【作者】 沈润溥；

【导师】 陈新志；

【作者基本信息】 浙江大学 ， 化学工程与技术， 2004， 博士

【摘要】 维生素A及其衍生物是一类重要的药品和饲料添加剂，最常用的维A衍生物是其乙酸酯。目前世界市场维生素A系列产品的年需求量约为一万二千吨到一万五千吨，而国内生产维生素A乙酸酯的厂家仅三家：浙江新和成有限公司、厦门金达威公司和东北制药总厂，总生产能力不到两千吨。目前世界上合成维生素A乙酸酯主要采用三种不同的技术路线：罗氏公司的C₁₄+C₆路线、BASF公司开发的C₁₅+C₅路线和罗纳-普朗克公司的串联路线。为打破国外对维A产品的技术垄断和市场垄断，开发出有工业价值的全合成路线具有很重要的意义。 本文就维生素A乙酸酯的全合成研究进行了探索性的工作。 本文的主要工作： 以脱氢芳樟醇为起始原料全合成维生素A乙酸酯，主要内容分章介绍如下 第2章，以聚钒有机硅氧烷作催化剂，催化脱氢芳樟醇直接重排为柠檬醛；进而通过Claisen-Schmidt缩合反应制备假紫罗兰酮；最后，用以浓硫酸和冰醋酸以1：1配成的混酸为催化剂，通过成环反应得到β-紫罗兰酮。三步反应制得的β-紫罗兰酮收率可达66.9％。 第3章，由β-紫罗兰酮与氯乙酸甲酯在碱性缩合剂存在下，经Darzens缩合反应合成2位双键十四碳醛，十四碳醛再与偕二膦酸酯经Wittig-Horner反应制得1，3位二双键的十五碳膦酸酯，然后在强碱催化下重排成2，4位二双键的十五碳膦酸酯。由β-紫罗兰酮出发三步总收率为62.6％。在本章中考察了制备偕二瞵酸酯的两种方法：Ⅰ．通过Arbuzow反应（即用亚膦酸三乙酯与二卤代甲烷反应）制备；Ⅱ．通过亚膦酸二乙酯的钠盐与二卤代甲烷反应制备；并进行了对比。 第4章，探索了关键中间体五碳醛的几种制备方法，初步确定了以异戊二烯为原料的工业合成路线，以异戊二烯合成五碳醛的总收率达到50.5％。 第5章，2，4-二双键十五碳膦酸酯与五碳醛经Wittig-Horner反应制备产品维生素A乙酸酯，收率84.8％；粗品含量为205.6万IU，精品含量为276.5万IU。 以脱氢芳樟醇为起始原料算，维生素A乙酸酯总收率为29.1％。 第6章，本文的主要创新点：以未重排的1，3-二双键十五碳膦酸酯与五碳醛摘要经wittig一Homer反应得到产品维生素A乙酸酷，收率87%，粗品含量为2 ro.3万IU，精品含量为273.5万llJ。采用新工艺后维生素A乙酸醋总收率为36.4%。本文的创新工作及意义:1发现了‘种改进的反应方法，可以用未重排的1，3一二双键十五碳麟酸醋直接 与五碳醛反应得到产物维A乙酸酷（见第6章）。新方法减少了步重排反 应，简化了工艺，提高了总收率（由29.1%到36.4%），降低了成本，在维A 衍生物的合成中具有重大意义。这种新方法已申请了中国专利 （CN1363553A）、美国专利（申请号101039，056，己批准授权为发明专利， U.S.P.6，727，381）和德国专利（Ger.offen.DE 10，164，041，[P]2001年，见CA 137: P295 1 16P）。文献中未见用末端双键的磷酸酷衍生物作Winig一Homer反应的 报道，因此本文中所述的新方法对类似的反应（如采用多双键的麟酸酷基化 合物为原料的Witrig一Homer反应等）也具有重要的指导作用。2在生产五碳醛的氧化反应中，推测并初步证实了若干含氮有机物协同络合催 化氧化烯醇的反应机理（见第4章4.3.5.）。认为:Cu(D与烯醇形成络合物: 含氮有机物的引入起到稳定络合物，降低活化能的作用:而TMPO则充当携 氧子起传递氧的作用，并具有选择氧化功能:这种新的方法和理论对类似的 反应（不饱和醇类在络合体系下选择性催化氧化为对应的醛）也具有重要的 指导作用。3在异戊二烯的氯醇化反应中，用次氯酸钙代替次氯酸钠（见第4章4.3.4（2）.A， 本方法未见文献报道），使反应系统更加温和，收率由52%提高到88.6%:并 解决了次氯酸钠稳定性差、有效氯含量低的实际问题，具有重要的实用意义。更多还原

【Abstract】 Vitamin A and its derivatives are important medicine as well feedstuff, in which VA acetate is the most important. The world market demand is about 12000 to 15000 tons per year, however there are only three manufacturers in China, i.e. Xinchang NHU Company, N. E. Pharm. Company and Xiamen Kingdomway Incorporation; the total output of these three companies is no more than 2000 tons per year.At present there are three main routes of producing Vitamin A, C\4+C6 route of Roche Co. Ltd., C15+C5 route of BASF and the route of Rhone Poulenc. In order to break the technical and market monopoly, to find a total synthetic route of industry scale is of importance.In this dissertation, the research work of VA acetate’s total synthesis is described in detail. P-Ionone is prepared via rearrangement of dehydrolinalool to afford Citral, and then to Pseudoionone by Claisen-Schmidt condensation reaction with Aceton, which is converted to P-Ionone by acid catalyzed circle-forming reaction. The yield from dehydrolinalool to β-Ionone is 66.9%.P-Ionone is converted to C14-aldehyde via Darzens reaction, which is converted to 3-methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-l,3-pentadienyl phosphonate via condensation reaction, and then rearrange to 2,4-pentadienyl phosphonate. The yield from P-Ionone to 2,4-pentadienyl phosphonate is 62.6%.Whereafter, 2,4-pentadienyl phosphonate is condensed with C5-aldehyde to afford VA acetate via the so called Wittig-Horner reaction, the yield of this step is 69.6%.The total yield from dehydrolinalool to VA acetate is 29.1%.At the end of this dissertation, an improved method of Wittig-Horner reaction is adopted to prepare VA acetate, by which 1,3-pentadienyl phosphonate condensed with C5-aldehyde. In this method, one step of rearrangement reaction is curtailed. The yield of condensation reaction is 87%, the total yield from dehydrolinalool to VA acetate increased to 36.4%.Meanwhile, a lot of research work of the key intermediates such as C5-aldehyde and Tetraalkyl methanebisphosphonaes is carried out.Innovation points in the dissertation and their significance:1 Wittig-Horner method for the synthesis of Vitamin A Derivatives is improved. 3-methyl-5 -(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-1,3-pentadienyl phosphonate are used directly with C5-aldehyde to synthesize VA derivatives without double bond migration catalyzed by base to 2,4-pentadienyl phosphonate firstly(see Chapter.6). In this method, one step of rearrange reaction is curtailed, so the route is more simple, the latter treatment is more easy, the total yield is higher (from 29.1% to 36.4%) , the cost is more little. Seeing of its greet significance, this method has applied for patents in some countries(China: (CN 1363553AX US: (APPL.No. 10/039,056, U.S.P. 6,727,381 ),DE(Ger.Offen.DE.10,164,041,[P]2001,CA 137:mp295116p) ).C1-double bond phosphonate is used in this kind of reaction directly, which hasn’t been reported in previous literature; it demonstrates significance to other similar organic reactions.2 In the oxidation reaction of C5-alcohol to C5-aldehyde(see Chapter4.4.3.5), the synergistic effect of some nitrogenous compound in complexing catalytic system of selective oxidation from unsaturated alcohol to unsaturated aldehyde is brought forward and validated. In my opinion, Cu(I) complexes with unsaturated alcohol to form a complex compound; the nitrogenous compound introduced serves as the complex compound’s stabilizing agent and reduces activation energy of reaction; TMPO serves as oxygen carrier and displays it’s selective oxidation function. This new method and mechanism also demonstrates significance to other similar organic reactions.3 In the chlorohydrin reaction, NaCIO is replaced by Ca(ClO)2(see Chapter4.4.3.4(2) .A), this method hasn’t been reported in previous literature),which exerts more buffer action to the react system, the yield increased from 52% to 88.6%; at the same time it solve the problem of poor stability and low percentage composition of NaCIO.更多还原