Synthesis Of Non-small Cell Lung Cancer Drug Crizotinib

The chemical name of crizotinib is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl) pyridin-2-amine, which was developedby Pfizer. Crizotinib (trade name: Xalkori) is an orally active, small moleculeinhibitor of multiple receptor tyrosine kinases, including anaplastic lymphoma kinase(ALK), c-Met/hepatocyte growth factor receptor and c-ros oncogene1. Crizotinib hasbeen conditionally approved for the treatment of adults with previously treated,ALK-positive, advanced non-small cell lung cancer (NSCLC), and undergoingclinical trials testing its safety and efficacy in anaplastic large cell lymphoma,neuroblastoma, and other advanced solid tumors in both adults and children.The initial medicinal chemistry route of crizotinib was designed to facilitatelate-stage variation of the (hetero) aryl group attached to the pyridine (Scheme1.13).Mitsunobu reaction of3-hydroxy-2-nitro-pyridine (compound2) with(R)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol (compound3) provided compound4,which was further reduced with iron chips in acetic acid and ethanol under reflux tocompound5. Bromination of5produced compound6.2-Amino function ofcompound6was protected as a bis-tert-butyl carbamate7. Crizotinib1was preparedvia palladium coupling of compound7with4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane), followed by Boc deprotection, and Suzuki couplingreaction with pyrazole derivative. Clearly this route was not ideal for the preparationof crizotinib. Subsequently, crizotinib was prepared by the more convergent routeshown in Scheme1.14. In this modified process, the chiral center was introducedthrough resolution of alcohol rac-3which was converted to aryl bromide6via thesequence illustrated in Scheme1.13. The aryl bromide was coupled with pinacol boronate14, providing efficient access to the desired product crizotinib.In this paper, the decision was taken to use the optimized synthetic route (Scheme1.14) to prepare crizotinib, focusing on streamlining product isolations. The processincludes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, anda bromination. Mitsunobu reaction of3-hydroxy-2-nitro-pyridine (compound2) with(R)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol (compound3) in THF providedcompound4in96%yield. Compound4was further reduced with iron chips in1NHCl and ethanol under reflux to afford compound5in98%yield, the original reactioncondition was modified with use of iron instead of sponge-nickel. Bromination of5with use of Br2instead of NBS produced compound6in86%yield, this was asignificant improvement on the previous process.