Chiral drugs related to guaifenesin: synthesis and phase properties of methocarbamol and mephenoxalone

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.

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(R)-1-Carbamoyloxy-2-hydroxy-3-(2-methoxyphenoxy)propane; (R)-MethocarbamolC11H15NO5Ee = 99.8% [chiral HPLC][α]D20=-0.6 (c 1.0, MeOH)Source of chirality: (S)-3-(2-methoxyphenoxy)-propane-1,2-diolAbsolute configuration: (R)

(R)-5-(2-Methoxyphenoxymethyl)-oxazolidin-2-one; (R)-MephenoxaloneC11H13NO4Ee = >99.9% [chiral HPLC][α]D20=-34.4 (c 1.3, EtOH),[α]D20=-37.2 (c 1.1, EtOH)Source of chirality: (R)-3-(2-methoxyphenoxy)-propane-1,2-diolAbsolute configuration: (R)

(R)-2-(2-Methoxyphenoxymethyl)-[1,3]dioxolan-2-oneC11H12O5Ee = 99.8% [chiral HPLC][α]D20=+17.7 (c 1.0, EtOH)Source of chirality: (S)-3-(2-methoxyphenoxy)-propane-1,2-diolAbsolute configuration: (R)