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Syntheses of [2H3, 15N], [14C]Nexavar™ and its labeled metabolites

✍ Scribed by U. Pleiss; M. Gerisch; D. Seidel

Publisher
John Wiley and Sons
Year
2006
Tongue
French
Weight
150 KB
Volume
49
Category
Article
ISSN
0022-2135

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✦ Synopsis

Nexavar TM , Sorafenib tosylate (BAY 43-9006 tosylate) is a potent small molecule Raf kinase inhibitor for the treatment of hyperproliferative disorders such as cancer. Both radiolabeled and stable isotope labeled compounds were required for drug absorption, distribution, metabolism and excretion (ADME) and quantitative mass spectrometry bio-analytical studies. Nexavar TM labeled with carbon-14 in the carboxamide group was prepared in two steps in an overall radiochemical yield of 42% starting from 4-chloro-N-methyl-2-pyridine-[ 14 C]carboxamide. The [ 2 H 3 , 15 N] version of Nexavar TM was prepared in 75% yield based on 4-chloro-N-[ 2 H 3 ]methyl-2-pyridine-[ 15 N]carboxamide. The pyridine N-oxide metabolite labeled with carbon-14 as well as with deuterium and nitrogen-15 and was synthesized by oxidation in yields of 59% and 87%, respectively. Starting from [ 2 H 2 , 13 C]formaldehyde the N-hydroxymethyl metabolite was labeled with carbon-13 and deuterium in one step in a 45% overall yield.

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