Atorvastatin, an HMG-CoA reductase inhibitor and efficient lipid-regulating agent. Part I. Synthesis of ring-labeled [C-14]atorvastatin.

Pyrrole-ring labeled [C-14]atorvastatin (Lipitor(R), CI-981), [R-(R*,R*)]-2 -(4-fluorophenyl)-beta,gamma-dihydroxy-5-(1-methyl)-3-phenyl-4-[(phenylamin o)-carbonyl]-1H-[3-C-14]pyrrole-1-heptanoic acid calcium salt (2:1) (15), w as synthesized in a 5-step synthesis from [7-C-14]benzaldehyde (5) with an overall yield of 6.9 to 9.6%. Thus, Knoevenagel condensation of 5 with isob utyryl-acetanilide (6) gave 4-methyl-3-oxo-N-phenyl-2-(phenyl[C-14]methylen e)-pentamide (2). Stetter condensation of (7) with p-fluorobenzaldehyde (8) , in the presence of the catalyst 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazo lium bromide (9) and triethylamine, gave the key labeled intermediate diket one, 4-fluoro-alpha-(2-methyl-1-oxopropyl)-gamma-oxo-N,beta-diphenylbenzene [3-C-14]butane-amide (10). Reaction of 10 with the protected chiral dihydro xyaminoheptanoic ester, [4R-cis]-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dim ethyl-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-C-14]pyrrol-1-y l]ethyl]-2,2-dimethyl- 1,3-dioxane-4-acetate (12). Deprotection of 12 led t o the sodium salt 13. Subsequent calcium salt formation gave the ring-label ed atorvastatin 15.