Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

5,11‐Dihydro‐11‐ethyl‐5‐methyl‐8‐{2‐{(1‐oxido‐4‐quinolinyl)oxy}ethyl}‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one, (1), labeled with carbon‐14 in the quinoline–benzene ring, in one of the pyridine rings of the dipyridodiazepinone tricyclic moiety, and in the side chain, was prepared in three different syntheses with specific activities ranging from 44 to 47 mCi/mmol (1.63–1.75 GBq/mmol). In the first synthesis, 5,11‐dihydro‐11‐ethyl‐8‐(2‐hydroxyethyl)‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (2) was coupled to 4‐hydroxyquinoline, [benzene‐¹⁴C(U)]‐, using Mitsunobu's reaction conditions, followed by the oxidation of the quinoline nitrogen with 3‐chloroperoxybenzoic acid to give ([¹⁴C]‐(1a)) in 43% radiochemical yield. Second, 3‐amino‐2‐chloropyridine, [2,6‐¹⁴C]‐, was used to prepare 8‐bromo‐5,11‐dihydro‐11‐ethyl‐5‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one (8), and then Stille coupled to allyl(tributyl)tin followed by ozonolysis of the terminal double bond and in situ reduction of the resulting aldehyde to alcohol (10). Mitsunobu etherification and oxidation as seen before gave ([¹⁴C]‐(1b)) in eight steps and in 11% radiochemical yield. Finally, carbon‐14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide (8) to labeled aryl acetic acid (13) under palladium catalysis. Trihydroborane reduction of the acid gave alcohol (14) labeled in the side chain, which was used as described above to prepare ([¹⁴C]‐(1c)) in 4.3% radiochemical yield. The radiochemical purities of these compounds were determined by radio‐HPLC and radio‐TLC to be more than 98%. To prepare [¹³C₆]‐(1), [¹³C₆]‐4‐hydroxyquinoline was prepared from [¹³C₆]‐aniline and then coupled to (2) and oxidized as seen before. Copyright © 2008 John Wiley & Sons, Ltd.