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

Abstract

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.

Reactivity Studies of Thiophosgene and its Halo Versions towards Diazo Derivatives

“…On treatment with mono substituted diazo 1c, we isolated the exclusively ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate 4c. The NMR value are consistent with reported values [25][26] where it synthesized by using Sandmeyer reaction The structure is further confirmed by single crystal data (hard copy only). The ethyl 5-bromo-1,2,3-thiadiazole-2-carboxylate 5c was not formed under this reaction conditions.…”

Recent trends in the chemistry of Sandmeyer reaction: a review

“…Research group of Schäfer reported a simple, efficient and cost-effective synthetic pathway for ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate ( 64 ) including Sandmeyer bromination and Suzuki–Miyaura couplings as key steps [ 40 ]. Reactions performed at gram scale and kilogram scale level under mild conditions.…”

“…Scheme 40 Sandmeyer approach for the preparation of trifluoromethylselenoethers [91]. Their methodology started from the Suzuki cross-coupling of bis(arylation) of 3,5-dibromopyridine (164) with 4-methoxyphenylboronic acid under optimized conditions resultantly afforded corresponding arylated compound 165 in 71% yield which was subsequently subjected to Sandmeyer reaction in the presence of t-BuONO, CH 2 I 2 and I 2 .…”

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

“…Schäfer and coworkers 21 from Idorsia pharmaceuticals developed a scalable synthetic route for the thiadiazole building block 53 to be used for a project at Idorsia Pharmaceuticals. The first-generation synthesis of 53 used Lawesson's reagent to produce the desired thiadiazole moiety, which hindered the scalability of the route.…”