Studies On The Ezetimibe’s Synthesis And Greener Blaise Reaction

This paper mainly include the study on the synthesis of ezetimibe and the greener Blaise reaction.Ezetimibe, a novel selective cholesterol absorption inhibitor, was developed by Schering-Plough and Merck, and launched firstly in Germany in 2002. Ezetimibe can effectively and selectively inhibit the absorption of cholesterol with less side-effect. There is few studies on the synthesis of ezetimibe in the domestic at present, so it is necessary to develop a practical synthesis of ezetimibe with high efficiency.Ezetimibe was got after an eight-step reaction with 47% total yield on the basis of the literature in this paper, in which two key intermediates were synthesized with new routes. When benzyl group is used for the protection of phenol instead of TMS, it can be seen that the stability of intermediates containing the protecting group were enhanced, and the subsequent cyclization reaction was more convenient to operate.The main contents are generalized as follows:1. A novel method for preparation of N-(4-(benzyloxy)benzylidene)-4-fluoroaniline(Imine) was developed. Mix 4-hydroxybenzaldehyde (1 equiv.), pota-ssium carbonate (1.1 equiv.), iodine (0.08 equiv.) and benzyl chloride (1.1 equiv.) reflux for 3 hours in ethanol, drop 4-fluoroaniline(1.2 equiv.) slowly and react for another 2 hours, the target product was obtained in 92% yield after post-processing. The costs and pollution were reduced by using benzyl chloride instead of benzyl bromide, the total yied was increased and the operation was simplified with one-pot reaction.2. (4S)-3-[(5S)-5-(4-fluoror)-5-hydrox-1-oxo-pentyl]-4-phenyl-oxazolidin-2-one (Chiral alcohol) was obtained by Friedel-Crafts acylation, cyclization, nucleophilic substitution reaction and asymmetric reduction with fluorobenzene as starting material.AlCl3 (2 equiv.), glutaric anhydride (1 equiv.) and fluorobenzene (1.8 equiv.) were reacted in CH2Cl2 to afford 4-(4-fluoro-benzoyl) butyric acid with 80.6%yield.Reflux the intermediates and oxalyl chloride (1.2 equiv.) for 5 hours in chloroform, obtain 6-(4-fluorophenyl)-3,4-dihydro-pyran-2-one, then react with (S)-4-phenyl- oxazolidinone (0.8 equiv.) and triethylamine (1.1 equiv.) in toluene to afford ((4S)-3-[5-(4-fluororphenyl)-1,5-dioxo-pentyl]-4-phenyl-oxazolidin-2-one with [α]25D =+53.2°(c= 0.5, CHCl3) in two-step yield of 96.1%. Compared with the process in literature, the new process shown lower cost, easily obtained raw materials, simply operation. The chiral alcohol with [a]25D=+21.5°(c=0.2, CHC13) was obtained through the reduction of condensation product with (-)-DPC (1.2 equiv.) in 96% yield after two reduction methods in the literrature being studied.3. Ezetimibe was obtained finally through Evans condensation, cyclization and deprotection from the imine and chiral alcohol.After in situ protected by TMSC1 (1.1 equiv.), chiral alcohol was condensed with imine(2.2 equiv.) in the presence of’Pr2NEt (2.5 equiv.) catalyzed by TiCl2(O’Pr)2(1.2 equiv.), (4S)-3-[(2R,5S)-1-oxo-2-[(S)-(4-fluoro-phenylamino)-(4-benzyloxy-phenyl) methyl]-5-(4-fluorophenyl-tr-imethylsilyloxy)pentyl]-4-phenyl-2-oxazolidinone was obtained, with [α]25D=-29.3°(c=0.32, CHCl3), in 77.7% yield. The mechanism of the condensation reaction was studied firstly. It was proposed that the chiral alcohol was changed into E-enolate after reacted with Ti reagent, and then reacted with imine with Zimmerman-Traxler transition state model. On the basis of this, different Lewis acid were evaluated in this reaction, and it was found that the catalytic efficiency of TiCl2(O’Pr)2 was better than TiCl4. And from the optimization of purification solvent, it can be seen that the yield and impurity have been improved when crystalized in CH3OH. After a series of improvements as mentioned above, the yield of this step has been substantial increased.The Evans condensation product was cyclized with TBAF (0.008 equiv.) in the presence of BSA (2 equiv.) in toluene to afford (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-trimethylsilyloxy-propyl]-4-(4-benzyloxy-phenyl)-2-azeti dinone (Cyclization compound) [a]25D=-29.2°,(c=0.25, CHC13). Used directly for next reaction without purification.The cyclized compound was deprotected by 5% Pd/C in CH3OH/H2O solution to obtain ezetimibe in 85.4% yield (calculated based on the Evans condensation product) with [α]D25=-29.1°(c=0.34, CH3OH). Ezetimibe is purified with iPrPOH/H2O for two times.Green chemistry is an important tools to prevent environmental pollution. Research and development of new environmentally friendly reaction is important in theoretical and practical significance. Solvent-free Blaise reaction with in situ generated Zn-Ag couple was studied in this paper. Compared with the current literature method, the main advantages of this method are: excellent yields, less raw materials consumed, easy operation because zinc activation and Blaise reaction were carried out in one pot and avoidance of organic solvents.1. A new and efficient zinc activation method that is the in situ generated Zn-Ag couple was discovered during studing various types of Zn-M couple in the Blaise reaction. The solvent-free Blaise reaction was researched under the above reaction conditions, and it is found that solvent-free conditions promoted the reaction a little. The better molar ratio of nitrile, zinc and ethyl bromoacetate in the reaction was 1:1.5:1.3.2. A series of β-amino-a,β-unsaturated esters were synthesized and the influence of different substrates on the reaction was researched. The reaction of three bromoacetate and some kinds of nitriles was studied under this condition, and it is found that the yields of the reaction with aromatic or heterocyclic aromatic nitriles were higher than that of the reaction with aliphatic or benzylic nitriles, the yields were almost the same when condensed with ethyl bromoacetate and tert-butyl bromoacetate, but they were higher than those with a-bromo propionate under the same condition.3. The mechanism of the Blaise reaction promoted by Zn-Ag couple was discussed. Ag is not involved in the Blaise reaction, but played the role of zinc activation, the rate-controlling step is the reaction of zinc and bromoacetate. The reactivity of zinc was enhanced by generating Zn-Ag couple, which can lead to a more moderate reaction conditions and avoid the side-reactions.