Synthesis And Characterization Of Bendamustine Hydrochloride And Its Derivatives

Chronic lymphocytic leukemia (CLL) is a disease of clones proliferation of malignant B-cell which caused by apoptosis. It is showed that mature small lymphocytes accumulate exceptionally in peripheral blood, bone marrow and other lymphoid tissues. However, the pathogenesis of CLL is still not fully understood. At present, there are three main ways for the treatment of CLL, such as:radiation therapy, chemotherapy and autologous stem cell transplantation. Chemotherapy consists of s single drug chemotherapy, combined chemotherapy and monoclonal antibodies and chemical immunotherapy.Bendamustine hydrochloride is a compound of containing purine analogue and alkylating agents that can destroy the DNA inside of tumor cells, which inducing cell apoptosis. It is for the treatment of the cases that CLL can't be cured by first-line therapy of chlorambucil and the inert B-cell non-Hodgkin's lymphoma that disease progress in 6 months by rituximab, or program with rituximab. The purpose of this research topic is to improve the Bendamustine hydrochloride synthetic route and synthesis some new analogues. The main contents are as follows:Chapter 1:This chapter describes the current stage of CLL's therapy, the progress of treatment, as well as hydrochloric acid Bendamustine current development status and clinical effects.Chapter 2:At this part, I want to design a new synthetic route of Bendamustine hydrochloride based on the analysis of existing synthetic route, and then synthese.Chapter 3:Synthesize four new analogues of Bendamustine hydrochloride. Their key intermediates and target compounds are characterized by 1H NMR,13C NMR, IR, MS. The four compounds are as follow:1:4-{1-ethyl-5-N,N-[-bis (2'-chloroethyl)-amino]-2-benzimidazolyl}-butyric acid; 2:3-{1-ethyl-5-N,N-[bis-(2'-chloroethyl)-amino]-2-benzimidazolyl}-propionic acid; 3:3-[1-phenyl-5-N,N-[bis-(2'-chloroethyl)-amino]-2-benzimidazolyl}-propionic acid; 4:3-[1-methyl-5-N,N-[bis-(2'-chloroethyl)-amino]-2-benzimidazolyl}-propionic acid.