Enzymatic Synthesis Of Racemic And Chiral Amine Derivatives And Preparation Of Their Polymers

Amines are important compounds because of their broad range of applications and their pharmacological properties. In this thesis, enzymatic synthesis of a series of polymerizable amine derivatives and amine-saccharide conjugates, and the water-solubility of drug-saccharide conjugates were also investigated, controlled enzymatic reaction, preparation of polymeric chiral compounds with saccharides, and investigation of amine derivatives and their polymers were developed.The enzymatic synthesis of amine derivatives in non-aqueous media was developed. Primary amines (mexiletine, 1-methyl-3-phenylpropylamine and 1-phenylethylamine) and secondary amines (metoprolol, bisoprolol and betaxolol) were chosen as substrates, divinyl dicarboxylates with different carbon length were used as acylating agents. Twelve kinds of new polymerizable N-(vinyloxycarbonyl)-amine were prepared in better yields through screening enzymes and solvents in enzyme-catalyzed reaction.Highly selective enzymatic acylation of N-(vinyloxycarbonyl)-secondary amines (metoprolol, bisoprolol and betaxolol) with different monosaccharides (glucose, galactose and mannose) and disaccharides (maltose and sucrose) were developed to prepare six kinds of new amine-saccharide conjugates, which showed better water-solubility. The reaction conditions, such as acylating agents, structures of substrates, and the water-solubility of amine-saccharide conjugates were also investigated, the results suggested that amine-saccharide conjugates can be considered as a promising prodrug form.A series of novel designed mexiletine derivatives and its analogues were prepared, the enantioseparations were performed on polysaccharide-based chiral stationary phase, Chiralcel OD-H column and Chiralcel OJ-H column, under normal-phase mode. The effects of the concentration of isopropanol in the mobile phase and the structures of the samples on enantioseparation, and the elution order of the enantiomers using optical rotation (OR) and circular dichroism (CD) detector were studied. It was resulted that when the ratio of n-hexane to isopropanol was 90/10,80/20 and 70/30 (v/v), seven of the eight enantiomers got baseline separation on Chiralcel OD-H column. When the ratio of n-hexane to isopropanol was 90/10 (v/v), five enantiomers got successfully separation on Chiralcel OJ-H column. When the ratio of n-hexane to isopropanol was 80/20 and 70/30 (v/v), the eight enantiomers were all partial revolved on Chiralcel OJ-H column. Moreover, at the same conditions of that the ratio of n-hexane to isopropanol was 90/10 (v/v), sample h was a single peak when it was separated on Chiralcel OD-H column, while it was successful separated on Chiralcel OJ-H column. The effects of structural features were also discussed. Using a CD detector and an OR detector, it showed that R-enantiomer appears before S-enantiomer separated on both Chiralcel OJ-H and OD-H column.The resolution of metoprolol was investigated by enzyme-catalyzed reaction with different donors. The good e.e. value and low yield of N-(5-vinyloxycarbonylpentanoyl) metoprolol was obtained. When N-(5-vinyloxycarbonylpentanoyl)mexiletine was chosen as substrate, the polymeriable R-and S-enantiomers of N-(5-vinyloxy carbonylpentanoyl)mexiletine were obtained through optimization the influences of reaction conditions (such as co-solvents, pH of PBS and ratio of co-solvents, etc). Lipozyme(?) provided polymerizable S-enantiomer in 93% e.e. in toluene. The R-enantiomer could be obtained in>98% e.e. by CAL-B in THF-PBS (pH=7.0,90/10, v/v). The addition of PBS could improve the stereoselectivity of CAL-B by 15-fold than that in pure THF. Moreover, the influences of the structures of amines on the reaction were also discussed. The hydrolysis position was occurred at the terminal ester bond, it was eight atoms away from the stereocenter, and it was indicated the reaction was a remote reaction.The chemo-enzymatic method for the preparation of polymeric compounds of metoprolol, mexiletine and chiral mexiletine using AIBN as initiator was developed. The products were obtained and characterized by IR, NMR and GPC. A series of homopolymer and copolymers containing drugs and glucose monomers had high molecular weight. The in-vitro release of homopolymer and copolymers with glucose of mexiletine was investigated in pH=7.4 buffer solution. The results showed that the release rate of copolymer was faster than that of homopolymer, and copolymeric amine derivatives were favor in acid condition in-vitro release.