Spontaneous resolution amongst chiral ortho-cyanophenyl glycerol derivatives: an effective preferential crystallization approach to a single enantiomer of the β-adrenoblocker bunitrolol

The β-adrenoblocker bunitrolol 1 as well as intermediate cyclic sulfate 6 and glycidyl ether 8 have been prepared in enantiopure form by starting from enantiopure o-cyanophenyl glycerol ether 2 by an entrainment resolution procedure. Thermal investigations reveal that 1·HCl forms a moderately stable racemic compound, whereas 2, 6 and 8 are conglomerate forming substances potentially capable of entrainment resolution. Some chemical and chiroptical characteristics for bunitrolol and possible intermediates in its synthesis were corrected, and configurations were verified with the configuration of 1·HCl.

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(S)-3-(2-Cyanophenoxy)-propane-1,2-diolC10H11NO3Ee = 99.4% [chiral HPLC of diacetate derivative][α]D20=+14.3 (c 0.5, H2O)[α]D20=+3.1 (c 1.0, EtOH)[α]D20=-9.5 (c 1.0, MTBE)Initial source of chirality: (S)-3-chloropropane-1,2-diolSubsequent source of chirality: spontaneous resolutionAbsolute configuration: (S)

(R)-4-(2-Cyanophenoxymethyl)-1,3,2-dioxathiolane-2,2-dioxideC10H9NO5SEe = 99.9% [chiral HPLC][α]D20=+17.0 (c 0.6, EtOH)Initial source of chirality: (S)-3-chloropropane-1,2-diolSubsequent source of chirality: spontaneous resolutionAbsolute configuration: (R)

(S)-1,2-Epoxy-3-(2-cyanophenoxy)-propaneC10H9NO2Ee >99% [d.s.c.][α]D20=+18.5 (c 0.5, EtOH)[α]D20=-5.0 (c 1.0, CHCl3)Source of chirality: (S)-3-chloropropane-1,2-diolAbsolute configuration: (S)

(S)-1-(2-Cyanophenoxy)-2-hydroxy-3-tert-butylaminopropane hydrochloride; (S)-bunitrolol hydrochlorideC14H21ClN2O2Ee >99.9% [d.s.c.][α]D20=-29.6 (c 0.9, EtOH)[α]D20=-14.7 (c 0.8, H2O)Source of chirality: (S)-3-(2-cyanophenoxy)propane-1,2-diolAbsolute configuration: (S)