Expeditious syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, and its metabolites

Abstract

Syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, that is, N-(benzo[b]thien-3-ylmethyl)-sulfamide and its metabolites are described. [13C15N]Benzo[b]thiophene-3- carbonitrile was first prepared by coupling of 3-bromo-benzo[b]thiophene with [13C15N]-copper cyanide. The resultant [ 13C15N]benzo[b]thiophene-3-carbonitrile was reduced with lithium aluminum deuteride to give [13CD215N]benzo[b]thiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [13CD215N]-N-(benzo[b] thien-3-ylmethyl)-sulfamide, the stable isotope-labeled compound with four stable isotope atoms. Direct oxidation of [13CD215N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope-labeled sulfoxide and sulfone metabolites. On the other hand, radioactive 14C-labeled N-(benzo[b]thien-3-ylmethyl)-sulfamide was prepared conveniently by sequential coupling of 3-bromo-benzo[b]thiophene with [14C]-copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide. Syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990 (N-(benzo[b]thien-3-ylmethyl)-sulfamide), and its metabolites are described. [13C15N]Benzo[b]thiophene-3- carbonitrile was first prepared by coupling of 3-bromo-benzo[b]thiophene with [13C15N]-copper cyanide. The resultant [ 13C15N]benzo[b]thiophene-3-carbonitrile obtained was reduced with lithium aluminum deuteride to give [13CD 215N]benzo[b]thiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [13CD215N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide (1), the stable isotope-labeled compound with four stable isotope atoms. Direct oxidation of [13CD215N]-N-(benzo[b]thien-3-ylmethyl)- sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope-labeled sulfoxide and sulfone metabolites correspondingly. On the other hand, radioactive 14C-labeled N-(benzo[b]thien-3-ylmethyl)-sulfamide (2) was prepared conveniently by sequential coupling of 3-bromo-benzo[b] thiophene with [14C]-copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide. Copyright © 2013 John Wiley & Sons, Ltd.