Mild, regioselective, high-yielding and scalable synthesis of 1,2-dibromo-4,5-diethoxy-3-fluorobenzene

ORGN 166

Seiji Yoshikawa, s-yoshikawa@hhc.eisai.co.jp, Process Research Laboratories, Eisai Co., Ltd, 22-Sunayama, Hasaki, Kashima, 314-0255, Japan
During the course of our work on a thrombin receptor antagonist, we sought a scalable method for 1,2-dibromo-4,5-diethoxy-3-fluorobenzene (3). The synthesis of 3 from commercial 4-bromo-2-fluorophenol (1) can be accomplished with high regioselectivity, high overall yields and easy purification. Dibromide 3 has been produced via 3-fluorocatechol derivatives 4, which is often problematic in its purity because of the instability to oxidation and moderate reactivity to bromination of 4. An improved synthetic approach, which will be presented, overcomes these problems. Furthermore, the new strategy needs no low reaction temperature and complicated purification. The key steps are Duff formylation and Dakin oxidation of para-brominated phenol 1.