A process for the synthesis of the potassium-competitive acid blocker BYK 405879 (8) was established based on the approach used in medicinal chemistry (asymmetric hydrogenation of prochiral ketone 15 and Mitsunobu cyclization of the resulting alcohol 34). Several critical reaction steps were optimized. The synthesis of prochiral ketones was accomplished using ethyl 3-(2-methylphenyl)-3-oxopropanoate instead of 1-[1-(2-methylphenyl)vinyl]pyrrolidine, a reagent that was difficult to prepare and possesses limited shelf life. The catalyst loading of the asymmetric hydrogenation step was reduced significantly from a S/C ratio of 100:1 to a S/C ratio of 2500:1 by benzyl protection of ketone 15. After the Mitsunobu cyclization, the removal of byproduct was easily accomplished through acid-base extraction, and pure BYK 405879 (8) was then obtained by means of crystallization in the presence of succinic acid.

An improved version of the simple N2‐gas‐stream heating device proposed by Böhm [J. Appl. Cryst. (1995), 28, 357] has been developed and tested in long time runs up to 100 h and at various temperatures up to 1290 K.

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An entirely new synthesis of the important benzimidazole building block BYK308944 was elaborated using the Stobbe reaction as central element. BYK308944 constitutes an important intermediate for the preparation of 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles as potassium-competitive acid blockers. The new route relies on the hydroxymethylation of 1,2-dimethylimidazole as cheap starting material followed by oxidation of the corresponding alcohol and Stobbe condensation of the resulting aldehyde with diethyl succinate. All synthetic steps of this new approach were optimized particularly with the goal to establish a process amenable for largescale preparation.

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