14C-labeling of a novel atypical β-adrenoceptor agonist, SM-11044

(2S,3R)-2-[3-(4-Fluorophenyl)]propylamino-3-(3,4-dihydroxyphenyl)-3-hydroxypropionic acid pyrrolidine amide hydrobromide (SM-11044) was labeled with carbon-14 for use in mammalian metabolic studies. The synthesis was achieved according to the scheme shown in Fig. 5. Grignard reaction of 3,4-methylenedioxy-phenylmagnesium bromide with [14C]carbon dioxide liberated from barium [14C]carbonate ((UNDERLINE)6(/UNDERLINE)) gave the acid ((UNDERLINE)5(/UNDERLINE)). Reduction of (UNDERLINE)5(/UNDERLINE) with lithium aluminum hydride followed by oxidation of the resulting benzyl alcohol ((UNDERLINE)11(/UNDERLINE)) with chromium oxide-pyridine complex afforded the aldehyde ((UNDERLINE)3(/UNDERLINE)). Condensation of (UNDERLINE)3(/UNDERLINE) with the optically active (R)-oxazolidinone ((UNDERLINE)10(/UNDERLINE)) yielded the alcohol ((UNDERLINE)12(/UNDERLINE)). Catalytic hydrogenation of (UNDERLINE)12(/UNDERLINE) and subsequent hydrolysis produced the optically active β-hydroxy-α-amino acid ((UNDERLINE)2(/UNDERLINE)), which was treated with N-carbomethoxyphthalimide to give the hydroxy acid ((UNDERLINE)13(/UNDERLINE)). Reaction of (UNDERLINE)13(/UNDERLINE) with pivaloyl chloride gave the corresponding mixed anhydride, which was allowed to react with pyrrolidine to provide the amide ((UNDERLINE)14(/UNDERLINE)). Deprotection of (UNDERLINE)14(/UNDERLINE) with hydrazine hydrate afforded the hydroxyamide (15). Condensation of (UNDERLINE)15(/UNDERLINE) with the aldehyde ((UNDERLINE)16(/UNDERLINE)) and subsequent reduction of the resulting imine with sodium cyanoborohydride produced the fluoride ((UNDERLINE)17(/UNDERLINE)). Cleavage of the methylenedioxy group of (UNDERLINE)17(/UNDERLINE) gave the free base of (UNDERLINE)1(/UNDERLINE), which was treated with hydrobromic acid to afford (UNDERLINE)1(/UNDERLINE). The overall yield was 11.1% from (UNDERLINE)6(/UNDERLINE).