Functionalization through Lithiation of (S)-N-(1-Phenylpropyl)-2-phenylquinoline-4-carboxamide. Application to the Labeling with Carbon-11 of NK-3 Receptor Antagonist SB 222200

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Lithiation of (S)-N-(1-phenylpropyl)-2-phenylquinoline-4-carboxamide with the complex n-BuLi/TMEDA (1/1 molar ratio) in THF at -60 degrees C for 5 h occurred selectively at the position 3 of the quinoline ring. This selectivity was shown by the absence of racemization of the stereogenic center and the formation of the corresponding functionalized quinolines in 59-74% yield by subsequent reaction with an electrophile at -60 degrees C for 1 h. The 3-trimethylstannyl derivative was subjected to a Stille reaction using methyl, phenyl, or thienyliodide to afford the alkyl or aryl quinolines in moderate to good yields. This methodology was successfully applied to the radiosynthesis of [11C]SB 222200 using methyl iodide labeled with carbon-11 (beta+ emitter, t1/2=20.4 min) for the in vivo study of NK-3 receptor by positron emission tomography (48-58% radiochemical yields from [11C]CH3I, decay corrected, 45 min total synthesis time).