Abstract：The atorvastatin key intermediate, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo- N-phenylpentanamide, was synthesized by Stetter reaction using p-fluorophenaldehyde and (Z)-2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide as starting materials and thiazolium bromide and triethylamine as catalysts. According to the possible reaction mechanism, suitable solvents were searched from protic or aprotic solvent, and solvents of different polarity to improve Stetter reaction yield and product quality. The effects of solvent type, reaction temperature, solvent dosage, catalyst type and reaction time on the reaction were studied, the optimized conditions were as follows: tetrahydrofuran as the reaction solvent, the amount was 2.7 times mass ratio that of 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and triethylamine as the catalysts, and the reaction time was 16 hours at 65 ℃. Under the above conditions, the purity of the atorvastatin key intermediate, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide was above 99.5%, and the yield was above 88%, which greatly improved the product quality and yield, and reduced Des-fluoro impurity and other side reactions. It is beneficial to improve the competitiveness of products.
CHEN Weirong,LV Zhiqing,ZHOU Gang et al. Synthesis Process Optimization of the Atorvastatin Key Intermediate[J]. Chemical Reaction Engineering and Technology, 2023, 39(2): 145-151.
