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Canagliflozin (Invokana, JNJ-28431754) is an orally bioavailable and selective SGLT2 (subtype 2 sodium-glucose transport protein) inhibitor approved for the treatment of type 2 diabetes. Herein, we report the synthesis of 13C and 14C-labeled canagliflozin. Stable isotope-labeled [13C6]canagliflozin was synthesized in 4 steps starting from [13C6]-labeled glucose. The [14C]-Labeled canagliflozin was synthesized by incorporation of [14C] into the benzylic position between the thiophene and benzene rings of the compound. Detailed synthesis of the isotope-labeled compounds is reported. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Synthesis of multiple stable isotope-labeled antibacterial agent RWJ-416457, ( N-{3-[3-fluoro-4-(2-methyl-2,6-dihydro-4 H-pyrrolo[3,4-c]pyrazol-5-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide), and its major metabolite, N-{3-[4-(2,6-dihydro-4 H-pyrrolo[3,4-c]pyrazol-5-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide, is described. The stable isotope-labeled [13CD3]RWJ-416457 was prepared readily by acetylation of the precursor amine, 5-aminomethyl-3-[3-fluoro-4-(2-methyl-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-5-yl)-phenyl]-oxazolidin-2-one with CD313COCl in pyridine. Synthesis of the stable isotope-labeled metabolite involved a construction of multiple isotope-labeled pyrazole ring. N, N-dimethyl(formyl-13C,D)amide dimethyl acetal was first prepared by treating N, N-dimethyl(formyl-13C,D)amide with dimethyl sulfate, followed by sodium methoxide. Then, N-{3-[3-fluoro-4-(3-oxo-pyrrolidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide was condensed with N, N-dimethyl(formyl-13C,D)amide dimethyl acetal, and the resultant β-ketoenamine intermediate underwent pyrazole ring formation with hydrazine-15N2, to give the [13C15N2D]-labeled metabolite. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]