Development of\na Scalable Asymmetric Process for the\nSynthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550)

A robust\nand scalable synthesis process for Nerandomilast (<b>1</b>,\nBI 1015550), a selective PDE4B inhibitor with potential\ntherapeutic properties for the treatment of respiratory diseases,\nwas developed and implemented at a pilot plant on a multikilogram\nscale. Key aspects of the process include the efficient synthesis\nof intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidin-4-yl)amino)cyclobutyl)methanol (<b>4</b>) by means\nof a regioselective S<sub>N</sub>Ar reaction between (1-aminocyclobutyl)methanol\n(<b>6</b>) and 2,4-dichloro-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidine (<b>5</b>), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine\n(<b>3</b>) by means of a Suzuki coupling, and a highly enantioselective\nsulfide oxidation to give chiral nonracemic (<i>R</i>)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-<i>d</i>]pyrimidine 5-oxide (<b>2</b>).