✍ Scribed by Richard C. Burrell; Samuel J. Bonacorsi Jr.; J. Kent Rinehart; Saleem Ahmad; Khehyong Ngu; Balu Balasubramanian
No coin nor oath required. For personal study only.
Inhibition of 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase (HMGR) is an effective method of lowering plasma low‐density 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 µCi/mg decomposed at a rate of about 1.9%/month when stored at −78°C 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 µCi/mg and the other two contained radical inhibitors, L‐ascorbic acid (1% by weight, specific activity of 10.5 µCi/mg) or BHT (1% by weight, specific activity of 9.8 µCi/mg). For these samples the decomposition rates were decreased to 0.5%/month, 0.2%/month and 0.1%/month, respectively. Copyright © 2010 John Wiley & Sons, Ltd.
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