The Asymmetric Synthesis Of Ethyl 4-Chloro-3-Hydroxybutyrate

Optically active ethyl-4-chloro-3-hydroxybutanoate which widely used in a large range of medicine is an important synthetical intermediate. (R)-(+)-ethyl-4-chloro-3-hydroxybutanoate is a synthetical intermediate of L-carnitine, (-)-Macrolaction A and (R)-γ-amido-β-oxybutanoate, and it can be transformed into (+)-Negamycin. While (S)-(-)-ethyl-4-chloro-3-hydroxybutanoate is a pivotal material of Slagenins B and C and the inhibitor of the HMG-CoA reductase, and it can be reduced into 1,4-dihydrpyridone-P-interdiction. It suggested that the CHBE is very important in asymmetry synthesis. CHBE can be synthesized from 4-chloro-3-oxo-butyric acid ethyl ester, and the chiral purity of the CHBE has relation to the method of the asymmetry synthesis. In this article, three methods of asymmetry synthesis of CHBE have been compared and modified.Using sodium borohydride modified by L-tartaric acid and Pd-C modified by L-tartaric acid, we asymmetry synthesized S-CHBE and R-CHBE respectively. Thespecific rotation of S-CHBE is [α ]_D²⁰=-8. 8° , and the specific rotation ofR-CHBE is [α ]_D²⁰=+1.7° . Their structures were elucidated by IR etc.. To producethe optical active CHBE, the process of the synthesis was carried out as follows. In the first place ,the L-tartaric acid thereof and the metal borohydride, are dispersed in an active medium—tetrahydrofuran and heated therein (first reaction). Thereafter, the temperature of the medium is lowered, and the carbonyl compound was added thereto so as to effect the reduction (second reaction). The first reaction is allowed to proceed at a temperature which is preferably in the range of from room temperature to the reflux temperature. The second reaction is allowed to proceed at a temperature which is preferably in the rnage of from -20 to 0°C.Optical active ethyl 4-cloro- (R) -3-hydroxybutyrate was prepared by stereo selective bioreduction of ethyl 4-chloro-acetoacetate with baker's yeast. It's structure was elucidated by IR, GC-MS, ¹HNMR and specific rotation. The factors influencing the synthesis were investigated such as dosage of baker's yeast, consistency ofglucose, concentration of substrate, pH, reaction time, reaction temperature, and so on. The optimum reaction conditions were as bellows: baker's yeast 600g/L, concentration of glucose 20g/L, concentration of substrate 16ml/ L, pH 5, reaction time 48 h, reaction temperature 34°C, and the specific rotation of the product is[ a ] d =+13.9° .In addition, we do something to process of the reducing of prechiral4-chloro-3-oxo-butyric acid ethyl ester to the corresponding (S)-(+)-4-Chloro-3-hydroxy-butyric acid ethyl ester by Baker's yeast. We found that the co-substrate in the reduction system was a pivotal factor. We gained R-CHBE using glucose as co-substrate, and we obtained S-CHBE using sucrose as co-substrate. We pay more attention to the research that reducing of prechiral 4-chloro-3-oxo-butyric acid ethyl ester by Baker's yeast, and its catalysis process and result have certain theory and application value.