p-Hydroxymethadone: synthesis, crystal structure and CD properties

Abstract

Alkylation of 2-chloro-N,N-dimethylpropylamine 2 with the lithium salt derived from 2-(p-methoxyphenyl)-2-phenylacetonitrile 1 afforded a mixture of p-methoxymethadone nitrile 3 and p-methoxyisomethadone nitrile 4. The nitriles were separated chromatographically and the amino nitrile 3 was converted subsequently into the diastereoisomeric p-hydroxymethadone 8 hydrochlorides. Careful recrystallization afforded a separation of the (4RS,6RS)- and (4RS,6SR)-p-hydroxymethadone hydrochlorides. Repetition of the synthesis using (R)-2-chloro-N,N-dimethylpropylamine, derived in three steps from (S)-dilactide 9, yielded the (4S,6S)- and (4R,6S)-p-hydroxymethadone hydrochlorides, which were also separated by fractional crystallization. The absolute configuration of the products was verified by X-ray crystallography. The (4R,6S)) salt exhibited a more intense Cotton effect than (S)-methadone hydrochloride while the (4S,6S) salt showed a less intense Cotton effect and less fine structure in the λ260–275 nm range.