本发明涉及一种有需要作为营养剂、食品着色剂和食品添加剂的类胡萝卜素例如β-胡萝卜素、玉米黄质、斑蝥黄、虾青素、番茄红素和藏花酸的制备方法。 The present invention relates to a need as nutrients, carotenoids food colorants and food additives such as β- carotene, zeaxanthin, canthaxanthin, astaxanthin, lycopene and preparation methods Crocein acids.

已知类胡萝卜素尤其是通过C15鏻盐(C15-P)与对称C10二醛的双Wittig缩合而制备的(Cartenoids(类胡萝卜素)，第2卷，89页起，Birkhuser Verlag，1996)。 Carotenoids are known especially through C15 phosphonium salt (C15-P) condensed with symmetrical C10 dialdehyde bis Wittig prepared (Cartenoids (carotenoids), Vol. 2, from 89, Birkhuser Verlag, 1996 ).

根据欲制备的类胡萝卜素的结构，例如可以在上述Wittig反应中，将以下C15鏻盐(P1-P5)反应，其中Ph是苯基，而X-是无机或有机酸的阴离子等同物： Carotene to be prepared based on the class structure, for example, in the above-mentioned Wittig reaction, the following C15 phosphonium salt (P1-P5) reaction, where Ph is phenyl, and X- is an inorganic anion or an organic acid equivalents:

为了合成藏花酸二酯(藏红花色素藏花酸的前体)，将C5酯鏻盐(C5-P)或C5酯膦酸酯(C5-EP)与C10二醛进行相应的Wittig或Wittig-Horner缩合(Angew.Chem.72，911(1960)；Chem.Ber.93，1349(1960))。 In order to take possession of synthetic diester (crocetin saffron pigment precursor), the C5 ester phosphonium salt (C5-P) or C5 ester phosphonate (C5-EP) and the corresponding aldehyde C10 two Wittig or Wittig- Horner condensation (Angew.Chem.72,911 (1960); Chem.Ber.93,1349 (1960)).

这些合成方法所需的C10二醛是一种结晶物质，仅微溶于许多溶剂。 These synthetic methods the desired C10 dialdehyde is a crystalline substance, only slightly soluble in many solvents. 因此，使用C10二醛进行的类胡萝卜素合成往往必须在作为溶剂或共溶剂的氯代烃诸如二氯甲烷或三氯甲烷或者环氧烷中进行(类胡萝卜素，第2卷，92页起；Birkhuser-Verlag，1996)。 Therefore, the use of C10 dialdehyde carotenoid synthesis must often chlorinated hydrocarbons as a solvent or co-solvent such as dichloromethane or chloroform, or an alkylene oxide is carried out (carotenoids, Vol. 2, 92 from ; Birkhuser-Verlag, 1996). 从毒性角度而言，将这些溶剂用于制备食品添加剂是不适宜的。 From the point of view of toxicity, these solvents are not suitable for the preparation of food additives.

这就是为什么有许多方法，尤其是EP-A-0 733 619和EP-A-0 908 449，致力于在毒性上更适宜的溶剂诸如低级醇中进行这些工业方法。 This is why there are many ways, especially EP-A-0 733 619 and EP-A-0 908 449, committed on the toxicity of these industrial methods more suitable solvent such as a lower alcohol were. 但是，所有这些方法仍然都需要制备和分离，以及处理和计量结晶C10二醛。 However, all these methods still need to be prepared and isolated, and the processing and measurement of crystallization C10 dialdehyde. 但处理固体将使得基本投资较高，生产成本因此较高。 But the treatment of solid basic investment will allow higher production costs and therefore higher.

在EP-A-0 509 273中公开了一种避免上述缺点的可能性。 Discloses a possibility to avoid the disadvantages mentioned above in EP-A-0 509 273 in.

其中描述的方法使用式(1)的2，5-二氢呋喃作为C10二醛的合成替代品，所述2，5-二氢呋喃是油状的，并且通过2，5-二烷氧基-2，5-二氢呋喃(2)与烷基丙烯基醚(3)反应制备。 Wherein 2,5-dihydrofuran using the method described in the formula (1) as a synthetic substitute for C10 dialdehyde, the 2,5-dihydrofuran is oil, and by 2,5-dialkoxy-- 2,5-dihydrofuran (2) with an alkyl propenyl ether (3) acid.

但是，该方法的缺点如下。 However, the disadvantage of this method are as follows. (1)的收率只有理论值的38-56％，对于工业过程而言是不足的。 (1) the yield of only 38-56% of the theoretical value, for the purposes of industrial processes is insufficient. 其它出版物证实，类似方法一般只给出了二烷基化产物(1)的较低收率(J.Gen.Chem.USSR，32，4，1082 f.(1962)；Tetrahedron Lett.42，10，2003 f.(2001))。 Other publications confirmed that a similar method generally gives a bis-alkylated product (1) the yield is low (J.Gen.Chem.USSR, 32,4,1082 f (1962);. Tetrahedron Lett.42, 10,2003 f. (2001)). 只有一个通过(1)的反应合成类胡萝卜素的实施例以52％的总收率得到β-胡萝卜素。 Only one embodiment by (1) reaction of the synthesis of carotenoids in 52% overall yield β- carotene. 该方法在工业化和经济上没有吸引力，因为(1)不易获得且收率低。 This method is not attractive in the industrialized and economically, because (1) are not readily available and low yield.

因此，本发明的目的是提供一种克服上述现有技术缺点的制备类胡萝卜素的方法。 Accordingly, an object of the invention is to provide a process for preparing the above-described prior art drawbacks class carotene overcome.

该目的是通过一种制备类胡萝卜素的方法实现的，包括将通式I的二烷氧基二醛 This object is achieved by a method of preparing a carotenoid, comprising the general formula I dialkoxy dialdehyde 其中R1＝C1-C6-烷基，在双Wittig缩合中与式II的鏻盐反应，或者在双Wittig-Horner缩合中与式III的膦酸酯反应， Wherein R1 = C1-C6- alkyl, in a double Wittig condensation with a phosphonium salt of formula II, or Formula III is reacted with the phosphonate in a double Wittig-Horner condensation,

其中取代基各自独立地具有以下含义：R2是： Wherein the substituents independently have the following meanings: R2 is: R3是芳基；R4-R6是C1-C6-烷基，和X-是无机或有机酸的阴离子等同物。 R3 is aryl; R4-R6 is C1-C6- alkyl, and X- is an inorganic anion or an organic acid equivalents.

上述R1和R4-R6中的烷基是支链或直链的C1-C6-烷基链，诸如甲基、乙基、正丙基、1-甲基乙基、正丁基、1-甲基丙基、2-甲基丙基、1，1-二甲基乙基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2，2-二甲基丙基、1-乙基丙基、正己基、1，1-二甲基丙基、1，2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，2-二甲基丁基、2，3-二甲基丁基、3，3-二甲基丁基、1-乙基丁基、2-乙基丁基、1，1，2-三甲基丙基、1，2，2-三甲基丙基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基。 Said R1 and R4-R6 are alkyl groups are C1-C6- alkyl chain branched or straight chain, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylbutyl propyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl methylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl. 优选的烷基是C1-C4-烷基，特别优选甲基、乙基、正丙基和1-甲基乙基，非常优选甲基和乙基。 Preferred alkyl groups are C1-C4- alkyl, particularly preferably methyl, ethyl, n-propyl and 1-methylethyl, very preferably methyl and ethyl.

R3的术语烷基是指膦和鏻盐中出现的常规芳基，诸如分别任选取代的苯基、甲苯基、萘基，优选苯基。 R3 term alkyl means a conventional aryl phosphines and phosphonium salts appearing, respectively, such as optionally substituted phenyl, tolyl, naphthyl, preferably phenyl.

基团X-是无机或有机酸的、优选强无机酸或有机酸的阴离子等同物。 Groups and X- is an inorganic or organic acid, preferably an anion of a strong inorganic or organic acid equivalents.

术语“强酸”包括氢卤酸(尤其是氢氯酸和氢溴酸)、硫酸、磷酸、磺酸和具有相当离解度的其它无机或有机酸。 The term "strong acid" includes hydrohalic acids (especially hydrochloric acid and hydrobromic acid), sulfuric acid, phosphoric acid, sulfonic acid, and have a considerable degree of dissociation of other inorganic or organic acids. 在本文中，强有机酸也指C1-C6-链烷酸。 As used herein, a strong organic acid also refers C1-C6- alkanoic acid.

优选提及的阴离子是选自氢卤酸、硫酸、磷酸、甲酸、乙酸和磺酸中的酸的阴离子。 Preferably the anion is selected from the mentioned hydrohalic acids, sulfuric acid, phosphoric acid, formic acid, acetic acid and sulfonic acid in an anion. 特别优选提及的阴离子是选自盐酸、氢溴酸、硫酸、膦酸、甲酸、乙酸和磺酸的那些酸的阴离子。 Particularly preferred anions mentioned is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, formic acid, acetic acid and the anion of those sulfonic acids. 特别优选Cl-、Br-、CnH2n+1-SO3-(n＝1-4)、Ph-SO3-、p-Tol-SO3-或CF3-SO3-。 Particularly preferably Cl-, Br-, CnH2n + 1-SO3- (n = 1-4), Ph-SO3-, p-Tol-SO3- or CF3-SO3-.

本发明方法的优选实施方案涉及制备选自虾青素、番茄红素和斑蝥黄的类胡萝卜素，包括将式Ia的二烷氧基二醛 Preferred embodiments of the present invention relates to the preparation method selected from astaxanthin, lycopene and canthaxanthin carotenoids, including Formula Ia dialkoxy dialdehyde 与式IIa的鏻盐反应， Reaction with phosphonium salt of the formula IIa, 其中取代基各自独立地具有以下含义：R2是： Wherein the substituents independently have the following meanings: R2 is: Ph是苯基；Hal是卤素，优选Cl-或Br-。 Ph is phenyl; Hal is halogen, preferably Cl- or Br-.

Wittig或Wittig-Horner反应是在已经描述用于这些反应的条件下进行(类胡萝卜素，第2卷，79页起，Birkhuser-Verlag，1996，及其中引用的参考文献；和EP-A-0 733 619)。 Wittig or Wittig-Horner reaction is performed (carotenoids have been described under the conditions used in these reactions, since Vol. 2, 79, Birkhuser-Verlag, 1996, and the references cited therein; and EP-A -0,733,619). 该反应可以在例如由惰性有机溶剂诸如卤代烃或者环状醚或开链醚以及碱金属或碱土金属醇盐组成的体系中进行，优选在相应链烷醇中的溶液。 The reaction can be for example an inert organic solvent such as a halogenated hydrocarbon open-chain or cyclic ether or an ether and an alkali metal or alkaline earth metal alkoxide of the system, preferably in solution in the corresponding alkanol. 此时，也可以使用环氧烷，优选1，2-环氧丁烷，按照本身已知的方式，作为潜在碱(latent base)和共溶剂与低级链烷醇结合。 In this case, the alkylene oxide may also be used, preferably 1,2-butylene oxide, in a manner known per se, as a potential base (latent base) and a co-solvent in combination with a lower alkanol.

常规用于Wittig缩合的所有碱均可用作碱，例如碱金属氢氧化物，诸如氢氧化钠、氢氧化钾或氢氧化锂；碱金属氢化物，诸如氢化钠或氢化钾。 All bases conventionally used in Wittig condensation may be used as a base, such as alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal hydrides such as sodium hydride or potassium hydride.

但优选使用的溶剂是所需终产物微溶于该溶剂中，而作为Wittig反应副产物得到的氧化三苯膦易溶于该溶剂中。 However, the solvent preferably used is the desired final product slightly soluble in the solvent, and as a byproduct of the Wittig reaction to give triphenylphosphine oxide soluble in the solvent.

适用于该目的的尤其是低级醇，优选C1-C6醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇，特别优选甲醇。 Suitable for this purpose, especially lower alcohols, preferably C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, particularly preferably methanol. 此时优选使用的碱是碱金属或碱土金属醇盐，优选甲醇钠。 In this case the base used is preferably an alkali metal alkaline earth metal alkoxide, preferably sodium or methanol. 可以通过用水稀释混合物除去氧化三苯基膦和无机盐。 Triphenylphosphine oxide can be removed by dilution with water and inorganic salt mixture.

缩合反应一般在-30℃至+50℃，优选-20至+30℃，特别优选-10℃至+25℃，非常优选0℃至+20℃的温度下进行。 The condensation reaction is generally at -30 ℃ to + 50 ℃, preferably from -20 to + 30 ℃, particularly preferably from -10 ℃ to + 25 ℃, very preferably at a temperature of 0 ℃ to + 20 ℃ performed.

在本文中，可以将两种原料化合物(鏻盐和醛)一起引入溶剂中并向其中加入碱，也可以向鏻盐的溶液中加入碱，随后才加入醛的溶液。 In this article, the two materials may be compound (phosphonium salt and aldehyde) introduced together with a solvent and adding thereto a base, a base may be added to a solution of the phosphonium salt, followed by a solution of the aldehyde was added.

碱的用量一般是按每摩尔使用的鏻盐II或膦酸酯III计的0.8-5摩尔，优选1-3摩尔。 The amount of base is generally per phosphonium salt II or III used phosphonate molar meter 0.8-5 moles, preferably 1-3 moles.

在Wittig或Wittig-Horner反应之后，可以按照已知方式，通过在70-120℃的温度范围、优选于所用溶剂的沸点下加热数小时，将产物热异构化为全部(E)形式，并且通过过滤以高收率和高纯度分离。 After the Wittig or Wittig-Horner reaction, according to known methods, by the temperature range 70-120 ℃, preferably heated at the boiling point of the solvent used for several hours, the product was thermally isomerized to all (E) form, and isolated by filtration in high yield and high purity.

用于本发明的二烷氧基二醛I或Ia For dialkoxy dialdehyde I or Ia of the present invention 是在用六烷氧基衍生物V作为原料、随后进行缩醛裂解和消去反应的C10二醛工业合成中以中间体形式出现的，但通常无需分离(类胡萝卜素，第2卷，117/118页和301/302页，Birkhuser Verlag，1996；CH专利.321 106).通过反应条件的适当选择，可以在I的中间阶段中止操作。 Is alkoxy derivative with six V as a starting material, followed by acetal cleavage and elimination reaction of C10 dialdehyde industrial synthesis occurs in an intermediate form, but usually without isolation (carotenoids, Vol. 2, 117 / 118 and 301/302 pages, Birkhuser Verlag, 1996;. CH Patent .321 106) by appropriately selecting the reaction conditions, may abort the I intermediate stage. 可以通过蒸馏分离和纯化I(J.Gen.Chem.USSR，34，1，64 f.(1964))。 Can be separated and purified by distillation I (J.Gen.Chem.USSR, 34,1,64 f. (1964)).

式I的二烷氧基二醛是易溶的稳定物质，并且是液体或油状的，因此省去了C10二醛固体的加工处理。 Formula I dialkoxy dialdehyde is soluble stabilizing substance, and is liquid or oily, thus eliminating the need for processing of C10 dialdehyde solid. 使用I的其它优点在于通过一步合成和一步除去固体而缩短了制备C10单元的工艺。 Other advantages of using that I synthesis and step by step removal of solids and shorten the process of preparation of C10 units.

已经令人惊奇地发现，式I的中间体，优选Ia，特别适用于上述所有Wittig和Wittig-Horner缩合。 It has surprisingly been found that the intermediates of formula I, preferably Ia, especially applicable to all the above-described Wittig and Wittig-Horner condensation. 此时出现的中间体是通式IV的烷氧基衍生物。 Appears intermediates is alkoxy derivative of formula IV.

如果需要，这些中间体阶段可以分离出来。 If desired, these intermediate stages can be separated. 但是，优选在反应条件下能消去所需的多烯，优选通过提高反应温度来进行。 Preferably, however, can be eliminated under the reaction conditions required polyene, preferably by increasing the reaction temperature employed.

本发明还涉及式IV的化合物， The present invention also relates to compounds of formula IV, 其中取代基各自独立地具有以下含义：R1是C1-C6-烷基；R2是： Wherein the substituents independently have the following meanings: R1 is C1-C6- alkyl; R2 is: R6是C1-C6-烷基。 R6 is C1-C6- alkyl.

优选的化合物是式IV的那些， Preferred compounds are those of formula IV,

其中R1是甲基或乙基，特别优选甲基；和R2是： Wherein R1 is methyl or ethyl, particularly preferably methyl; and R2 is: 以下实施例用于更详细地解释本发明的方法。 The following examples of the present invention is explained in more detail a method for.

实施例1制备虾青素将71.9g(0.125mol)虾青素C15鏻盐P5(X-＝溴离子)引入150ml甲醇中。 Example 1 Preparation of astaxanthin implementation would 71.9g (0.125mol) astaxanthin C15 phosphonium P5 (X- = bromine ions) into 150ml of methanol. 于0℃下加入11.4g C10二醛Ia(纯度95％；相当于0.0475mol)。 Was added at 0 ℃ in 11.4g C10 dialdehyde Ia (purity 95%; equivalent 0.0475mol). 随后于0℃下经1小时滴加24.8g浓度30％的甲醇钠的甲醇溶液(＝0.137molNaOMe)，混合物于0℃下再搅拌1小时，并随后达到室温。 Then dried for 1 hour at 0 ℃ dropwise 24.8g concentration of 30% sodium methoxide in methanol (= 0.137molNaOMe), the mixture was further stirred at 0 ℃ for 1 hour and then brought to room temperature. 滴加1.5g(25mmol)乙酸于115ml水中的溶液，混合物加热至回流(约75℃)并接着在回流下搅拌20小时。 Solution of 1.5g (25mmol) of acetic acid in a solution of 115ml of water, the mixture was heated to reflux (about 75 ℃) and then stirred at reflux for 20 hours. 使其达到室温，滤出结晶。 To reach room temperature, crystals were filtered off. 用60∶40(v/v)甲醇/水混合物洗涤滤饼二次，每次100ml，用热水(100ml)洗涤一次，用甲醇(100ml；25℃)洗涤一次，并在+50℃下于真空干燥箱中干燥。 With 60:40 (v / v) methanol / water mixture the filter cake was washed twice, each time 100ml, with hot water (100ml) and washed once with methanol (100ml; 25 ℃) were washed once, and in at + 50 ℃ vacuum oven drying.

最终重量：23.5g虾青素＝收率83.0％(基于使用的Ia)；HPLC纯度：99.17％实施例2虾青素中间体阶段IVe的分离将71.9g(0.125mol)虾青素C15鏻盐P5(X-＝溴离子)溶于250ml二氯甲烷中。 Final weight: 23.5g astaxanthin yield = 83.0% (based on the use of Ia); HPLC purity: 99.17% implemented two separate cases of astaxanthin intermediate stage IVe will 71.9g (0.125mol) astaxanthin C15 phosphonium salt P5 (X- = bromide ion) was dissolved in 250ml of dichloromethane. 在0℃下加入11.4g C10二醛Ia(纯度95％；相当于0.0475mol)。 At 0 ℃ added 11.4g C10 dialdehyde Ia (purity 95%; equivalent 0.0475mol). 随后于0℃下经1小时滴加46.8g浓度20％的乙醇钠的乙醇溶液(0.137molNaOEt)。 Then at 0 ℃ in ethanol was added dropwise over 1 hour a solution of 46.8g 20% ​​ethanol concentration of sodium (0.137molNaOEt). 混合物于0℃下搅拌1小时。 The mixture was stirred for 1 hour at 0 ℃. 然后滴加1.5g乙酸于250ml水中的溶液。 Then added dropwise 1.5g of acetic acid in 250ml of water was added. 分离有机相。 Organic phase was separated. 水相用40ml二氯甲烷反萃取二次。 The aqueous phase was back-extracted twice with 40ml of dichloromethane. 用水洗涤合并的有机相两次，每次125ml，经硫酸钠干燥并在旋转蒸发器中浓缩。 The organic phase was washed with water twice, each time 125ml, dried over sodium sulfate and concentrated in a rotary evaporator. 通过在硅胶上闪蒸色谱法纯化亮红色糊状残余物(洗脱液：环己烷/甲基叔丁基醚＝4∶1-1∶1)。 By flash chromatography on silica gel bright red paste residue was purified (eluent: cyclohexane / MTBE = 4:1-1:1).

得到27.05g(理论值的86.3％)粘稠的红色油状物，根据H-NMR、C-NMR和IR分析，获得了含有立体异构体混合物形式的IVe。 To give 27.05g (86.3% of theory) of a viscous red oil, based on H-NMR, C-NMR and IR analysis, to obtain a three-dimensional form containing IVe isomer mixture. E11(CHCl3)：335(260nm)；468(351nm)。 E11 (CHCl3): 335 (260nm); 468 (351nm).

实施例3制备玉米黄质将14.9g(0.0288mol)玉米黄质C15鏻盐P3(X-＝氯离子)溶于63ml乙醇。 Example 3 Preparation of zeaxanthin will 14.9g (0.0288mol) zeaxanthin C15 phosphonium salt P3 (X- = chloride) was dissolved in 63ml of ethanol. 加入2.85g C10二醛Ia(纯度95％；相当于0.012mol)和16.6g环氧丁烷(1，2-环氧丁烷)。 Was added 2.85g C10 dialdehyde Ia (purity 95%; equivalent 0.012mol) and 16.6g butylene oxide (1,2-butylene). 随后将混合物在回流下加热20小时。 The mixture is then heated at reflux for 20 hours. 得到的悬浮液冷却至0℃，并于该温度下搅拌1小时。 The resulting suspension was cooled to 0 ℃, and stirred at this temperature for 1 hour. 抽滤出结晶。 The crystals were suction filtered. 使用乙醇洗涤滤饼三次，每次50ml，并于真空干燥箱中干燥。 The filter cake was washed with ethanol three times, each 50ml, and dried in a vacuum oven.

最终重量：5.52g玉米黄质＝理论值的81％(基于使用的Ia)。 Final weight: 81% 5.52g zeaxanthin = theoretical value (based on the use of Ia).