Study On Syntheses Of Analogues Of Methylnaltrexone Bromide-A New Peripherally ?-Opioid Receptor Antagonist

Methylnaltrexone Bromide?MNTX?, developed by the US Wyeth Pharmaceuticals and Progenics Pharmaceuticals, was ?-opioid receptor antagonist of outer periphery. Methylnaltrexone bromide Relistor, injected to treat opioid-induced constipation?OIC? when it is invalid to the use of laxatives, was approved by Canada, the United States and the European Union in 2008, however it is contraindicated in known or suspected mechanical gastrointestinal obstruction patients.Methylnaltrexone Bromide is the first drug approved to use in opioid-induced constipation with a novel mechanism of action and represents a new direction, therefore, the study of its synthetic in order to applied to industrial production have important application value.In this paper, the synthetic route of Methylnaltrexone Bromide were investigated and optimized by which establish a new synthetic route, in this routes naltrexone was used as the starting material, through the protection of the hydroxyl, quaternary ammonium, deprotection and purification, the purity was above 99.0%, and the total yield was above 45%.Compared to other process, the new was shorten, the raw materials was cheap and easy to get, the use of bromide ions ion-exchange chromatography was avoided by the use of methyl bromide, furthermore the new synthetic process have higher yields compared to the reported, so the new developed synthetic process was good prospects.The impurities was crucial when the product was used as medicine, particularly if some of the analogues of Methylnaltrexone Bromide was genotoxic. So it is a must to establish sensitive and independent detection method to the quality control, therefore, the synthesis of the impurities was also discussed in this paper. The structure of Methylnaltrexone Bromide, and its analogues?R-MNX-1,2,3,4,5? was confirmed by ¹H-NMR, ¹³C-NMR, IR, MS. The paper carried out the quality research of Methylnaltrexone Bromide APIs in detail by the study of related substance.