Synthesis Of Vitamin A Acetate

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.