合成路线1

Condensation of 1,2,3,5-tetrafluoro-4-nitrobenzene (I) with 2-fluoro-4-iodoaniline (II) by means of LiHMDS in THF gives diaryl amine (III),which undergoes selective fluoride substitution with NaOMe in THF to yield 5-methoxy-6-nitroaniline derivative (IV). Nitro group reduction in intermediate (IV) by means of Fe and NH4Cl in refluxing EtOH provides the corresponding diamine (V), which is then condensed with 1-allylcyclopropanesulfonyl chloride (VI) in the presence of pyridine at 40 °C to produce the sulfonamide (VII). Dihydroxylation of the allyl group of compound (VII) with OsO4 and NMMO in THF affords racemic refametinib, which is finally resolved using chiral HPLC .
In an alternative method, coupling of the primary amine (V) with the chiral sulfonyl chloride (VIII) in the presence of pyridine yields the corresponding sulfonamide (IX), which is finally hydrolyzed at the acetonide moiety with HCl in THF .
1-Allylcyclopropanesulfonyl chloride intermediate (VI) is prepared as follows. Treatment of 3-chloro-1-propanesulfonyl chloride (X) with BuOH affords butyl 3-chloro-1-propanesulfonate (XI), which cyclizes in the presence of BuLi to yield butyl cyclopropanesulfonate (XII),which can also be obtained by treatment of cyclopropanesulfonyl chloride (XIII) with BuOH in the presence of pyridine. Alkylation of butyl cyclopropanesulfonate (XII) with allyl iodide (XIV) using BuLi in THF at –78 °C yields butyl 1-allylcyclopropanesulfonate (XV), which is hydrolyzed by treatment with KSCN in DME/H2O at reflux producing potassium 1-allylcyclopropanesulfonate (XVI). Finally, the potassium sulfonate (XVI) is chlorinated with refluxing SOCl2 in the presence of a catalytic amount of DMF .