Enzymatic Resolution of Racemic Ethyl-2,2- Dimethylcyclopropanecarboxylate To S-(+)-2,2- Dimethylcyclopropanecarboxylic Acid in a Polar Organic Solvent—Water Medium

ABSTRACT

Optically pure S-(+)-2,2-dimethylcyclopropanecarboxylic acid [S-(+)-DMCPA], an important chiral building block for the production of Cilastatin, was prepared by enzymatic resolution of racemic ethyl-2,2-dimethylcyclopropanecarboxylate (DMCPE) in a N, N-dimethylformamide (DMF)—water medium using lipase Novozym 435. Several hydrophilic organic co-solvents were added into the reaction buffer respectively to evaluate their ability to improve the substrate solubility and efficiency of the chiral resolution reaction. DMF was found to be the most suitable co-solvent for this resolution process. When the concentration of DMF reached a volume fraction of 15 %, the solubility of DMCPE (up to 847.6 mg/L) was about eight times greater than that (112.0 mg/L) in phosphate buffer. Some key reaction parameters such as buffer pH, ionic strength, substrate concentration, reaction temperature, and reaction time were examined. The optimum conditions for the preparation of S-(+)-DMCPA were found to be as follows: 15% DMF, 16 g/L of Novozym 435 65 mmol/L DMCPE, 1 mol/L phosphate buffer, pH 7.2, reaction at 30 °C for 56 h. Under the above optimal conditions, a 49.0% yield and 98.7% of enantiomeric excess (ee) were obtained. With the addition of 15% DMF in the reaction buffer, the optimum reaction time was shortened by 8 h and the yield of S-(+)-DMCPA increased from 45.6% to 49.0%, compared with that for the phosphate buffer solution only.

Keywords:

• solvent effect
• enzymatic resolution
• S-(+)-2,2-dimethylcyclopropanecarboxylic acid
• polar organic solvent-water medium