6533b871fe1ef96bd12d18d0

RESEARCH PRODUCT

Timolol derivatives. I. X-ray, NMR and theoretical studies of the crystallization of (S)-timolol O,O-diacetyl-l-tartaric acid monoester

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Abstract The absolute configurations of (S)-timolol hemihydrate and (S)-timolol O,O-diacetyl-(R,R)-tartaric acid monoester were determined by single crystal X-ray diffraction. An NMR analysis based on the temperature dependence of vicinal coupling constants was carried out to characterize the conformational behaviour of the S,R,R- and R,R,R-forms in solution. The same conformation as in crystalline state was also found in solution, although with a rather low preference over some other conformations. Results of theoretical calculations using MNDO and AMBER force field methods are reported. An infinite chain of hydrogen bonds, along with other favourable inter- and intramolecular forces that are present in the crystal framework of the (S)-timolol-(R,R)-tartrate but not possible for (R)-timolol-(R,R)-tartrate, explain the astonishingly dominating crystallization of the S,R,R-form. Racemic timolol is accordingly easily resolved.