1. Synthesis And Structure Modification Of Vorinostat 2. Synthesis And Structure Modification Of Bendamustine Hydrochloride

Vorinostat was the first histone deacetylase inhibitor approved by the FDA in Oct.2006. It was mainly used in the treatment of metastatic therapy skin T cell lymphoma. It has the structure of hydroxamate which complex with zinc iron, and lead to histone deacetylase inhibition.According to the synthetic problems of Vorinostat, we made some modification of the process route:First, we choose suberic acid as raw material and dehydrated in acetic anhydride and obtained suberic anhydride. Second, acylated with aniline in dichloromethane and obtained 8-anilino-8-oxooctanoic acid. Third, esterified with methanol and obtained methyl-8-anilino-8-oxooctanoate. Finally, aminolysised with hydroxyl amine and got Vorinostat. The overall yield was 75%.In addition, we have tested ammonolysis of mixed anhydride and active sulphur acetate, then obtained Vorinostat.At last, we modified the structure of Vorinostat and the conjugate of Vorinostat-P-[N, N-bis(2-chloroethyl)amino]benzoic acid was synthesised. Bendamustine Hydrochloride is a kind of double function bioalkylating agents used for treatment of chronic lymphoblastic leukemia (CLL). It was first synthesised in German during the 1960s.Having summerized the previous synthetic route, we found some deficiencies:low total yield, bad quality and low purity, the intermediates were difficult to purification. Especially the process of chlorination. We made some improvements, the total yield raised, intermediates of each step were easy to purification.Bendamustine Hydrochloride was synthesized from 2,4-dinitrochlorobenzen as a starting material via ten steps including amination, reduction, acylation, cyclization, reduction, substitution, esterification, chlorination, hydrolization and salification. The total yield was increased to 48.4%. The key process of this route is construction of (3-chlorethyl:change the hydroxyl into sulphonate, then exchange chloride ion with LiCl in anhydrous DMF. We also used microwave to promote the synthesis of [1-methyl-2-(4'-Ethylbutyrate)-5-nitro]-1H-benzimidazole.Combined with the synthesis of HDAC inhibitor—Vorinostat and combination principle, we made structure modification of Bendamustine:convert the carboxyl into hydroxamate. It is a potential multi-function antitumor compounds, with the both function of HDAC inhibitors and bioalkylating agents.