Synthesis Of Several Kinds Of Medicinal Materials Containing Polyethylene Glycol

Polyethylene Glycol (PEG) has been widely used to modify the structure of biological macromolecules or small molecule drugs. The biological macromolecules and small molecule drugs modified by PEG can significantly improve the aqueous solubility and stability, reduce the renal clearance effect, and prolong circulation time of drugs in organism. Since the PEG has good biocompatibility, a variety of PEGylated drugs have been used to treat different diseases. For example, siRNA drugs have potential effect in the treatment of many diseases. However, due to their high molecular weight and polyanion center, siRNA drugs are usually required to load into a complex delivery system to target and then demonstrate efficacy. mPEG2000-DMG has been proved to play a vital role on the delivery of siRNA drugs and it can be assembled into macromolecular nanoparticles through electrostatic interactions with polyanion nucleic acid to wrap siRNA.The first part of this dissertation is the synthesis of mPEG2000-DMG.The synthesis of mPEG2000-DMG:the starting material (R)-(-)-glycols acetonide was reacted with benzyl bromide to obtain (R)-4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolane. It was then hydrolyzed under acidic conditions to achieve (S)-3-(benzyloxy)propane-1,2-diol. The former compound and myristic acid were condensed together to give (S)-3-(benzyloxy)propane-1,2-diyl ditetradecanoate, which was reduced by hydrogen with palladium/carbon catalyst to cleave the benzyl group to obtain (S)-3-hydroxypropane-1,2-diyl ditetradecanoate. The condensation of (S)-3-hydroxypropane-1,2-diyl ditetradecanoate and mPEG2000NH2 was the key step of this synthetic method. In order to activate the primary alcohols of diacyl glycerol, a variety of methods including triphosgene, CDI, DSC was investigated, but failed to effect the condensation reaction. Finally, we found that activated carbonate ester prepared from 4-nitrophenyl chloroformate was not only stable, easy to purify, but also capable to condense with polyethylene glycol to yield the product with a high purity.In the fields such as medicine, materials and engineering, monodisperse long chain of PEG has bright application prospect. For example, in pharmaceutics, drugs modified with PEG, such as peptides and proteins have a significant impact on the stability of the drug, immunogenicity and pharmacokinetic properties.The second part of this dissertation is the synthesis of monodisperse long chain polyethylene glycol.In the synthetic route of dodecaethylene glycol, tetraethylene glycol was used as the starting material. First, a hydroxyl group of tetraethylene glycol was protected with triphenylmethylchloride to give tetraethylene glycol monotrityl ether. Meanwhile, two hydroxyl groups of another tetraethylene glycol were reacted with p-toluenesulfonyl chloride to gain tetraethylene glycol ditosylate. Later on, the two tosyl groups of tetraethylene glycol ditosylate were substituted by tetraethylene glycol monotrityl ether to form dodecaethylene glycol ditrityl ether, which was eventually hydrolyzed to give dodecaethylene glycol. A series of monodisperse long chain polyethylene glycol of high purity can be prepared with this synthetic strategy.