Synthesis of (~(14)C)- and (~(13)C_6)-labeled potent HIV non-nucleoside reverse transcriptase inhibitor

摘要

Compound 1 (Figure 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 to 1.75 GBq/mmol). In the first synthesis, 2 was coupled to 4-hydroxyquinoline, [benzene-~(14)C(U)]- under Mitsunobu conditions, followed by oxidation of the quinoline nitrogen with m-CPBA to give [~(14)C]-(1a) in 43% radiochemical yield. Secondly, 3-Amino-2-chloropyridine,[2,6-~(14)C]- was used to prepare 8, which was converted to 10. Mitsunobu etherification and oxidation as seen before, gave [~(14)C]-(1b) in eight steps and in 11% radiochemical overall yield. Finally, carbon-14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide 8 to aryl acetic acid 13 under palladium catalysis. Alcohol 14, obtained from the reduction of acid 13, was used as described above to prepare [~(14)C]-(1c) in 4.3% radiochemical yield. To prepare [~(13)C_6]-(1), [~(13)C _6]-4-hydroxyquinoline was prepared from [~(13)C _6]-aniline and then coupled to 2 and oxidized as seen before.