Synthesis of hydroxylated derivatives of topiramate, a novel antiepileptic drug based on D-fructose: investigation of oxidative metabolites.
To corroborate the structures of two monohydroxylated metabolites of topiramate (1), we synthesized four monosaccharide derivatives from D-fructose: 4,5-O-[(1R)- and 4,5-O-[(1S)-1-hydroxymethylethylidene]-2,3-O-isopropylidene-beta-D -fructopyranose sulfamates (2a and 2b); 2,3-O-[(1R)- and 2,3-O-[(1R)-1-hydroxymethylethylidene]-4,5-O-isopropylidene-beta-D -fructopyranose sulfamates (3a and 3b). The route to 2a and 2b was brief and straightforward, while that to 3a and 3b was more involved. In the latter case, the D-fructose bis-acetal 10 was benzylated and converted to a monoacetal dibenzoate (14) (50% yield), which was then transacetalized to give a mixture of 4,5-dibenzoyl-2,3-O-[(1R)- and 4,5-dibenzoyl-2,3-O-[(1S)-1-benzyloxymethylethylidene]- beta-D-fructopyranose (16a and 16b) (22%). The individual diastereomers were separated and processed via ester saponification, acetonation, sulfamoylation, and hydrogenolysis into 3a (36%) and 3b (27%). Structure 2b was confirmed for one oxidative metabolite, but the other metabolite was found not to correspond with either 2a, 3a, or 3b. On the basis of CI-MS and 1H NMR data, a (2-hydroxy-1,4-dioxano)pyran structure, 4, is proposed for this unidentified metabolite.
Nortey
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The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
Wu
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Maryanoff
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D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D004285:Dogs; D005632:Fructose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D051381:Rats; D013237:Stereoisomerism; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose