Atorvastatin, an HMG‐COA reductase inhibitor and efficient lipid‐regulating agent. Part I. Synthesis of ring‐labeled [14C6]atorvastatin

Pyrrole-ring labeled [14C]atorvastatin (Lipitor®, CI-981), [R-(R*,R*)]-2-(4-fluorophenyl)-β,γ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-[3-14C]pyrrole-1-heptanoic acid calcium salt (2:1) (15), was synthesized in a 5-step synthesis from [7-14C]benzaldehyde (5) with an overall yield of 6.9 to 9.6%. Thus, Knoevenagel condensation of 5 with isobutyryl-acetanilide (6) gave 4-methyl-3-oxo-N-phenyl-2-(phenyl[14C]methylene)-pentamide (7). Stetter condensation of (7) with p-fluorobenzaldehyde (8), in the presence of the catalyst 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (9) and triethylamine, gave the key labeled intermediate diketone, 4-fluoro-α-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenylbenzene[3-14C]butaneamide (10). Reaction of 10 with the protected chiral dihydroxyaminoheptanoic ester, [4R-cis]]-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (11), synthesized separately, gave atorvastatin in its protected form, [4R-cis]-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-[3-14C]pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (12). Deprotection of 12 led to the sodium salt 13. Subsequent calcium salt formation gave the ring-labeled atorvastatin 15. Copyright © 1999 John Wiley & Sons, Ltd.