美普他酚合成、拆分及光学活性体的研究-药物化学专业毕业论文.docxVIP

塞里查兰堡主鲎垡堡塞Studies 塞里查兰堡主鲎垡堡塞 Studies on the Synthesis，Resolution and Optical Isomers of Meptazinol Abstract Meptazinol is a opioid agonist／antagonist．In order to introduce it into China market． we have established a synthetic routine which began谢t11 a low commercial material N—methylcaprolactam，followed by condensation，atomatisation，ethylation， reduction and salt formation．T11c arnide was reducted by IG3H4／ZnCl2 system instead of LAH in our studies．We investigated the reduction and t11e interrnediate for probing the best reaction conditions．The yield of this step was raised bv 20％or so．After 5 stages we could get meptazinol with a total yield 33．50％．Thc routine has been improved for the industrial production．The structure of meptazinol hydrochloride Was confmned bv IR，UV 1HNMR，”CNMR，MS and DSC．The content iS above 99．6％ determined by HPLC． Based on血e popular drug RD strategy of Racemic switch and Me—too drug design，the influence of proportion，pH，and solvent has been studied in resolution of meptazin01．The(+)and(一)meptazinol were separated in methanol using dibenzoyl tartaric acid or ditoluoyl tartaric acid as血e resolution reagent．the yield Was 60％or so after seperating once．And this method has the advantage of higher yields thall the previous method．We confirm the absolute confignration of the two enantiomers by the single—crystal X—ray structure analysis，The absolute configuration of the levo．and dextro—meptazinol is respectively S and R．Wj confmu the structure of enantiomers by IR，w，1HNMR，”CNMR，MS and DSC．The optical rotation of也e two enantiomer hydrochloride is—10．72。(c=0．167，H20)and+10．06。(c=O．168，H20)．The analgesic potencies were determined by mouse acetylcholine writhing assays．The ED50 of (-)and(+)-meptazinol hydrochloride is 31．333 u m01／Kg and 14．583 u mol／Kg separately． The high perfofinance capillary electrophoresis(HPCE)method was established for determining the optical purity of(+)and(一)meptazinol hydrochloride． Fused—silica capillary used was 72×5