Bromide ion → Methylnaltrexone Bromide

Participants

Reaction Steps

Suitable conditions for the conversion of quaternary ammonium salt 9a to endoperoxide 10a were developed. Hydrogenation of the endoperoxide intermediate furnished a mixture of methylnaltrexone chloride salts 11 in 70-71% yield. Exchange of the counter ion from chloride to bromide was achieved by ion exchange chromatography and furnished a mixture of (R)- to (S)-methylnaltrexone bromide in an approximate ratio of 10:1. Alternatively, the chloride counter ion was converted to the bromide by first converting the methylnaltrexone chloride to the corresponding zwitterion by precipitating with potassium carbonate, and then adding hydrobromic acid to the zwitterion [see Dlubala, WO 2008/034973, US 2008/0214817 for the conversion N-methylnaltrexone methylsulfate to N-methyl naltrexone bromide]. By following the same ion-exchange protocol, the conversion of the oripavine chloride salt 9a to the bromide salt 9b proceeded in excellent yield. Subsequent oxidation with singlet oxygen followed by hydrogenation gave N-methylnaltrexone bromide salt 8 in a similar overall yield compared to the results of the chloride series.

Provenance & Evidence