Synthesis and chromatographic separation of the glucuronides of R- and S-propranolol

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Abstract
One of the major metabolites of propranolol (Inderal) is the O-glucuronide. To further study its disposition, possible metabolism and contribution to the antihypertensive effect of propranolol, the 2 diastereomeric propranolol O-.beta.-D-glucuronides (9a,b) were synthesized and separated. These compounds were prepared by reaction of naphthol with epichlorohydrin and treatment of the resulting (2RS)-1''-(2,3-epoxypropoxy)naphthalene with sodium azide to give (2RS)-1-(1''-naphthoxy)-3-azido-2-propanol (3). Alkylation of 3 with methyl (2,3,4-tri-O-acetyl-1-bromo-1-deoxy-.alpha.-D-glucopyranosid)uronate gave methyl (2RS)-[1-(1''-naphthoxy)-3-azido-2-propyl-2",3",4"-tri-O-acetyl-.beta.-D-glucopyranosid]uronate. Reductive alkylation, followed by HPLC [high performance liquid chromatography] separation of the diastereomers, gave methyl (2R)- and (2S)-[1-(1''-naphthoxy)-3-(isopropylamino)-2-propyl-2",3",4"-tri-O-acetyl-.beta.-D-glucorpyranoside]uronate. Hydrolytic removal of the acetyl and methyl protecting groups gave the free glucuronides, which were then converted to the sodium salts, 9a,b. The stereochemistry of the glycoside linkage was deduced from the 400-MHz 1H NMR spectra. The absolute configuration of the aglycon portion was determined after Glusulase hydrolysis by derivatization with (R)-(+)- or -(-)-.alpha.-methylbenzyl isocyanate and comparison of the HPLC retention volumes with those of derivatized reference (R)- and (S)-propranolols.