Study On The Asymmetric Synthesis Of Statins Intermediate Ethyl (S)-4-Chloro-3-Hydroxybutyrate

Optical active hydroxyl ester is a kind of important intermediates which was widely used in medicine, food, spices, pesticide and chemical industry. Ethyl 4-chloro-3-hydroxybutyrate is hydroxyl ester and has two optical isomers which both of them are very important chiral intermediate in drug synthesis, ethyl (R)-4-chloro-3-hydroxybutyrate((R)-CHBE) which can be used for synthesis L-carnitine, atorvastatin calcium, Macrolaction A and (R)-y-amino-β-oxybutanoate and transformed into 2,5-Cyclohexadiene synthetic fiber and (+)-Negamycin. While ethyl (S)-4-chloro-3-hydroxy-butyrate((S)-CHBE) is a pivotal material of HMG-CoA reductase inhibitor, antibiotics and Slagenins B and C and it can be reduced intoβ-1,4-dihydropyridine calcium channel blockers. Therefore, it has important theoretical significance and application value to research the synthesis method of them.(S)-CHBE of high optical purity was obtained by use ethyl 4-chioroace-toacetate(COBE) as material. In this article, a chiral ruthenium catalytic complexes ([RuCl(p-cymene)(R-BINAP)]Cl) of high catalytic activity have been compared on the basis of generalize extensive literature and the structure was characterized by use of IR,1H NMR and 13C NMR. Then reaction time, reaction temperature, hydrogen pressure, quality ratio of catalyst and chiral ligands, quality ratio of substrate and ruthenium complexes and stirring speed was be studied by using the catalyst complexes in order to get the relationship between those factors and the catalytic reaction. Finally the orthogonal experiments was designed and we got the optimum reaction conditions of COBE asymmetric catalysis hydrogenation for (S)-CHBE as bellows:reaction time is 3 h, reaction temperature is 373.15 K, hydrogen pressure is 4 MPa, m(C1)/m(L) is 1/2.4, m(S) /m(C) is 9000/1, stirring speed is 500 r-min-1 and the conversion of the asymmetric catalytic reaction is 100%, the specific rotation of (S)-CHBE is [a]D20=-13.9°. The structure of the final product was characterized by IR,1H NMR and MS.