3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione → Tivantinib

Participants

Reaction Steps

Compound 6 was hydrogenated with palladium hydroxide, THF, and potassium tert-butoxide to produce crude trans racemate, (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (Compound 8). As described in the examples, the preparation of Compound 8, does not require the isolation of crude cis racemate (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione (Compound 7). Rather, during the hydrogenation of Compound 6, conditions were modified to effect the isomerization of the resultant Compound 7 in situ. The resulting process provides a means to control key impurities in Compound 8, specifically Compound 6. Specifically, the reaction is carried out in THF solvent, and the catalyst employed is palladium hydroxide. Potassium tert-butoxide is also added to the reaction mixture to promote the isomerization. A detailed description of this process is shown in Example 2.

Provenance & Evidence