Synthesis and stability of a carbon‐14‐labeled 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase inhibitor

Abstract

Inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) is an effective method of lowering plasma lowdensity lipoprotein cholesterol levels. Hemi-calcium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (1) is a cholesterol-lowering statin drug that effectively inhibits HMGR. An important step in the development of this compound was the synthesis of a carbon-14-labeled analog for use in preclinical absorption, distribution, metabolism and excretion studies.The synthesis of a carbon-14-labeled analog of the cholesterol-lowering statin drug 1 is described. The carbon-14-labeled compound [14 C]-1 was prepared in 11 steps from [ 14 C]-labeled urea. The overall radiochemical yield for the synthesis was 22% and the radiochemical purity of [ 14 C]-1 was 99.9% immediately after synthesis. It was found that [ 14 C]-1 with a specific activity of 43.2 mCi/mg decomposed at a rate of about 1.9%/month when stored at À781C under argon. Three samples of [ 14 C]-1 were prepared to study the chemical stability of the molecule. One sample had a specific activity of 3.8 mCi/mg and the other two contained radical inhibitors, L-ascorbic acid (1% by weight, specific activity of 10.5 mCi/mg) or BHT (1% by weight, specific activity of 9.8 mCi/mg). For these samples the decomposition rates were decreased to 0.5%/month, 0.2%/month and 0.1%/month, respectively.