ChEBI: A hydrate that is the monohydrate form of anhydrous bosutinib.
Clinical Use
Bosulif ® (Bosutinib hydrate), also known as (SKI-606), is a novel 4-phenylamino-3-quinolinecarbonitrile kinase inhibitor approved for treatment of adults with chronic, accelerated, or blast
phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML). Bosutinib is an
orally-dosed, dual Src/Abl kinase inhibitor which provides an alternative treatment to patients
exhibiting immunity to imatinib and other kinase inhibitors utilized for this treatment. In contrast to
competitor tyrosine inhibitors, bosutinib inhibits autophosphorylation of both Srs and Abl kinases,
leading to decreased cell growth and apoptosis. Bosutinib was originally developed by Wyeth and
continues to be marketed by Pfizer after the merger of Wyeth and Pfizer in 2009.
Synthesis
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.
