Development of Hybrid Process for Antidiabetic Agent, CS-1036

Abstract

CS-1036 was a candidate compound for antidiabetic drug and synthesized with 3 key intermediates. The 5-membered iminocyclitol intermediate (C unit), one of the key intermediates for CS-1036 synthesis, was prepared by chemical synthesis in 12 steps previously. By using microbial metabolite, Nectrisine, as a starting material, the manufacturing process of C unit was shortened to 5 steps. Thus, the hybrid process between biological synthesis of Nectrisine and chemical synthesis from Nectrisine to C unit improved the productivity of C unit production dramatically. Nectrisine was originally purified with 2 ion-exchange chromatographies which posed disadvantage for large scale production to remove the residual protein impurities. The combination of denaturation by MeOH and crystallization from brine gave the important intermediate of C unit synthesis with high quality and yield without ion-exchange chromatographies.