Synthesis of [14C]CI-980, ethyl [5-amino-1,2-dihydro-2(S)-methyl-3-[14C]phenylpyrido[3,4-b]pyrazin-7 -yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent

Article abstract of DOI:10.1002/jlcr.2580340102

[¹⁴C]CI-980 (14b) was synthesized in eight steps starting from [U-¹⁴C]benzene (5), which was converted to bromo[¹⁴C]benzene (6) in the presence of tetrabutylammonium bromide as catalyst. Reaction of 6 with the anion of N-ethoxycarbonyl-N'-methoxy-N'-methyl-L-alaninamide (4a) gave the chiral (S)-ketone 8 with ee exceeding 96%. Sodium borohydride reduction of 8, followed by sequential condensation with ethyl 6-amino-4-chloro-4-nitro-2-pyridine carbamate (11), chromium trioxide oxidation, and catalytic hydrogenation over Raney nickel gave the free base form of [¹⁴C]CI-980 (14a), which was extremely unstable and readily aromatized to 15. The free base 14a was, however, isolated under specially developed conditions and converted to the crystalline isethionate salt 14b in pure form.