Characteristics
Structurally, tramadol closely
resembles a stripped down version of codeine. Both codeine and tramadol share
the 3-methyl ether group, and both compounds are metabolized along the same
hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs.
For codeine, this is morphine, and for tramadol, it is the O-desmethyltramadol.
Comparison with related substances
Structurally, tapentadol is the
closest chemical relative of tramadol in clinical use. Tapentadol is also an
opioid, but unlike both tramadol and venlafaxine, tapentadol represents only
one stereoisomer and is the weaker of the two, in terms of opioid effect. Both
tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also
differs from tramadol in being a phenol, and not an ether. Also, both tramadol
and venlafaxine incorporate a cyclohexyl moiety, attached directly to the
aromatic, while tapentadol lacks this feature. In reality, the closest
structural chemical entity to tapentadol in clinical use is the over-the-counter
drug phenylephrine. Both share a meta phenol, attached to a straight chain
hydrocarbon. In both cases, the hydrocarbon terminates in an amine.
Synthesis and stereoisomerism
The chemical synthesis of
tramadol is described in the literature. Tramadol
[2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic
centers at the cyclohexane ring. Thus,
2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four
different configurational forms:
- (1R,2R)-isomer
- (1S,2S)-isomer
- (1R,2S)-isomer
- (1S,2R)-isomer
The synthetic pathway leads to
the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main
products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the
(1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the
(1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and
(1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The
drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the
(1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer /
(1S,2S)-(–)-isomer] was described[62] employing (R)-(–)- or (S)-(+)-mandelic
acid. This process does not find industrial application, since tramadol is used
as a racemate, despite known different physiological effects of the (1R,2R)-
and (1S,2S)-isomers, because the racemate showed higher analgesic activity than
either enantiomer in animals and in humans.
