Syntheses of stable and radioactive isotopically labeled anticonvulsant agent N-(benzothien-3-ylmethyl)-sulfamide (JNJ-26990990) and its metabolites (1-4) are described. [13C15N]Benzothiophene-3-carbonitrile was first prepared by coupling of 3-bromo-benzothiophene with [13C15N]-copper (I) cyanide. The resultant [13C15N]benzothiophene-3-carbonitrile was reduced with lithium aluminum deuteride to give [13CD215N]benzothiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [13CD215N]-N-(benzothien-3-ylmethyl)-sulfamide, the stable-isotope labeled compound with four stable isotope atoms. Direct oxidation of [13CD215N]-N-(benzothien-3-ylmethyl)-sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope labeled sulfoxide and sulfone metabolites. Synthesis of 14C-radiolabeled N-(benzothien-3-ylmethyl)-sulfamide was prepared conveniently by sequential coupling of 3-bromo-benzothiophene with [14C]copper(I) cyanide, reduction of the resulting nitrile to carboxaldehyde, and reductive amination with sulfamide.

Expeditious syntheses of isotopically labeled anticonvulsant agent N-(benzothien-3-ylmethyl)-sulfamide (JNJ-26990990) and its metabolites

239th National Meeting (2010)

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