Development of a Scalable Asymmetric Process for the Synthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550)

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