Syntheses of [4-14c] and [6-14c]nisoldipine

The synthesis of [4-14C]nisoldipine started from dimethyl [14C]formamide which was allowed to react with 2-nitrophenyllithium yielding 2-nitro[7-14C]benzaldehyde. Knovenagel condensation with isobutyl acetoacetate yielded isobutyl 2-(2-nitro[7-14C]benzylidene) acetoacetate. Key reaction step was the cyclizing Michael addition with methyl 3-aminocrotonate to obtain 3-isobutyl 5-methyl 1, 4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-[4-14C]pyridine-3,5-dicarboxylate (= [4-14C]nisoldipine). Starting material of the synthesis of [6-14C]nisoldipine was barium[14C]carbonate which was converted to [1-14C]acetyl chloride. The acid chloride was condensed with Meldrum's acid (2,2-dimethyl-1, 3-dioxane-4,6-dione). The resulting intermediate was treated with boiling methanol to give methyl [3-14C]acetoacetate. Reaction of the s-ketoester with gaseous ammonia in toluene afforded the corresponding aminocrotonate, which was condensed with isobutyl 2-(2-nitrobenzylidene)-acetoacetate to yield [6-14C]nisoldipine.