Study On The Synthesis Of Reggylline For Diabetes Therapy

Some oral anti-diabetic agents were briefly described in this thesis.Comparing to the traditional anti-diabetic agents,Repaglinide can stimulate the release of insulin from pancreaticβ-cells by inhibiting potassium efflux via closure of ATP-regulated K⁺ channels and opening of voltage-dependent Ca²⁺channels,which increases influx of calcium into theβ-cells and causes release of insulin.The drug lowers postprandial glucose excursions by targeting early-phase insulin release,an effect thought to be important in reducing long-term cardiovascular complications of diabetes.In order to synthesize Repaglinide,it had to be taken into consideration for the synthesis of two key intermediates as 3-methyl-1-[2-（1-piperidinyl）phenyl]butylamine（3）and 3-Ethoxy-4-（methoxycarbonyl）phenylacetic acid（4）.After intensive study,rac-3 was prepared from 2-fluorobenzonitrile via an 4-step sequence such as substitution,addition,oxime formation and reduction. Rac-3 was preliminarily resoluted for the first time in this paper by L-（+）-Tartaric acid in methanol and acetonitrile in the presence of 2-butanone for the racimization of the undesired isomer.The successful resolution of 3 is crucial for the synthesis of the target.Compound 4 was prepared from 4-methylsalicylic acid by successive treatment with bromoethane for esterification/etherification,bromination,cyanation,hydrolysis and second-time esterification to obtain the diester of compound 4 which was then selectively hydrolyzed to give the monoester 4.Starting from rac-3,the synthesis of racemic Repaglinide was also intensively studied,and the procedures related were optimized here.Based upon the resolution result got in this paper, the asymmetric synthesis of Repaglinide for drug purpose will be doubtlessly possible.Further study is now under investigation.All the key intermediates and the target are confirmed by b ¹H-NMR and MS spectra.