Phase behavior and crystal structure of 3-(1-naphthyloxy)- and 3-(4-indolyloxy)-propane-1,2-diol, synthetic precursors of chiral drugs propranolol and pindolol

• Crystallization features of chiral drugs propranolol and pindolol precursors are investigated.
• 3-(4-Indolyloxy)-propane-1,2-diol is a conglomerate formative compound.
• Hydrogen N–H⋯N bonds are responsible for conglomerate stabilization.
• 3-(1-Naphthyloxy)-propane-1,2-diol forms weakly stable solid racemic compound.
• The predominant formation of the racemic compound may be due to kinetic effects.

Valuable precursors of popular chiral drugs propranolol and pindolol, 3-(1-naphthyloxy)-propane-1,2-diol 3 and 3-(4-indolyloxy)-propane-1,2-diol 4 were investigated by IR spectroscopy, DSC, and X-ray diffraction methods. Both compounds, crystallizing from enantiopure feed material, form “guaifenesin-like” crystal packing in which the classic H-bonded bilayers, framed in both sides by hydrophobic fragments of the molecules, acts as the basic crystal-forming motif. Diol 4 prone to spontaneous resolution and conserves its packing pattern crystallizing from racemate. Under the same conditions, diol 3 forms weakly stable solid racemic compound. Some reasons for such a behavior are identified and discussed.