Synthesis And Analysis Of 5-Hydroxytrptamin₃ Antagonist Palonosetron Hydrochloride

The main of this thesis include two parts:1)synthesis and configurable corroboration of palonosetron hydrochloride as an 5-HT3 antagonist ;2)study on the analysis quality control standard of palonosetron hydrochloride.Palonosetron hydrochloride,commercially named Aloxi,chemically called 2-[1-Azabicyclo[2,2,2]oct-3(S)-yl]-2,3,3a(S),4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one hydrochloride.It is a high effective,high elective and high emulative 5-hydroxytrptamin3(5-HT3) antagonist,developed by Helsinn Corp. in Swizerland. This drug is used to prevent the emesis witch is caused by chemical therapy in the beginning course,and to treat the cute and delayed nausea and vomiting in repetitive period of treatment.It is the only drug witch can act on delayed nausea and vomiting.And it's the fourth 5-HT3 antagonist approved by FDA.Synthesis of palonosetron hydrochloride was done according to newly developed pathways based on many patents.Target compound was synthesized using 1,2,3,4-tetrahydro naphthylin as starting material.By five steps,total yield reaches 40.28%,and purity reaches 99.5% detected by high performance liquid chromatography(HPLC).Finally the target molecular structure is in perfect agreement with those of the reference standards by HPLC,uv-vis spectrophotometry(UV-VIS),infrared spectroscopy(IR),mass spectroscopy(MS),nuclear magnetic resonance spectroscopy(NMR),and so on.For the sake of controlling the optical purity of the target compound , a pre-column derivatization high-performance liquid chromatographic method was developed to separate and analyse 1-azabicyclo[2.2.2]octan-3-amine,witch is an important intermediate for the preparation of palonosetron hydrochloride. The results show that the enantiomers can be separated with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate(GITC) as the derivatization reagent. Then a HPLC chiral stationary phase method was developed to separate two diastereoisomers of palonosetron hydrochloride.According to the Chinese pharmacopoeia 2005 and the synthetical technics of this thesis ,the quality control standard of palonosetron hydrochloride was established.And the description,identification , solubility,specific rotation,pH value,clarify, relational substances,weight loss of drying,residue on ignition,heavy metal, sulphate, the residual organic volalile solvents,and the contence of palonosetron hydrochloride were detected. Thereinto, a headspace sampling GC method was developed to detect the residual organic volalile solvents.It is proved that the study of this thesis have high applied value.