Scalable Synthesis of the Key Fexuprazan Intermediate and Investigation of a Reaction Mechanism

A three-step method for the synthesis of methyl 5-(2,4-difluorophenyl)-4-methoxy-1<i>H</i>-pyrrole-3-carboxylate <b>1</b>, a key intermediate of fexuprazan, is reported in this paper. Using low-priced sodium <i>p</i>-tolylsulfinate as the starting material, compound <b>28</b> was obtained with a 96.8% yield in the first step by optimizing the experimental parameters with a Box-Behnken experimental design. Subsequently, isonitrile compound <b>29</b> was obtained by dehydration. Finally, impurities <b>31</b> and <b>32</b> in the last step of the reaction were identified and converted into target product <b>1</b> by a one-pot method, which significantly improves the utilization of atoms. Key intermediate <b>1</b> was obtained via a three-step process with a yield of 68-70% and purity that exceeded 99%. In addition, the mechanism of the cyclization reaction was proposed. This method has potential for industrial production because the raw materials are inexpensive, the procedure is simple, and a high yield is obtained.