Chiral separation of pheniramine-like 3-phenyl-3-heteroarylpropylamines by CE and HPLC methods

Analytical CE and HPLC methods were developed for the chiral separation of halogen‐substituted 3‐phenyl‐3‐(2‐pyridyl)propylamines 1–4 (1: 3‐(4‐fluorophenyl)∼, 2: 3‐(3,4‐difluorophenyl)∼, 3: 3‐(4‐chlorophenyl)∼, 4: 3‐(3,4‐dichlorophenyl)∼), 3‐(4‐fluorophenyl)‐3‐(2‐thiazolyl)propylamine (5), and 3‐(4‐fluorophenyl)‐3‐(1‐benzylimidazol‐2‐yl)propylamine (6), which are building blocks for the preparation of very potent arpromidine‐type histamine H2 receptor agonists. All amines were enantioseparated by CE with resolutions of at least 1.8 using α‐, β‐, or γ‐cyclodextrin (CD) as chiral selectors. With heparin as buffer additive for CE the optical antipodes of 1–4 and 6 were separated with resolutions ≥1.8. On RP‐18 columns the separation of the (+)‐(S)‐acetylmandelic acid amides of racemic 2 (R = 0.9, α = 1.07) and the thioureas prepared by addition of 6 to 2,3,4,6‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl isothiocyanate (R = 2.0, α = 1.20) was successful, whereas the diastereomeric ureas prepared from 3 and (+)‐(S)‐1‐(1‐naphthyl)ethyl isocyanate could not be resolved. Separation of the diastereomeric isoindoles prepared from 1–5, o‐phthaldialdehyde and 2,3,4,6‐tetra‐O‐acetyl‐1‐thio‐β‐D‐glucopyranoside was achieved on a RP‐18 phase (R ≥ 0.4, a ≥ 1.02). Direct separation of the enantiomers of 3 and 4 was achieved on a Cyclobond I column (R ≥ 0.9, α ≥ 1.07). α‐ and β‐CD were also useful as mobile phase additives for HPLC (3 and 4: RP‐18 column, β‐CD, R ≥ 0.4, α ≥ 1.03; 3: RP‐18 column, α‐CD: R = 0.5, α = 1.04). Chirality 13:285–293, 2001. © 2001 Wiley‐Liss, Inc.