Novel strategy for synthesis of 2-(tributylstannyl)benzoate succinimide as a precursor for radio-iodination

Objectives Iodine radioisotopes are widely applied in labeling molecular probes for radionuclide imaging with favorable properties, due to their specific physical characteristics. Functionalized aryl stannanes as the critical precursors continue playing a considerably important role in preparing iodine labeled probes. Mostly, the aryl stannanes are conventionally synthesized by palladium-catalyzed procedure. However, this strategy has some disadvantages, such as expensive catalyst usage and time-consuming. With an aim to discovery a novel method to prepare the key precursor and overcome above shortcoming, herein we reported a non-palladium-catalyzed process for synthesizing the precursor for iodine radiolabeling.

Methods [2-(Ethoxycarbonyl)phenyl]zinc(II) iodide 3, was designed as a good candidate for its advantages of compatibility with many functional groups, and it was prepared by direct insertion of zinc into ethyl 2-iodobenzoate 2 in the presence of LiCl. Then, the key intermediate 4 was prepared via the organometallic exchange reaction of a carboxyl group protected organozinc reagent 3 with nBu3SnCl in THF for 4h at 80oC. Finally, 6 was formulated by reacting 2-(tributylstannyl)benzoic acid 5 with N-hydroxy succinimide (HOSu) and N,N'-dicyclohexylcarbodiimide (DCC) for 30 min at room temperature ( Scheme 1). 6 could be used as an active ester form for increase the reactivity of carboxyl group for conjugation to amino group on proteins.

Results Active ester 6 was designed as a novel precursor for iodine radiolabeling of proteins and synthesized in a total yield of 58% in five steps, and it was characterized by 1H, 13C NMR and IR spectroscopies.

Conclusions We successfully developed a non-palladium-catalyzed approach for preparing active ester 6. This method was high efficient, convenient and easily handled.

Research Support This work was supported by grants from National Natural Science Foundation of China (30900377), New Century Excellent Talents Project (NCET-10-0800), and the Fundamental Research Funds for the Central Universities