Methanol → Methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate

Participants

Reaction Conditions

Reaction Steps

To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72 g, 159 mmol) in dimethyl sulfoxide (1057 mL) was added copper(I) iodide (60.4 g, 317 mmol) and isopropyl sulfinic acid sodium salt (41.3 g, 317 mmol). The mixture was evacuated and purged with N2 three times and then heated at 120° C. for 6 h, then cooled to 65° C. Stirring was continued at 65° C. overnight then cooled to room temperature and MeI (39.6 mL, 634 mmol) was added. After stirring for 1 h, the mixture was diluted with DCM (750 mL) and water (1 L), followed by vigorous stirring for 30 min. The mixture was then filtered over celite and washed with DCM. The two layers were separated and the aqueous layer was extracted twice with DCM. The DCM extracts were washed 2× brine, dried over Na2SO4, filtered and concentrated to afford a thick dark residue. To the residue was added MeOH (500 mL) and the solvent was removed under reduced pressure until a precipitate formed. This solution was then heated to reflux with stirring and then allowed to cool slowly overnight. The following day, the mixture was filtered and washed with MeOH (100 mL) to give 44 g of an off white solid. The filtrate was concentrated and the process was repeated to give an additional 20 g. The resulting off white solids were a mixture of product, the acid of the product, and some unreacted starting material. The 44 g crop was dissolved in DCM (500 mL) and washed with 2N NaOH (400 mL). The DCM was separated and the aqueous layer extracted 2 times with DCM (100 ml). The combined DCM extracts were dried over Na2SO4 and concentrated under reduced pressure to afford a light yellow residue. The same procedure was repeated with the 20 g crop. This process removed the acid from the mixture. The first residue was dissolved in DCM (100 mL) and this mixture was heated to reflux and hexanes (500 mL) was added. The mixture was again heated to reflux making sure all the material was in solution. The solution was allowed to stir at reflux without a condenser. This reduced the amount of DCM in the solution allowing the product to crystallize. Once solid material began to appear in the solution, the solution was allowed to slowly cool to room temperature then filtered and washed with hexanes. The same procedure was repeated with the other residue. The two solids were combined in a 1 L flask and the DCM/Hex procedure was repeated. The filter cake was transferred into a 1 L flask and dried under reduced pressure to afford methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (53 g, 69% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.92 (d, J=8.03 Hz, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.78 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+).

Provenance & Evidence