Synthesis Of Drug Derivatives By Enzymatic Strategy And Preparation Of Their Polymeric Prodrug

Enzymatic methods play an important role in the synthesis of pharmaceutical compounds and their derivatives in organic media, which have potential in controllable selective synthesis and chiral resolution of racemic drugs. In this thesis, selective enzymatic synthesis of polymerizable drug derivatives, preparation of polymeric prodrugs with saccharides, and investigation of drugs derivatives and their polymers were developed.The controllable selective enzymatic synthesis ofβ-blockers drugs derivatives containing hydroxyl and amino group in non-aqueous media was developed. Propranolol, atenolol and clorprenaline were chosen as substrates, divinyl dicarboxylates with different carbon length were used as donor agents. 9 kinds of polymerizable vinyl esters of drugs were controllable selectively prepared in better yields through screening enzymes and solvents in enzymatic reaction. Moreover, the relationship between selectivity of reaction and the structures of drugs was discussed.24 kinds polymerizable vinyl esters of 1,2-diol drugs was synthesis by selective enzymatic approach, when mephenesin, chlorphenesin and MOPOPPD were selected as substrates. It was a facial and quickly method. The influence factors of enzymatic synthesis such as enzyme sources, reaction media, water content, reaction time, the effect of enzyme reused were investigated. Furthermore, the initial reaction rate and the optimal reaction time were obtained by the study of reaction kinetics.High selective enzymatic acylation of vinyl esters of chlorphenesin, mephenesin, guaifenesin, propranolol and clorprenaline with different sugar (glucose, mannose, galactose, lactose, maltose, sucrose) were developed to prepare 13 kinds of drug-saccharide conjugates, which showed better water solubility. In particular, the novel amphipathic drugs were obtained when the products were synthesized with 1,2-diol drugs and monosaccharides. The reaction conditions, water-solubility and in-vitro release of drug-saccharide conjugates were also investigated, and the results suggested that drug-saccharide conjugates can be considered as a promising prodrug form.Enantioseparations of Propranolol and six N-acyl and O-acyl propranolol vinyl ester derivatives were carried out on Chiral OD-H Column. Then the resolution of propranolol vinyl ester derivatives was investigated by enzymatic kinetic resolution. The good e. e. value of N-acy vinyladipyl propranolol was realized. When OVAC was chosen as substrate, high efficient and excellent resolution results (Cov. 50%, e. e. 99.99%, 3.5h) were obtained through optimization the influence of resolution reaction condition. Moreover, the relationship between resolution results and the structures of drugs was discussed.The chemo-enzymatic method for preparation of propranolol, mephenesin, chlorphenesin and optically active chlorphenesin polymeric prodrug using AIBN as initiator was developed. 10 products were obtained and these products were characterized by IR, NMR and GPC. A series of homopolymer and copolymers containing drugs monomers and methyl methacrylate or glucose vinyl esters with different chain length had high molecular weight. The in-vitro release of homopolymer and copolymers with glucose of chlorphenesin was investigated in different pH buffer solution. The results showed that polymeric prodrugs were favor in acid condition in-vitro release.