％ (H2O，0.26％)实施例12鸡油菌黄质(式I中R1代表氢，m和n都代表1)(“直通法”)3，4，3'，4'-四脱氢-7，8，7'，8'-四氢-4，4'-二异丁氧基-8，8'-二甲氧基-β，β'-胡萝卜素(式V中R2代表甲基，R4代表异丁氧基，m和n都代表1)的制备将25ml二氯甲烷与25ml乙酸乙酯的混合物中的60mg(0.4mmol，5mol％)无水氯化铁(III)和5滴1-异丁氧基-2，4，4-三甲基-3-外亚甲基-1-环己烯置于带有磁搅拌器、温度计和氩气化装置的100ml双颈圆底烧瓶中，混合物在室温下搅拌2小时。 Microanalysis: Calculated: C79.62% H9.63% (with0.26% H2O) Found: C79.43% H9.63% (H2O, 0.26%) Example 12 canthaxanthin (formula I R1 represents hydrogen, m and n represent 1) ("direct method"), 3,4,3 ', 4'-tetracarboxylic dehydrogenation -7,8,7', 8'-tetrahydro-4,4'- Preparation isobutoxy -8,8'- dimethoxy -β, β'- carotene (formula V in which R2 represents methyl, R4 representative isobutoxy, m and n represent 1) of the two 25ml a mixture of methylene chloride and ethyl acetate in 25ml 60mg (0.4mmol, 5mol%) of anhydrous ferric chloride (III) and 5 drops of 1- isobutoxy-2,4,4-trimethyl-3-outer methylene-1-cyclohexene placed with a magnetic stirrer, 100ml two-necked round bottom flask thermometer and argon gasification means, and the mixture was stirred at room temperature for 2 hours. 然后，将混合物冷却至-20℃，连续加入3.0g(7.5mmol)番红花酸二醛二甲基缩醛(HPLC：纯度≥99％)和4.0g(19mmol，2.6当量)1-异丁氧基-2，4，4-三甲基-3-外亚甲基-1-环己烯。 Then, the mixture was cooled to -20 ℃, continuous addition of 3.0g (7.5mmol) saffron di dimethyl acetal (HPLC: purity ≥99%) and 4.0g (19mmol, 2.6 equiv) 1- isobutoxy oxy-2,4,4-trimethyl-3-exo-methylene-1-cyclohexene. 混合物在-20℃至-15℃下搅拌2小时，再在-10℃至-5℃下搅拌2小时。 The mixture was stirred for 2 hours at -20 ℃ to -15 ℃, stirred at -10 ℃ to -5 ℃ 2 hours. 再加入1.0g(4.6mmol)1-异丁氧基-2，4，4-三甲基-3-外亚甲基-1-环己烯，混合物在-10℃至-5℃下再搅拌2小时。 Was added 1.0g (4.6mmol) 1- isobutoxy-2,4,4-trimethyl-3-exo-methylene-1-cyclohexene, and the mixture was stirred at -10 ℃ to -5 ℃ 2 hours. 然后，混合物用0.5ml三乙胺中和，加入20ml甲醇，在20-30℃、减压(350mbar/35kPa)下除去二氯甲烷。 Then, the mixture was neutralized with 0.5ml of triethylamine, 20ml of methanol was added, at 20-30 ℃, under reduced pressure (350mbar / 35kPa) under remove dichloromethane. 下面将所得橙色晶体在-5℃下冷却2小时。 The resulting orange crystals will be cooled at -5 ℃ 2 hours. 吸滤法过滤后，洗涤(甲醇，0℃)并在室温、高真空下干燥18小时，得到5.3g(产率约95％)3，4，3'，4'-四脱氢-7，8，7'，8'-四氢-4，4'-二异丁氧基-8，8'-二甲氧基-β，β'-胡萝卜素，为橙色晶体，立即用在下一个反应(ii)中。 After filtered off by suction, washed (methanol, 0 ℃) and at room temperature, dried under high vacuum for 18 hours to give 5.3g (yield about 95%) 3,4,3 ', 4'-tetracarboxylic dehydrogenation -7, 8,7 ', 8'-tetrahydro-4,4'-dimethoxy-isobutoxy -8,8'- -β, β'- carotene as orange crystals immediately in the next reaction ( ii).

(ii)7，8，7'，8'-四氢-8，8'-二甲氧基鸡油菌黄质(式IV中R1代表氢，R2代表甲基，m和n都代表1)的制备在带有磁搅拌器和氩气化装置的100ml双颈圆底烧瓶中，将5.2g(约7mmol)3，4，3'，4'-四脱氢-7，8，7'，8'-四氢-4，4'-二异丁氧基-8，8'-二甲氧基-β，β'-胡萝卜素悬浮在35ml甲醇中。 (Ii) 7,8,7 ', 8'- tetrahydro -8,8'- dimethoxy canthaxanthin (formula IV wherein R1 represents hydrogen, R2 represents a methyl group, m and n represents 1) prepared in 100ml two-necked round bottom flask equipped with a magnetic stirrer and argon gasification means, a 5.2g (approximately 7mmol) 3,4,3 ', 4'- tetradehydro -7,8,7', 8'-tetrahydro-4,4'-dimethoxy-isobutoxy -8,8'- -β, β'- carotene was suspended in 35ml of methanol. 向该混悬液中加入5ml的50％含水乙酸和一小刀尖的对甲苯磺酸一水合物，混合物在40-45℃下搅拌3.5小时。 To this suspension was added 50% 5ml of aqueous acetic acid and a small tip of p-toluenesulfonic acid monohydrate, and the mixture was stirred at 40-45 ℃ 3.5 hours. 混合物冷却至3℃后，向其中加入15ml水，30分钟后，混合物用P3玻璃原料进行吸滤，并用-20℃的10ml甲醇洗涤。 After the mixture was cooled to 3 ℃, 15ml of water was added thereto. After 30 minutes, the mixture was filtered off with suction P3 glass frit and washed with 10ml of methanol -20 ℃. 产物在室温、高真空下干燥后，得到4.0g标题名称的化合物，为橙色晶体，熔点169-179℃。 After the product was at room temperature, dried under high vacuum to give 4.0g of the title compound name, as orange crystals, mp 169-179 ℃. 将该晶体重结晶，方法是使其溶于30ml二氯甲烷，并在减压下用20ml甲醇代替(如(i)所述)。 The crystals were recrystallized method is that it is dissolved in 30ml of dichloromethane and 20ml of methanol under reduced pressure to replace (e.g. (i) above). 得到3.0g(产率68％)7，8，7'，8'-四氢-8，8'-二甲氧基鸡油菌黄质，为橙色晶体，熔点188-201℃(异构体混合物；光谱学数据：见实施例11(ii))。 Obtain 3.0g (68% yield) 7,8,7 ', 8'-tetrahydro -8,8'- dimethoxy canthaxanthin as orange crystals, mp 188-201 ℃ (isomer The mixture; spectroscopy data: see Example 11 (ii)). 它们立即用在下一个反应(iii)中。 They immediately used in the next reaction step (iii).

(iii)鸡油菌黄质的制备在带有磁搅拌器、温度计和氩气化装置的50ml双颈圆底烧瓶中，将2.8g(4.5mmol)7，8，7'，8'-四氢-8，8'-二甲氧基鸡油菌黄质溶于30ml二氯甲烷。 (Iii) Preparation of canthaxanthin in a 50ml two-necked round bottom flask equipped with a magnetic stirrer, thermometer and argon gasification means, a 2.8g (4.5mmol) 7,8,7 ', 8'- four Hydrogen -8,8'- dimethoxy canthaxanthin dissolved 30ml dichloromethane. 然后，将混合物冷却至-15℃，一边搅拌一边加入1ml(约9mmol)的48％含水氢溴酸。 Then, the mixture was cooled to -15 ℃, stirring was added 1ml (approximately 9mmol) 48% aqueous hydrobromic acid. 断裂完成后(约1.25小时后；HPLC控制)，一次性加入10ml(约10mmol)的1N氢氧化钠溶液，混合物在0℃下搅拌15分钟。 After the fracture is complete (after about 1.25 hours; HPLC control), was added in one 10ml (approximately 10mmol) in 1N sodium hydroxide solution, the mixture was stirred at 0 ℃ 15 minutes. 然后分离含水相，用二氯甲烷萃取两次，每次10ml。 The aqueous phase was then separated, extracted twice with dichloromethane, each 10ml. 合并了的有机相用15ml饱和碳酸氢钠溶液洗涤，经无水硫酸钠干燥，浓缩至约20ml。 The organic phase was washed with 15ml of saturated sodium bicarbonate solution, combined, dried over anhydrous sodium sulfate, concentrated to about 20ml. 下面，通过20g硅胶垫过滤，并用二氯甲烷/二乙醚(9∶1)回洗。 Below, filtered through a pad of silica gel 20g, and treated with dichloromethane / diethyl ether (9:1) backwashed. 过滤后的产物再在减压下浓缩，压力约为100mbar(10kPa)，同时与20ml庚烷交换。 Product was filtered and then concentrated under reduced pressure, a pressure of about 100mbar (10kPa), while exchange with 20ml heptane.

异构化前的E/Z比为：全E∶77％，9Z+13Z∶13％。 Before isomerization E / Z ratio: Full E:77%, 9Z + 13Z:13%.

进行异构化，混合物在约100℃的回流条件下沸腾7小时进行异化，然后冷却至室温，并过滤。 Isomerization, the mixture was boiled under reflux conditions for about 100 ℃ alienation 7 hours, then cooled to room temperature, and filtered. 在高真空、70℃下干燥4小时后，得到2.3g(产率约82％)粗的鸡油菌黄质，为棕紫色晶体，HPLC含量(面积％)为90.5％(全E)。 In a high vacuum, after 70 ℃ dried for 4 hours to give 2.3g (yield about 82%) of crude of canthaxanthin, brown-purple crystals, HPLC content (area%) 90.5% (all-E). 为了进行重结晶，将该粗产物溶于30ml二氯甲烷，在约100mbar(10kPa)下与15ml丙酮交换。 For recrystallization, the crude product was dissolved in 30ml of dichloromethane, at about 100mbar (10kPa) under exchanged with 15ml of acetone. 在-25℃下冷却后，滤出晶体，用0℃的丙酮洗涤，在高真空、70℃下干燥4小时。 After cooling at -25 ℃, crystals were filtered off, washed with acetone 0 ℃ used in high vacuum dried for 4 hours at 70 ℃. 得到2.0g(产率76％)鸡油菌黄质，为深紫色晶体，熔点207-208℃；HPLC含量(面积％)：(全E)-鸡油菌黄质：95.7％(9Z+13Z)-鸡油菌黄质：1.6％8'-阿朴鸡油菌黄质醛：2.1％UV(环己烷/3％CHCl3)：470nm(logE＝5.09)；IR(KBr)：1657cm-1；质谱：564(M+，22)；1H-NMR(400MHz，CDCl3)：1.20(s，12H)，1.85(t，J～8Hz，4H)，1.87(s，6H)，1.99和2.00(2s，12H)，2.50(t，J～7Hz，4H)，6.2-6.7(div.m，14H). Obtain 2.0g (76% yield) canthaxanthin, dark purple crystals, mp 207-208 ℃; HPLC content (area%) :( whole E) - canthaxanthin: 95.7% (9Z + 13Z ) - canthaxanthin: 1.6% 8'-apo canthaxanthin aldehyde: 2.1% UV (cyclohexane /3%CHCl3):470nm(logE=5.09);IR(KBr):1657cm-1 ; Mass spectrum: 564 (M +, 22); 1H-NMR (400MHz, CDCl3): 1.20 (s, 12H), 1.85 (t, J ~ 8Hz, 4H), 1.87 (s, 6H), 1.99 and 2.00 (2s, 12H), 2.50 (t, J ~ 7Hz, 4H), 6.2-6.7 (div.m, 14H).

实施例138，8'-二甲氧基-7，8，7'，8'-四氢-3，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素中间体(式IV中R1代表羟基，R2代表甲基，m和n都代表1)的制备和分离将582mg(1.5mmol)番红花酸二醛二甲基缩醛(HPLC纯度＞97％)和937mg(4.5mmol)2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环置于带有磁搅拌器和氩气化装置的25ml圆底烧瓶中的8ml乙腈中。 Example 138,8'- dimethoxy -7,8,7 ', 8'-tetrahydro-3,3'-dihydroxy-4,4'-diketo -β, β'- carotene intermediate body (formula IV wherein R1 represents a hydroxyl group, R2 represents a methyl group, m and n represent 1) the preparation and isolation of the 582mg (1.5mmol) saffron di dimethyl acetal (HPLC purity> 97%) and 937mg (4.5mmol) 2,2,4,6,6- pentamethyl -5,6,7,7a- tetrahydro-5-methylene-1,3-benzodioxol-placed with 25ml round bottom flask with a magnetic stirrer and argon gasification means in 8ml acetonitrile. 加入25mg(0.2mmol)无水氯化锌后，反应溶液在室温下搅拌16小时，用薄层色谱法控制。 After addition of 25mg (0.2mmol) of anhydrous zinc chloride, the reaction solution was stirred at room temperature for 16 hours, thin layer chromatography control. 所得暗红色溶液浓缩，所得的油在50g硅胶(0.04-0.063mm)上纯化，用二氯甲烷/二乙醚(9∶1)作为溶剂。 The resulting dark red solution was concentrated, the resulting oil was 50g silica gel (0.04-0.063mm) on eluting with methylene chloride / diethyl ether (9:1) as a solvent. 得到331mg(产率33％)橙色晶体。 To give 331mg (yield 33%) as orange crystals. 为得到光谱学数据而进行进一步纯化，将其在热甲醇中消化，冷却至-20℃，滤出并在高真空下干燥。 Spectroscopic data obtained for further purification, which was digested in hot methanol, cooled to -20 ℃, filtered off and dried under high vacuum. 得到190mg 8，8'-二甲氧基-7，8，7'，8'-四氢-3，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素，为淡橙色晶体，熔点171℃；HPLC纯度为99.5％纯；UV(环己烷/3％CHCl3)：429nm(logE＝5.12)，403nm(logE＝5.11)，382nm(logE＝4.90)；IR(KBr)：1657cm-1；1H-NMR(CDCl3，400Mhz)：特别是1.17，1.23，1.24，1.28(4s，12H)，3.09，3.10(2s，2xOCH3)，约3.7(m，4H)，4.3(m，2H)，61-6.7(10烯烃的H). To give 190mg 8,8'- dimethoxy -7,8,7 ', 8'-tetrahydro-3,3'-dihydroxy-4,4'-diketo -β, β'- carotene, as a pale orange crystals, mp 171 ℃; HPLC purity of 99.5% pure; UV (cyclohexane / 3% CHCl3): 429nm (logE = 5.12), 403nm (logE = 5.11), 382nm (logE = 4.90); IR ( KBr): 1657cm-1; 1H-NMR (CDCl3,400Mhz): in particular, 1.17,1.23,1.24,1.28 (4s, 12H), 3.09,3.10 (2s, 2xOCH3), about 3.7 (m, 4H), 4.3 ( m, 2H), 61-6.7 (10 olefin H).

微量分析：计算值：C76.33％ H9.15％实测值：C76.13％ H9.18％实施例14 Microanalysis: Calcd: C76.33% H9.15% Found: C76.13% H9.18% Example 14

3，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素、即虾青素(式I中R1代表羟基，m和n都代表1；“直通法”II+III→I)的制备将580mg(1.5mmol)番红花酸二醛二甲基缩醛(HPLC纯度＞97％)和940mg 2，2，4，6，6-五甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环置于带有磁搅拌器和氩气化装置的25ml圆底烧瓶中的8ml乙腈中。 3,3'-dihydroxy-4,4'-diketo -β, β'- carotene, i.e. astaxanthin (formula I wherein R1 represents a hydroxyl group, m and n represent 1; "direct method" II + III → I) A mixture of 580mg (1.5mmol) saffron di dimethyl acetal (HPLC purity> 97%) and 940mg 2,2,4,6,6- pentamethyl-5,6, 7,7a- tetrahydro-5-methylene-1,3-benzodioxol-placed 25ml round bottomed flask equipped with a magnetic stirrer and argon gasification means in 8ml acetonitrile. 加入50mg(0.4mmol)无水氯化锌后，反应溶液在室温下搅拌2.5小时，用薄层色谱法控制。 After addition of 50mg (0.4mmol) of anhydrous zinc chloride, the reaction solution was stirred at room temperature for 2.5 hours, thin layer chromatography control. 将该暗色混悬液冷却至-20℃，加入5滴37％含水氢氯酸。 The dark suspension was cooled to -20 ℃, was added 5 drops of 37% aqueous hydrochloric acid. 5分钟后，使混合物温度升至0℃，在该温度下再搅拌15分钟。 After 5 minutes, the mixture temperature was raised to 0 ℃, stirred at this temperature for 15 minutes. 随后，将反应溶液倾入100ml水中，用二氯甲烷萃取两次，每次50ml。 Subsequently, the reaction solution was poured into 100ml water and extracted twice with dichloromethane, each 50ml. 将如此得到的暗红色油状粗产物在70g硅胶(0.04-0.063mm)上进行色谱法分析，用二氯甲烷/二乙醚(5∶1)作为溶剂。 The dark red oily crude product thus obtained was 70g silica gel (0.04-0.063mm) chromatographed on, with dichloromethane / diethyl ether (5:1) as a solvent. 以这种方法得到358mg(产率40％)虾青素，为暗红色晶体(与薄层色谱法结果是一致的)。 In this way obtain 358mg (40% yield) of astaxanthin as dark red crystals (with a thin layer chromatographic method is consistent with the results). 为了得到光谱学数据，将320mg在热甲醇中消化，冷却后滤出，在高真空下干燥。 In order to obtain spectroscopic data, 320mg digested in hot methanol, cooled and filtered off, dried under high vacuum. 得到198mg虾青素，为闪光的深紫色晶体，熔点212-218℃。 Get 198mg of astaxanthin for flash purple crystals, mp 212-218 ℃. IR(KBr)：1657，1610cm-1；质谱：596.5(M+，40)；1H-NMR(CDCl3，400MHz)：1.29，1.32(2s，2x6H)，1.84(t，J＝12Hz，2H)，1.94(s，2x 3H)，2.00，2.03(2s，2x 6H)，2.16(q，J＝6Hz，2H)，3.68(d，J～1-2Hz，2H)，4.8(m，2H)，6.2-6.7(14烯烃的H). IR (KBr): 1657,1610cm-1; MS: 596.5 (M +, 40); 1H-NMR (CDCl3,400MHz): 1.29,1.32 (2s, 2x6H), 1.84 (t, J = 12Hz, 2H), 1.94 (s, 2x 3H), 2.00,2.03 (2s, 2x 6H), 2.16 (q, J = 6Hz, 2H), 3.68 (d, J ~ 1-2Hz, 2H), 4.8 (m, 2H), 6.2- 6.7 (14 olefin H).

实施例158，8'-二乙氧基-7，8，7'，8'-四氢-3，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素(式IV中R1代表羟基，R2代表乙基，m和n都代表1)的制备将20ml二氯甲烷置于带有磁搅拌器和氩气化装置的50ml圆底烧瓶中，加入约40mg(4滴；0.4mmol)丙酮二甲基缩醛和约25mg(2滴；0.2mmol，8mol％)三氟化硼二乙醚合物。 Example 158,8'- diethoxy -7,8,7 ', 8'-tetrahydro-3,3'-dihydroxy-4,4'-diketo -β, β'- carotene ( Preparation of formula IV wherein R1 represents a hydroxyl group, R2 represents an ethyl group, m and n represent 1) will be placed in 20ml of dichloromethane 50ml round bottomed flask equipped with a magnetic stirrer and argon gasification means were added about 40mg (4 drops; 0.4mmol) in acetone dimethyl acetal and about 25mg (2 drops; 0.2mmol, 8mol%) boron trifluoride diethyl etherate. 将该溶液在室温下搅拌一小时(以从溶剂中除去残留的水)后，冷却至-25℃，连续向其中加入没有溶剂的1.11g(2.5mmol)番红花酸二醛二乙基缩醛和1.30g(7.2mmol)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环，混合物在-20至-25℃下搅拌，用HPLC控制。 The solution was stirred at room temperature for one hour (to remove residual water from the solvent) was cooled to -25 ℃, continuously added thereto without solvent 1.11g (2.5mmol), di-aldehyde di-ethyl saffron reduction aldehydes and 1.30g (7.2mmol) 4,6,6- trimethyl -5,6,7,7a- tetrahydro-5-methyl-1,3-benzo times dioxolane, mixture at -20 stirred at -25 ℃ to, by HPLC control.

在-20℃下加入90％含水乙酸，混合物在室温下搅拌10分钟进行水解。 Added 90% aqueous acetic acid at -20 ℃, the mixture was stirred at room temperature for 10 minutes for hydrolysis. 然后倾入水中，用己烷萃取两次，每次100ml，用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，用无水硫酸钠干燥，过滤并浓缩。 Then poured into water and extracted with hexane twice, each time 100ml, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. 得到2.80g红色的油，在100g硅胶(0.04-0.063mm)上进行色谱法分析，用二氯甲烷/二乙醚(9∶1)作为溶剂。 To give 2.80g of a red oil, was chromatographed on 100g of silica gel analysis (0.04-0.063mm) on, with dichloromethane / diethyl ether (9:1) as a solvent. 由此可能分离到1.00g(产率58％)8，8'-二乙氧基-7，8，7'，8'-四氢-3，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素，为淡红色固体；HPLC含量：98.1％(面积％)。 Which may isolated 1.00g (yield 58%) 8,8'- diethoxy -7,8,7 ', 8'-tetrahydro-3,3'-dihydroxy-4,4'- keto -β, β'- carotene as a pale red solid; HPLC content: 98.1% (area%). 为了获得光谱学数据，将该物质在15ml热甲醇中消化，冷却至-20℃，滤出并在高真空下干燥。 In order to obtain spectroscopic data, This material was digested in 15ml hot methanol, cooled to -20 ℃, filtered off and dried under high vacuum. 由此得到620mg橙色晶体，熔点140-150℃，根据HPLC结果，含量为98.8％(面积％)。 Whereby 620mg orange crystals, mp 140-150 ℃, based on HPLC results, content of 98.8% (area%).

UV(环己烷/3％CHCl3)：429nm(logE＝5.14)，403nm(logE＝5.13)，382nm(logE＝4.91)；IR(Nujol)：1664cm-1，1607cm-1；质谱：688.6(M+，5)，521.4(30)；1H-NMR(CDCl3，400MHz；非对映体混合物)：特别是2.3(dxd，J1＝14Hz，J2＝3Hz，1H)，2.45(dxd，J1＝14Hz，J2＝4.5Hz，1H)，2.6(dxd，J1＝14Hz，J2＝7.5Hz，1H)，2.7(dxd，J1＝14Hz，J2＝8.5Hz，1H)，3.1和3.35(2m，4H，2x OCH2)，3.65(2d，J～6Hz，2xOH)，3.8(m，2H，CH-OC2H5)，4.3(m，2H，CH-OH)，6.1-6.7(div.m，10烯烃的H). UV (cyclohexane /3%CHCl3):429nm(logE=5.14),403nm(logE=5.13),382nm(logE=4.91);IR(Nujol):1664cm-1,1607cm-1; MS: 688.6 (M + , 5), 521.4 (30); 1H-NMR (CDCl3,400MHz; mixture of diastereomers): in particular, 2.3 (dxd, J1 = 14Hz, J2 = 3Hz, 1H), 2.45 (dxd, J1 = 14Hz, J2 = 4.5Hz, 1H), 2.6 (dxd, J1 = 14Hz, J2 = 7.5Hz, 1H), 2.7 (dxd, J1 = 14Hz, J2 = 8.5Hz, 1H), 3.1 and 3.35 (2m, 4H, 2x OCH2) , 3.65 (2d, J ~ 6Hz, 2xOH), 3.8 (m, 2H, CH-OC2H5), 4.3 (m, 2H, CH-OH), 6.1-6.7 (div.m, 10 olefin H).

微量分析(结晶中含20mol％甲醇)：计算值：C76.34％ H9.36％实测值：C75.92％ H9.02％实施例163，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素、即虾青素(式I中R1代表羟基，m和n都代表1；“直通法”)的制备将60ml二氯甲烷置于带有磁搅拌器和氩气化装置的100ml四颈磺化烧瓶中，加入约55mg(6滴；0.5mmol)丙酮二甲基缩醛和约25mg(2滴；0.2mmol，2mol％)三氟化硼二乙醚合物。 Microanalysis (crystals containing 20mol% methanol): Calculated: C76.34% H9.36% Found: C75.92% H9.02% Example 163,3'--dihydroxy-4,4'-dione group -β, β'- carotene, i.e. astaxanthin (formula I wherein R1 represents a hydroxyl group, m and n represent 1; "direct method") will be prepared in 60ml of dichloromethane and placed on a magnetic stirrer with argon 100ml four-necked sulfonation flask gasification apparatus, adding about 55mg (6 drops; 0.5mmol) in acetone dimethyl acetal and about 25mg (2 drops; 0.2mmol, 2mol%) boron trifluoride diethyl etherate. 将该溶液在室温下保持约16小时(以除去残留的水)后，冷却至-25℃，一次性向其中加入没有溶剂的3.33g(7.3mmol)番红花酸二醛二乙基缩醛(HPLC纯度为97.5％)和3.80g(21mmol，29当量)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环。 The solution was held for about 16 hours (to remove the residual water) and then cooled to -25 ℃ at room temperature, which was added at one time without a solvent 3.33g (7.3mmol) saffron diethyl diethylacetal ( HPLC purity 97.5%) and 3.80g (21mmol, 29 eq.) 4,6,6-trimethyl--5,6,7,7a- tetrahydro-5-methyl-1,3-benzodioxol times E ring. 下面，混合物在-20至-15℃下搅拌9小时，用HPLC控制。 Next, the mixture was stirred at -20 to -15 ℃ 9 hours by HPLC control. 在-20℃下向其中加入0.7ml(约1g，6mmol)48％含水氢溴酸，混合物在该温度下搅拌30分钟。 At -20 ℃ thereto was added 0.7ml (approximately 1g, 6mmol) 48% aqueous hydrobromic acid, and the mixture was stirred at this temperature for 30 minutes.

向混合物中一次性加入10ml(10mmol)的1N氢氧化钠溶液进行中和。 To the mixture was added in one 10ml (10mmol) of 1N sodium hydroxide solution for neutralization. 随后，混合物在0℃冰浴中搅拌45分钟，然后用1ml乙酸酸化。 Subsequently, the mixture was stirred for 45 minutes at 0 ℃ ice bath, and then acidified with 1ml of acetic acid. 然后，反应溶液用二氯甲烷萃取，用水洗涤两次，经无水硫酸钠干燥后浓缩。 Then, the reaction solution was extracted with dichloromethane, washed twice with water, dried over anhydrous sodium sulfate and concentrated. 得到5.84g暗红色固体残余物，将其悬浮在60ml庚烷中。 To give 5.84g of dark red solid residue, which was suspended in 60ml of heptane. 混悬液在100℃下回流3小时，缓慢冷却至室温后过滤。 The suspension was refluxed for 3 hours at 100 ℃, slowly cooled to room temperature and filtered. 所得晶体用庚烷洗涤。 The resulting crystals were washed with heptane. 晶体在高真空、室温下干燥后，得到4.10g棕红色粉末。 Crystals under high vacuum, room temperature, and dried to obtain 4.10g brown-red powder. 使其溶于二氯甲烷(60ml或35ml)，并在减压下连续用丙酮(40ml或30ml)代替，进行重结晶。 Which was dissolved in dichloromethane (60ml or 35ml), under reduced pressure and continuously replaced with acetone (40ml or 30ml), was recrystallized. 冷却(-20℃)，用冷(-20℃)丙酮洗涤，在高真空、55℃下干燥一小时后，得到2.20g(产率45％，以所用的番红花酸二乙基缩醛计)虾青素，为紫色闪光的晶体，熔点219℃；HPLC：97％(面积％)。 Cooled (-20 ℃), washed with cold (-20 ℃) ​​was washed with acetone, under high vacuum, 55 ℃ dried after one hour, to give 2.20g (45% yield, saffron diethyl acetal according to the type of meter) astaxanthin, purple shiny crystals, melting point 219 ℃; HPLC: 97% (area%).

为了获得分析数据，进行两次以上重结晶。 To obtain analytical data, two or more times recrystallization. 所得虾青素是具有金属光泽的晶体，熔点219℃；HPLC：97％(面积％)；HPLC(与标准物比较的wt.％)：(全E)-虾青素：94％(9Z+13Z)-虾青素：0.3％单乙氧基甲氧基虾青素：1.6％8'-阿朴虾青素醛：1.6％3，3'-二羟基-2，3-二脱氢-4，4'-二酮基-β，β'-胡萝卜素(“halbastacin”)：0.1％二氯甲烷：2％UV(环己烷/3％CHCl3)：476nm(logE＝5.10)微量分析(用晶体中的2％二氯甲烷修正过)：计算值：C78.95％ H8.65％实测值：C78.79％ H8.52％实施例174，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素中间体（式VI中R2代表甲基，R5与R6都代表氢，m和n都代表1)的制备和分离(a)由氯化锌催化，用乙腈作为溶剂将580mg(1.5mmol)番红花酸二醛二甲基缩醛(HPLC纯度＞97％)和815mg(4.5mmol)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环置于带有磁搅拌器和氩气化装置的25ml圆底烧瓶中的10ml丙酮中，在0℃下，混合物用约20mg(10mol％)无水氯化锌处理。 The resulting astaxanthin is crystal having a metallic luster, melting point 219 ℃; HPLC: 97% (area%); (compare with the standard of wt%.) HPLC :( Full E) - Astaxanthin: 94% (9Z + 13Z) - astaxanthin: 0.3% single ethoxymethoxy astaxanthin: 1.6% 8'-apo aldehyde astaxanthin: 1.6% 3,3'-hydroxy-2,3-dehydro - 4,4'-diketo -β, β'- carotene ("halbastacin"): 0.1% methylene chloride: 2% UV (cyclohexane /3%CHCl3):476nm(logE=5.10) microanalysis ( correction crystal over 2% dichloromethane): Calculated: C78.95% H8.65% Found: C78.79% H8.52% Example 174,8,4 ', 8'tetramethoxysilane group -7,8,7 ', 8'-tetrahydro-3,4,3', 4'-bis (O- methylene) -β, β'- carotene intermediate (formula VI, R2 represents a methyl group, R5 and R6 are hydrogen, m and n represent 1) the preparation and isolation of (a) by catalytic zinc chloride, with acetonitrile as solvent 580mg (1.5mmol) saffron di dimethyl acetal (HPLC purity> 97%) and 815mg (4.5mmol) 4,6,6- trimethyl -5,6,7,7a- tetrahydro-5-methylene-1,3-benzo-dioxolane placed in 25ml round bottomed flask equipped with a magnetic stirrer and argon gasification means in 10ml of acetone, at 0 ℃, the mixture with about 20mg (10mol%) of anhydrous zinc chloride. 所得橙色混悬液在-5℃下搅拌4天，其后在室温下搅拌5天，得到淡黄色混悬液。 The resulting orange suspension was stirred at -5 ℃ 4 days followed by stirring at room temperature for 5 days, to give a pale yellow suspension. 下面，冷却至-10℃，用吸滤法过滤，在-20℃下用8ml乙腈洗涤。 Here, cooled to -10 ℃, filtered by suction filtration, washed with 8ml of acetonitrile at -20 ℃. 在进行纯化时，将黄色晶体在10ml热甲醇中消化，冷却至-10℃，滤出并在高真空、室温下干燥。 When carrying out the purification, the yellow crystals in the digestion 10ml hot methanol, cooled to -10 ℃, filtered off and at a high vacuum, dried at room temperature. 得到690mg(产率62％)4，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素，为橙色粉末。 To give 690mg (62% yield) 4,8,4 ', 8'tetramethoxysilane -7,8,7', 8'-tetrahydro-3,4,3 ', 4'-bis (O- methylene) -β, β'- carotene, as an orange powder.

为了获得分析数据，再次将来自丙酮中的样本以类似方法进行消化。 To obtain analytical data, again from acetone samples digested in a similar manner. 得到淡橙色晶体，熔点170.5℃。 To give pale orange crystals, mp 170.5 ℃.

UV(环己烷/3％ CHCl3)：429nm(logE＝5.14)，403nm(logE＝5.12)，382nm(logE＝4.91)；IR(cm-1)：no C＝O bands；质谱：748.5(M+，5)，537.3(50)，179(100)；1H-NMR(d6-DMSO，400Mhz；非对映体混合物)：特别是3.05，3.17(2s，OCH3)，3.60，3.70(2s，C(3)-H)，4.98和5.07(2m，OCH2O)，6.10-6.70(div.m，烯烃的H). UV (cyclohexane / 3% CHCl3): 429nm (logE = 5.14), 403nm (logE = 5.12), 382nm (logE = 4.91); IR (cm-1): no C = O bands; Mass spectrum: 748.5 (M + , 5), 537.3 (50), 179 (100); 1H-NMR (d6-DMSO, 400Mhz; mixture of diastereomers): in particular, 3.05,3.17 (2s, OCH3), 3.60,3.70 (2s, C ( 3) -H), 4.98 and 5.07 (2m, OCH2O), 6.10-6.70 (div.m, olefin H).

微量分析：计算值：C74.16％ H8.66％实测值：C74.07％ H8.96％(b)由二(三氟磺酸)锌催化，用乙腈作为溶剂向40ml乙腈中加入72mg(约8滴)丙酮二甲基缩醛，然后是43mg(0.12mmol，1.2mol％)三氟甲磺酸锌，混合物搅拌约16小时。 Microanalysis: Calcd: C74.16% H8.66% Found: C74.07% H8.96% (b) by two (trifluoromethyl sulfonate) zinc catalysis, using acetonitrile as the solvent to 40ml of acetonitrile was added 72mg ( about 8 drops) of acetone dimethyl acetal, followed by 43mg (0.12mmol, 1.2mol%) zinc triflate, and the mixture was stirred for about 16 hours. 然后，在0℃下向其中加入4.01g(10mmol)番红花酸二醛二甲基缩醛(HPLC纯度≥97％)和4.60g(25.6mmol，2.6当量)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环，混合物在0℃下搅拌8小时，在室温下搅拌24小时。 Then, at 0 ℃ added thereto 4.01g (10mmol) saffron di dimethyl acetal (HPLC purity ≥97%) and 4.60g (25.6mmol, 2.6 eq.) 4,6,6-trimethoxy yl -5,6,7,7a- tetrahydro-5-methyl-1,3-benzo sub-dioxolane, and the mixture was stirred for 8 hours at 0 ℃, stirred at room temperature for 24 hours. 按照类似于(a)所述的方法，用约0.2ml三乙胺中和后，混合物冷却至-20℃，滤出深黄色糊状物，在高真空、室温下干燥。 According to the procedure analogous to (a), with about 0.2ml of triethylamine and the mixture was cooled to -20 ℃, yellow paste was filtered off, dried under high vacuum at room temperature. 得到7.06g(产率94％)4，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素，为橙色晶体。 To give 7.06g (94% yield) 4,8,4 ', 8'tetramethoxysilane -7,8,7', 8'-tetrahydro-3,4,3 ', 4'-bis (O - methylene) -β, β'- carotene as orange crystals.

(c)由氯化铁(III)催化，用二氯甲烷作为溶剂将100ml二氯甲烷中的100mg(1mmol)丙酮二甲基缩醛和76mg(0.5mmol，4mol％)无水氯化铁(III)在带有磁搅拌器和氩气化装置的150ml圆底烧瓶中保持约16小时。 (C) by ferric chloride (III) catalysis, using methylene chloride as solvent 100ml dichloromethane 100mg (1mmol) of acetone dimethyl acetal and 76mg (0.5mmol, 4mol%) of anhydrous ferric chloride ( III) maintained at 150ml round bottom flask equipped with a magnetic stirrer and argon gasification means for about 16 hours. 然后将混合物冷却至-30℃，一次性向其中加入没有溶剂的5.6g(14.0mmol)番红花酸二醛二甲基缩醛(HPLC纯度≥97％)，然后是6.5g(36mmol)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环。 The mixture was then cooled to -30 ℃, one time without a solvent added thereto 5.6g (14.0mmol) saffron di dimethyl acetal (HPLC purity ≥97%), followed by 6.5g (36mmol) 4, 6,6-trimethyl--5,6,7,7a- tetrahydro-5-methyl-1,3-benzo times dioxolane. 混合物在-25至30℃下搅拌7小时，并用HPLC控制。 The mixture was stirred at -25 to 30 ℃ 7 hours and analyzed by HPLC control. 加入0.5ml三乙胺中和催化剂，在减压下(150mbar＝15kPa)，二氯甲烷缓慢用约90ml甲醇代替，混合物冷却至-20℃，滤出所得晶体，用冷(-20℃)甲醇洗涤，在高真空下干燥约16小时。 Was added 0.5ml triethylamine catalyst under a reduced pressure (150mbar = 15kPa), dichloromethane was slowly replaced with about 90ml of methanol, the mixture was cooled to -20 ℃, the resulting crystals were filtered off, washed with cold (-20 ℃) ​​methanol washed, and dried under high vacuum for about 16 hours. 得到9.90g(产率94％)4，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素，为黄橙色晶体，熔点169-172℃。 To give 9.90g (94% yield) 4,8,4 ', 8'tetramethoxysilane -7,8,7', 8'-tetrahydro-3,4,3 ', 4'-bis (O - methylene) -β, β'- carotene as a yellow-orange crystals, mp 169-172 ℃. 质谱：748.5(M+，2)537.3(10)；1H-NMR(C6D6，400MHz；非对映体混合物)：特别是2.40，2.75(2m，4H)，3.12(s，OCH3，6H)，～3.35(2s，OCH3，6H)，3.8(m，2H)，4.6(m，2H)，5.11和5.14(2s，2H)，5.33(s，2H)，6.3-6.8(m，10烯烃的H). Mass spectrum: 748.5 (M +, 2) 537.3 (10); 1H-NMR (C6D6,400MHz; mixture of diastereomers): In particular 2.40,2.75 (2m, 4H), 3.12 (s, OCH3,6H), ~ 3.35 (2s, OCH3,6H), 3.8 (m, 2H), 4.6 (m, 2H), 5.11 and 5.14 (2s, 2H), 5.33 (s, 2H), 6.3-6.8 (m, 10 olefin H).

(d)由三氟化硼二乙醚合物催化，用二氯甲烷与乙腈的混合物作为溶剂在-30℃下，用约40mg(3滴，0.3mmol，4mol％)三氟化硼二乙醚合物催化2.72g(6.8mmol)番红花酸二醛二甲基缩醛(HPLC纯度≥97％)与3.28g(18.2mmol)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环在50ml二氯甲烷与10ml乙腈的混合物中进行类似反应(如(b)所述)2小时，用三乙胺中和并结晶(类似于(c))后，得到4.71g(产率92％)4，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素，为淡黄色晶体，熔点175-177℃。 (D) by boron trifluoride diethyl etherate catalysis, with a mixture of methylene chloride and acetonitrile as the solvent at -30 ℃, with about 40mg (3 drops, 0.3mmol, 4mol%) of boron trifluoride diethyl etherate Catalytic 2.72g (6.8mmol) saffron di dimethyl acetal (HPLC purity ≥97%) and 3.28g (18.2mmol) 4,6,6- trimethyl -5,6,7,7a - tetrahydro-5-methylene-1,3-benzo-dioxolane similar reaction (e.g. (b) above) 2 hours in a mixture of 50ml of dichloromethane and 10ml of acetonitrile with triethylamine. and and crystallization (similar to (c)) after, to give 4.71g (yield 92%) of 4,8,4 ', 8'tetramethoxysilane -7,8,7', 8'-tetrahydro-3 , 4,3 ', 4'-bis (O- methylene) -β, β'- carotene, as pale yellow crystals, mp 175-177 ℃.

实施例183，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素、即虾青素(式I中R1代表羟基，m和n都代表1)的制备(a)二氯甲烷中的水解和裂解反应在带有磁搅拌器和氩气化装置的100ml圆底烧瓶中，将4.90g(6.55mmol)4，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素溶于60ml二氯甲烷。 Preparation Example 183,3'- dihydroxy-4,4'-diketo -β, β'- carotene, i.e. astaxanthin (formula I wherein R1 represents a hydroxyl group, m and n represent 1) (a ) dichloromethane hydrolysis and cleavage reaction in a 100ml round bottom flask equipped with a magnetic stirrer and argon gasification means, a 4.90g (6.55mmol) 4,8,4 ', 8'- tetramethoxysilane - 7,8,7 ', 8'-tetrahydro-3,4,3', 4'-bis (O- methylene) -β, β'- carotene was dissolved in 60ml of dichloromethane. 将溶液冷却至-20℃，用2ml的48％含水氢溴酸处理，并用HPLC控制。 The solution was cooled to -20 ℃, treated with 2ml of 48% aqueous hydrobromic acid and analyzed by HPLC control. 1.5小时后，在-15至-20℃下，混合物用20ml的2N氢氧化钠溶液中和，在分液漏斗中分离。 After 1.5 h at -15 to -20 ℃, the mixture was treated with 20ml 2N sodium hydroxide solution and separated in a separatory funnel. 有机相用饱和碳酸氢钠溶液洗涤，其后用半饱和的氯化钠溶液洗涤，经无水硫酸钠干燥，过滤并浓缩至约35ml。 The organic phase was washed with saturated sodium bicarbonate solution, subsequently washed with half-saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to about 35ml. 溶液通过15g硅胶垫过滤(0.04-0.065mm；溶剂：二氯甲烷/二乙醚(3∶1))，在减压下略为浓缩，连续用乙醇代替，直至最后残留约20ml溶液，从中进行结晶。 Solution was filtered through a pad of silica gel 15g (0.04-0.065mm; solvent: dichloromethane / diethyl ether (3:1)), and concentrated under reduced pressure slightly, washed successively with ethanol instead, until finally the residual solution about 20ml, which crystallized. 所得混悬液用一小刀尖丁基化的羟基甲苯处理，回流约16小时进行异构化。 The resulting suspension was extracted with a small tip butylated hydroxy toluene, refluxed for about 16 hours isomerization. 然后冷却至0℃，用吸滤法过滤，用冷乙醇洗涤。 Then cooled to 0 ℃, filtered by suction filtration, washed with cold ethanol. 在高真空、70℃下干燥后得到3.00g暗红色晶体，使其溶于50ml二氯甲烷，溶剂在40℃/400mbar(40kPa)下连续用丙酮代替(最后的液体约为30ml)，冷却至0℃，过滤并用-20℃丙酮洗涤，进行结晶。 In high vacuum at 70 ℃ dried to give 3.00g of dark red crystals, which was dissolved in 50ml of dichloromethane, the solvent at 40 ℃ / 400mbar (40kPa) under continuous use in place of acetone (final liquid approximately 30ml), cooled to 0 ℃, -20 ℃ was filtered and washed with acetone, and crystallized. 在高真空、室温下干燥18小时后得到2.80g(产率68％，修正过)虾青素，为具有金属光泽的晶体，熔点219-220℃。 Under high vacuum, room temperature for 18 hours and dried to give 2.80g (68% yield, corrected) astaxanthin as crystals with metallic luster, melting point 219-220 ℃.

HPLC含量(与标准物比较的wt.％)：(全E)-虾青素：94％(9Z+13Z)-虾青素：0.7％8'-阿朴虾青素醛：1.3％单甲氧基甲基虾青素：1.6％3，3'-二羟基-2，3-二脱氢-4，4'-二酮基-β，β'-胡萝卜素(“Halbastacin”)：0.3％二氯甲烷：1％UV(环己烷/3％CHCl3)：467nm(logE＝5.10)；质谱：596(M+，10)，147(100)；1H-NMR(CDCl3，400MHz)：1.21和1.32(2s，每种情况6H)，1.81(t，J＝12Hz，2H)，1.95，1.99和2.00(3s，3x6H)，2.16(dxd，J1＝12Hz，J2＝6Hz，2Hz)，3.68(d，J～2Hz，2x OH)，4.32(dxdxd，J1＝12Hz，J2＝6Hz，J3～2Hz)，6.2-6.7(div.m，14烯烃的H). HPLC content (compared with the standard wt%.) :( Whole E) - Astaxanthin: 94% (9Z + 13Z) - astaxanthin: 0.7% 8'-apo aldehyde astaxanthin: 1.3% monomethyl methyl group astaxanthin: 1.6% 3,3'-dihydroxy-4,4'-diketo-2,3-dehydrogenation -β, β'- carotene ("Halbastacin"): 0.3% dichloromethane: 1% UV (cyclohexane /3%CHCl3):467nm(logE=5.10); Mass spectrum: 596 (M +, 10), 147 (100); 1H-NMR (CDCl3,400MHz): 1.21 and 1.32 (2s, in each case 6H), 1.81 (t, J = 12Hz, 2H), 1.95,1.99 and 2.00 (3s, 3x6H), 2.16 (dxd, J1 = 12Hz, J2 = 6Hz, 2Hz), 3.68 (d, J ~ 2Hz, 2x OH), 4.32 (dxdxd, J1 = 12Hz, J2 = 6Hz, J3 ~ 2Hz), 6.2-6.7 (div.m, 14 olefin H).

(b)乙腈中的水解和裂解反应在氩气下，将4.9g(约6.5mmol)4，8，4'，8'-四甲氧基-7，8，7'，8'-四氢-3，4，3'，4'-双(O-亚甲基)-β，β'-胡萝卜素(熔点167-174℃)置于带有磁搅拌器和氩气化装置的100ml圆底烧瓶中。 (B) acetonitrile hydrolysis and cracking reaction under argon, to 4.9g (about 6.5mmol) 4,8,4 ', 8'- tetramethoxysilane -7,8,7', 8'-tetrahydro- 3,4,3 ', 4'-bis (O- methylene) -β, β'- carotene (m.p. 167-174 ℃) placed in a 100ml round bottom with a magnetic stirrer and argon gasification means flask. 在-15℃下，一边搅拌一边向该黄色混悬液中加入2ml(3g，20mmol)的48％含水氢溴酸，溶液的颜色立即变暗。 At -15 ℃, stirring To this yellow suspension was added 2ml (3g, 20mmol) in 48% aqueous hydrobromic acid, color of the solution immediately darkens. 15分钟后，温度升至0℃(冰浴)，混悬液在该温度下再搅拌4小时，并用HPLC控制。 After 15 minutes, the temperature was raised to 0 ℃ (ice bath), the suspension was stirred for 4 hours at this temperature and analyzed by HPLC control. 随后，用20ml(20mmol)的1N氢氧化钠溶液使混合物呈碱性，用吸滤法过滤，固体用大量水洗涤。 Subsequently, 20ml (20mmol) of 1N sodium hydroxide solution and the mixture was made alkaline and filtered by suction filtration, the solid washed with copious amounts of water. 下面，将潮湿的晶体溶于250ml二氯甲烷，溶液经无水硫酸钠干燥，过滤并在减压下浓缩至约50ml。 Next, the wet crystals were dissolved in 250ml of methylene chloride, the solution dried over anhydrous sodium sulfate, filtered, and concentrated to approximately 50ml under reduced pressure. 下面，将浓缩了的溶液通过15g硅胶垫(0.04-0.065mm)过滤，并使用二氯甲烷/二乙醚(3∶1)溶剂混合物，滤液在减压下略为浓缩。 Next, the concentrated solution was passed through 15g of silica gel pad (0.04-0.065mm) was filtered, and the use of methylene chloride / diethyl ether (3:1) solvent mixture, and the filtrate was concentrated under reduced pressure slightly. 然后，连续向其中加入60ml乙醇，溶液浓缩，直至最后的体积约为15-20ml。 Then, 60ml of ethanol was added thereto continuously, the solution was concentrated until a final volume of about 15-20ml. 所得混悬液在回流下沸腾2小时进行异构化，冷却至室温，过滤，晶体用-20℃的10ml乙醇洗涤。 The resulting suspension was boiled under reflux for 2 hours isomerization, cooled to room temperature, filtered, the crystals were washed with -20 ℃ 10ml ethanol. 在高真空、80℃下干燥两小时后得到3.30g虾青素，为暗紫色晶体，使其如(a)所述从70ml二氯甲烷与40ml丙酮中重结晶。 In high vacuum, and dried for two hours at 80 ℃ obtained after 3.30g of astaxanthin as a dark purple crystals, so as (a) above from 70ml of dichloromethane and 40ml of acetone and recrystallized. 得到3.10g(产率74％)虾青素，为深紫色闪光的晶体，熔点222℃；HPLC含量(与标准物比较的wt.％)：(全E)-虾青素：91％(9Z+13Z)-虾青素：0.3％8'-阿朴虾青素醛：1.7％单甲氧基甲基虾青素：1.9％3，3'-二羟基-2，3-二脱氢-4，4'-二酮基-β，β'-胡萝卜素(“Halbastacin”)：3.6％二氯甲烷：1.4％UV(环己烷/3％CHCl3)：477nm(logE＝5.07)；质谱和1H-NMR与被公认的物质相同。 Obtain 3.10g (74% yield) astaxanthin, for purple shiny crystals, melting point 222 ℃; (compared with the standard wt%.) HPLC full content :( E) - Astaxanthin: 91% (9Z + 13Z) - astaxanthin: 0.3% 8'-apo aldehyde astaxanthin: 1.7% single-methoxymethyl astaxanthin: 1.9% 3,3'-hydroxy-2,3-dehydro - 4,4'-diketo -β, β'- carotene ("Halbastacin"): 3.6% methylene chloride: 1.4% UV (cyclohexane /3%CHCl3):477nm(logE=5.07); mass spectrometry and 1H-NMR identical with the substance to be recognized.

实施例193，3'-二羟基-4，4'-二酮基-β，β'-胡萝卜素、即虾青素(式I中R1代表羟基，m和n都代表1；“直通法”II+III→I)的制备将50ml二氯甲烷置于带有磁搅拌器、温度计和氩气化装置的100ml四颈磺化烧瓶中，加入约55mg(6滴，0.5mmol)丙酮二甲基缩醛和40mg(3mol％)无水氯化铁(III)。 Example 193,3'- dihydroxy-4,4'-diketo -β embodiment, β'- carotene, i.e. astaxanthin (formula I wherein R1 represents a hydroxyl group, m and n represent 1; "direct method" Preparation II + III → I) will be placed in 50ml of dichloromethane 100ml four-necked sulfonation flask equipped with magnetic stirrer, thermometer and argon gasification means were added about 55mg (6 drops, 0.5mmol) in acetone dimethyl acetal and 40mg (3mol%) of anhydrous ferric chloride (III). 混合物在35-40℃下搅拌2小时。 The mixture was stirred at 35-40 ℃ 2 hours. 下面，冷却至-30℃，一次性向其中加入没有溶剂的2.80g(7mmol)番红花酸二醛二甲基缩醛(HPLC纯度≥97％)和3.28g(18.2mmol，2.6当量)4，6，6-三甲基-5，6，7，7a-四氢-5-次甲基-1，3-苯并二氧戊环。 Here, cooled to -30 ℃, disposable without a solvent added thereto 2.80g (7mmol) saffron di dimethyl acetal (HPLC purity ≥97%) and 3.28g (18.2mmol, 2.6 eq.) 4, 6,6-trimethyl--5,6,7,7a- tetrahydro-5-methyl-1,3-benzo times dioxolane. 下面，混合物在-30℃至-25℃下搅拌4.5小时，并用HPLC控制。 Next, the mixture was stirred at -30 ℃ to -25 ℃ 4.5 h by HPLC control. 然后，在-25℃下向其中加入1ml(约1.5g/9mmol)的48％含水氢溴酸和50ml二氯甲烷，混合物在-15℃下再搅拌1.25小时。 Then, at -25 ℃ added thereto 1ml (about 1.5g / 9mmol) 48% aqueous hydrobromic acid and 50ml of methylene chloride, and the mixture was stirred at -15 ℃ 1.25 hours.

向混合物中一次性加入5ml(10mmol)的2N氢氧化钠溶液，混合物搅拌5分钟，进行中和。 To the mixture was added in one 5ml (10mmol) of 2N sodium hydroxide solution, the mixture was stirred for 5 minutes to carry out neutralization. 然后，倾入水中，分离出水，有机相用饱和碳酸氢钠溶液和半饱和的氯化钠溶液洗涤，经无水硫酸钠干燥，在减压下浓缩至约30ml。 Then, poured into water, water is separated, the organic phase was washed with saturated sodium bicarbonate solution and half-saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to approximately 30ml under reduced pressure. 使浓缩了的溶液通过15g硅胶垫(0.04-0.056mm)过滤，并使用二氯甲烷/二乙醚(3∶1)溶剂混合物，在减压下略为浓缩，连续用乙醇代替，直至最终体积为20ml，此时发生结晶。 The concentrated solution was passed through a 15g silica gel pad (0.04-0.056mm) was filtered, and the use of methylene chloride / diethyl ether (3:1) solvent mixture, slightly concentrated under reduced pressure, washed successively with ethanol in place, until a final volume of 20ml In this case crystallization occurs. 所得混悬液用一小刀尖丁基化的羟基甲苯处理，回流约16小时进行异构化。 The resulting suspension was extracted with a small tip butylated hydroxy toluene, refluxed for about 16 hours isomerization. 然后冷却至室温，用吸滤法过滤，用冷乙醇洗涤。 Then cooled to room temperature, filtered by suction filtration, washed with cold ethanol. 在高真空、70℃下干燥两小时后得到3.60g紫色晶体，将其如实施例18(a)所述从二氯甲烷/丙酮中重结晶两次。 In high vacuum at 70 ℃ dried for two hours to give 3.60g purple crystals, which was as described in Example 18 (a) of the recrystallized twice from methylene chloride / acetone. 以这种方式得到3.00g(产率68％，以所用的番红花酸二醛二甲基缩醛计)虾青素，为深紫色闪光的晶体，熔点219℃。 In this manner 3.00g (68% yield, with the use of saffron diethyl dimethyl acetal meter) astaxanthin, for purple shiny crystals, melting point 219 ℃. HPLC含量(与标准物比较的wt.％)：(全E)-虾青素：95％(9Z+13Z)-虾青素：0.2％单甲氧基甲基虾青素：1％8'-阿朴虾青素醛：1％3，3'-二羟基-2，3-二脱氢-4，4'-二酮基-β，β'-胡萝卜素(“halbastacin”)：0.3％二氯甲烷：1％UV(环己烷/3％CHCl3)：476nm(logE＝5.10)；质谱和1H-NMR与被公认的物质相同。 HPLC content (compare with the standard of wt%.) :( Full E) - Astaxanthin: 95% (9Z + 13Z) - Astaxanthin: 0.2% mono-methoxymethyl-astaxanthin: 1% 8 ' - A Park astaxanthin aldehyde: 1% 3,3'-hydroxy-2,3-dimethyl-4,4'-diketo dehydrogenation -β, β'- carotene ("halbastacin"): 0.3% dichloromethane: 1% UV (cyclohexane /3%CHCl3):476nm(logE=5.10); mass spectrum and 1H-NMR identical with the substance to be recognized.