Several synthetic routes to bosutinib have been reported, including synthetic work for scale up and
processing to obtain pure salt forms of bosutinib for pharmaceutical applications.56-59 The current
manufacturing route begins with reaction of 2-methoxy-5-nitrophenol (36) and 1-bromo-3-
chloropropane (37) to provide aryl chloroether 38 in 82% yield. Reaction of 38 with Nmethylpiperazine
(39) and NaI in refluxing DME provided the functionalized aryl-nitro-piperazine 40
(77% yield), which was converted directly to aniline 41 under hydrogenolysis conditions. Aniline 41
was then reacted with triethyl orthoformate and aryl cyanoamide 42, which was generated in one step
from 2,4-dichloro-5-methoxy-aniline (44), 1,3-diisopropylcabodiimide (DIC), and cyanoacetic acid (45)
under refluxing conditions, to yield advanced intermediate 43 (93% over 2 steps). Finally,
conversion of 43 to bosutinib was facilitated by a POCl3-promoted cyclization in the presence of
sulfolane. As shown in Scheme 8, employment of carefully optimized conditions for the isolation of
bosutinib hydrate (VII) provided material in 75-82% yields and >99% purity.
