合成路线1

Condensation of methyl 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylacetate (I) with methyl (3-indolyl)glyoxylate (II) in the presence of LDA in THF affords the butenedioate derivative (III), which can also be prepared by condensation of methyl 5,6-dihydropyrrolo[3,2,1-ij] quinoline-1-glyoxylate (IV) with methyl 3-indolylacetate (V) in the presence of LDA in THF. Hydrogenation of alkene (III) over Pd/C gives the saturated diester (VI), which upon cyclocondensation with benzylamine in THF yields the 1-benzyl-2,5-pyrrolidinedione derivative (VII). Debenzylation of compound (VII) by means of H2 over Pd/C then provides the 2,3-diarylsuccinimide (VIII) as a cis/trans mixture. Alternatively, succinimide (VIII) can be produced by the direct cyclocondensation of diester (VI) with NH3 in MeOH at elevated temperature. Isomerization of intermediate (VIII) with t-BuOK in t-BuOH or THF/t-BuOH leads to the (±)-trans-isomer, racemic tivantinib (IX) . Resolution of racemate (IX) can be effected by means of chiral preparative SFC or MCC , or by fractional crystallization with (1S,2S)-(+)-pseudoephedrine .
Racemic tivantinib (IX) can also be obtained by the following methods:
Reduction of the maleimide derivative (X) with Mg in refluxing MeOH produces the trans-succinimide (IX) . Alternatively, the reduction of maleimide (X) by catalytic hydrogenation over Pd/C in MeOH or Pd(OH)2/C in toluene provides the (±)-cis-succinimide (XI), which can be isomerized to the corresponding trans-succinimide (IX) by treatment with t-BuOK in t-BuOH at 50 °C . Similarly, reduction of the maleimide (X) with Zn(Hg) in HCl/EtOH leads to a mixture of cis- and trans-maleimides . The tricyclic compound (IX) can also be obtained by intramolecular Heck reaction of the 1-allyl-7-bromoindole derivative (XII) in the presence of 9-BBN and Pd(PPh3)4 . In a further method, condensation of 1-benzyl-3,4-dibromopyrrole-2,5-dione (XIII) with indole (XIV) using methyl magnesium bromide yields 1-benzyl-3-bromo-4-(3-indolyl)pyrrole-2,5-dione (XV), which by Suzuki coupling with 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylboronic acid (XVI) in the presence of Pd(PPh3)4 or by condensation with 5,6-dihydropyrrolo[3,2,1-ij]quinoline (XVII) by means of LiHMDS affords the maleimide (XVIII). Finally, adduct (XVIII) is reduced with Mg in refluxing MeOH, followed by debenzylation with H2 over Pd/C in MeOH (IX) .