Chiral drug Albicar: resolution of racemate via complexation with BINOL
Dedicated to Fumio Toda's 75th birthday
Denis A. Lenev
Semenov Institute of Chemical Physics, Russian Academy of Sciences 4 ul. Kosygina, 119991 Moscow, Russia
Abstract:
Resolution of synthetic chiral drugs by crystallization is the main route for their production. One of the resolving agents which is gaining increasing importance is BINOL.1 It has been found previously by Toda that BINOL forms crystalline H-bonded diastereomeric complexes with racemates.2 Recent work has shown the utility of this general method for resolution of omeprazol.3
Racemic bicyclic bis-urea 1 (Albicar) is an original psychotropic drug and its (1R,5R)-(+)-enantiomer is more active in mice, with the active dose of 75 mg/kg being two times lower compared to racemate.5 It is believed that the drug acts via adrenergic pathways.5 Kravchenko et al. has developed enantioseparation of 1 by chromatography on chiral phases.5 However, for pre-clinical studies efficient crystallization methods were needed. We found that BINOL gives crystalline complexes with 1 in the presence of H2O. Thus, both enantiomers of the title drug were prepared from their complexes with (R)- and (S)-BINOL in 59% ((+)-1) and 43% ((-)-1) yield from racemate.
We are grateful to JSC „Olainfarm” (Olaine, Latvia) for financial support. This work was also supported by the Russian Foundation for Basic Research (RFBR) (grant 09-03-00537a).
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