Improved Synthesis Of GGS-Top^TM As ?-Glutamyl Transpeptidase Inhibitor

?-Glutamyl transpeptidase??-GGT? is a cell membrane binding enzyme in the hydrolysis of glycine and cysteine in glutathione. It exists in all kinds of living entity. Clinically the change of ?-GGT can be used as an important indicator of liver and gallbladder disease.?-GGT inhibitors are the main basis for the study on ?-GGT. In vitro experiments it has been found that ?-GGT inhibitors can block the nutritional supply and provide a new way for cancer treatment. Currently the most widely used inhibitor is Acivicin, which is effective in the treatment of several kinds of tumor. But its specificity is not high and it exhibits not only inhibition toward ?-GGT but also inhibits the asparagine synthetase. The inhibitor shows certain toxic side effects. GGs-Top^TM as a highly selective ?-GGT inhibitor was newly discovered. There are very few reports in the literature about the synthetic methods of GGs-Top^TM and the reported yield is low. In the synthesis of the two related ester compounds, the proportion of the formed byproduct was very high.The main purpose of this paper is to optimize the synthetic route of GGs-Top^TM and to reduce the cost of the GGs-Top^TM synthesis technology. There are two main reasons for the high cost of GGs-Top^TM synthesis, one is the high cost of the raw material DL-2-amino-5-phosphonopentanoic acid and the other is easy to produce the two methyl esters byproduct.Because the product of DL-2-amino-5-phosphonopentanoic acid is of large polarity, it is difficult to purify. In this paper trimethyl phosphite of low price was employed as the raw material to synthesize the strongly polar intermediate DL-2-amino-5-phosphonopentanoic acid. The intermediate recrystallization process was improved to increase the yield and to reduce the cost.In the synthesis of the two ester compounds, changing the order of addition of reactants can greatly reduce the production of the byproduct of the two methyl esters. Because the phenol compound is more resistant than methanol, the two reactants are not easy to react with each other. Through the steric effect of the large group, the formation of the byproduct was effectively limited. The proportion between the target compound and the byproduct was improved from 50:50 to 95:5 and the step yield was improved from 30% to 70% finally. This methodology can greatly improve the synthesis yield, reduce the production of the byproduct, and reduce the cost of GGs-Top^TM synthesis.