3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione → Tivantinib
Reaction equation
[C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.CC(C)([O-])C.[K+]>[OH-].[Pd+2].[OH-].C1COCC1>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1Participants
Procedure
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.
Sources & evidence
- ORD record
- ord-af7967db9eb5406d935b0b0fa51ae559
- Source dataset
- uspto-grants-2014_10
- Patent number
- US08871933B2
Reaction notes
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