Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki–Miyaura Coupling

To avoid the use and handling of Lawesson's reagent or other thiation agents in the in-house kilolab, a new scalable route to ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1) was developed. The key to success was the use of a commercially available amino-thiadiazole building block, which was converted into the desired product via a sequence of Sandmeyer bromination and Suzuki–Miyaura coupling. The different parameters of the Pd-catalyzed coupling have been studied in detail and allowed the reaction to be performed under mild conditions at room temperature and with low catalyst loading. The inconsistencies of the initial scale-up runs with regard to the sluggish conversion of the Suzuki–Miyaura coupling due to Cu contamination were addressed, and the findings were directly implemented in the subsequent batches, which finally led to an improved overall understanding and robustness of the process.