Method of preparing nerandomilast and its crystalline form b.

Abstract

The application refers to an improved method for preparing Intermediate VIII, wherein in step a) 5-Chloro-2-iodopyrimidine and boronic ester Boc V are reacted in the presence of bis(amphos)palladium-II chloride catalyst to give Intermediate VI and wherein in step b) Intermediate VI is hydrogenated to give unisolated Intermediate VII and wherein in step c) unisolated Intermediate VII is reacted with hydrochloric acid to give Intermediate VIII. The application further refers to a method of preparing Intermediate XVIII, which is substantially enantiomerically pure with a content of = 0.5% of the undesired enantiomer ent-XVII, preferably with an enantiomeric excess relative to the undesired enantiomer ent-XVII of at least 99.88%, and with a titanium content of less than 30 ppm, wherein this substantially enantiomerically pure Intermediate XVII is prepared by the steps a), b), c) and d) described in claim 18.The application also refers to a method of recrystallizing Intermediate XIX from a mixture of 5 VP of n-propanol and 1.25 VP of water to give the PDE4B inhibitor of formula XX in the Crystalline Form B (Nerandomilast).