Selumetinib Sulfate

Selumetinib Sulfate (Koselugo) is a selective ATP-noncompetitive MEK1/2 inhibitor developed by Array BioPharma for the treatment of neurofibromatosis type 1 (NF1).

Koselugo

As a MEK1/2 inhibitor, Selumetinib Sulfate inhibits the activity of mitogen-activated protein kinase (MEK), thereby affecting the RAS/RAF/MEK/ERK signaling pathway, which plays a key role in the occurrence and development of NF1-related tumors.

The synthesis started from 2,3,4-trifluorobenzoic acid (345). Nitration of 345 gave compound 346. SNAr amination of 346 gave compound 348. Esterification of 348 gave the carboxylic acid derivative 347. Final SNAr amination of 347. Reduction of the nitro group in 349 with Pd(OH)2 and in situ condensation with formic acid gave 1H-benzimidazole 350 in good yield. Sequential halogenation of 350 with NBS and NCS gave the 4-bromo-2-chloroaniline group 352. Methylation of the 1H-benzimidazole gave 353 in moderate yield. Saponification (hydrolysis) of the ester group in 353 gave compound 356. 356 was reacted with hydroxylamine 355 using an EDCI/HOBt-mediated amidation reaction to give amide 356. Acid hydrolysis of the vinyl ether in 356 gave the alcohol 357 quantitatively. Finally, selumetinib sulfate was obtained by salt formation with sulfuric acid H2SO4 in 2-butanone.