Enzymatic Synthesis Of Antidiabetic Drug Repaglinide

Repaglinide, (a new kind of antidiabetic drug), (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoic acid, was synthesized by employing Ph3P catalytic condensation and LDA/DMPU catalytic carboxylation as a pivotal step from the starting material 4-methylsalicylic acid and 2-chlorobenzonitrile. Repaglinide was synthesized by the total yield 6%. The route does not require high pressure and high temperature that may be applied to industrial production. With lipase Novozym435 as catalyst, ethyl acetate as solvent as well as acyl donor, the crucial intermediates S(+)3—Methyl-1-(2-(1-piperidinyl) phenyl) butylamine of Repaglinide was synthesized enzymatically. Comparing with chemical catalyst, the enzymatic resolution method has enriched the methodology.The acylations reaction of finasteride with acetyl chloride and polimod were examined respectively. The results showed that the product of acetylation reaction was C-18 amide N-acetylation. Under this condition, polimod did not react. The acylation product of finasteride C-18 amide N-polimod was synthesized by employing acylation reaction with polimod amide as a pivotal intermediate. The structure of the key intermediate and target molecule was confirmed by infrared spectrum,1H-NMR and 13C-NMR spectra and mass spectrum in our experiments, and the inhibition of the sterod 5a-reductase and the rats'benign prostatic hyperplasia by the molecular conjugates and finasteride was determined as well. Thus, the activity detection system of vitro and vivo experiments on finasteride conjugates was established.