Synthesis Of Chiral Aminoalkylphenols

Racemic 2-methyl-1-phenylpropylamine was obtained by Friedel-Crafts reaction of benzene and isobutyryl chloride with the yield of 75.0%, then followed by Leuckart reaction in 85.0% yield. Enantiomeric (R)- 2-methyl-1-phenylpropylamine (up to 99% e.e. by chiral HPLC) was resolved with (S)-(+)-mandelic acid as resolving reagents in a mixed solvent of ethyl acetate/hexane, [α]_D¹² = +17.4°(c = 0.5, ether).Novel chiral aminoalkylphenols (R,R)-6a-d were synthesized by stereoselective reduction with NaBH4 of the imine derivatives from enantiomeric (R)-(+)-2-methyl- -1-phenylpropylamine with prochiral (2-hydroxy-5-methyl)phenyl alkyl ketones such as 2-hydroxy-5-methyl acetophenone, 1-(2-hydroxy-5-methyl-phenyl)-propan-1-one, 1-(2-hydroxy-5-methyl-phenyl)-butan-1-one, (2-hydroxy-5-methyl-phenyl)-phenyl-metha- none, respectively. All chiral aminoalkylphenols (R,R)-6a-d were obtained in good chemical yields (66.0⁸0.9%).Enantiomerically enriched (R,R)-6a-d were further derived to (R,R)-7a-d {N-[(1R)-1- (2-hydroxy-5-methylphenyl)alkyl]-N-((1R)-2-methyl-1-phenyl-propyl)acteamide}(alkyl are methyl, ethyl, n-propyl and phenyl) for chiral HPLC analysis to show (R,R)-7a-d were≥89.0% pure. Structures of all intermediates and terminal products prepared in this paper were confirmed by IR, 1HNMR and element analysis.Compounds (R,R)-7a and (R,R)-7b were dissolved in THF, then two kinds of single crystals were obtained after the solvent was evaporated at room temperature. Compounds (R,R)-6b, (R,R)-6c and concentrated HCl were reacted at room temperature and two kinds of white solids were precipitated, respectively. The solvent was removed and the two kinds of white solids were recrystallized from a mixed solvent of ethyl ethanol/hexane (V/V=7:3) and a mixed solvent of ethyl acetate/ethanol (V/V=5:1) to yield single crystals (R,R)-6b·HCl and (R,R)-6c·HCl, respectively. The single crystal of (R,R)-8 was obtained from (R,R)-6d and formaldehyde, then recrystallized by a mixed solvent of acetate/ethanol (V/V=5:1).The absolute configurations of (R,R)-6a-d were established by means of an X-ray crystallographic analysis of atomic coordinates and equivalent isotropic displacement parameters, bond lengths, angles, 3D structure and a displacement ellipsoids for single...