sodium;propane-2-sulfinate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (10.0 g, 22.01 mmol) in dimethyl sulfoxide (200 mL) was added copper(I) iodide (8.39 g, 44.0 mmol) and sodium isopropanesulfinate (5.73 g, 44.0 mmol). The mixture was evacuated, purged with N2 three times, and heated at 120° C. overnight. The mixture was cooled to room temperature, treated with iodomethane (4.13 mL, 66.0 mmol), and stirred for 1 h. The reaction mixture was diluted with methylene chloride (150 mL) and water (150 mL), stirred for 30 min, and filtered through Celite®. The filtrate was extracted with methylene chloride, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride) to give methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.55 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.91 (s, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.84 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+). The mixture was evacuated purged with N2 three times The mixture was cooled to room temperature stirred for 30 min filtered through Celite® The filtrate was extracted with methylene chloride the organic phase was washed with brine dried over Na2SO4 filtered concentrated The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (10.0 g, 22.01 mmol) in dimethyl sulfoxide (200 mL) was added copper(I) iodide (8.39 g, 44.0 mmol) and sodium isopropanesulfinate (5.73 g, 44.0 mmol). The mixture was evacuated, purged with N2 three times, and heated at 120° C. overnight. The mixture was cooled to room temperature, treated with iodomethane (4.13 mL, 66.0 mmol), and stirred for 1 h. The reaction mixture was diluted with methylene chloride (150 mL) and water (150 mL), stirred for 30 min, and filtered through Celite®. The filtrate was extracted with methylene chloride, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride) to give methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.55 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.91 (s, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.84 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+). The mixture was evacuated purged with N2 three times The mixture was cooled to room temperature stirred for 30 min filtered through Celite® The filtrate was extracted with methylene chloride the organic phase was washed with brine dried over Na2SO4 filtered concentrated The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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+). The mixture was evacuated purged with N2 three times cooled to 65° C then cooled to room temperature After stirring for 1 h by vigorous stirring for 30 min The mixture was then filtered over celite washed with DCM The two layers were separated the aqueous layer was extracted twice with DCM The DCM extracts were washed 2× brine dried over Na2SO4 filtered concentrated to afford a thick dark residue the solvent was removed under reduced pressure until a precipitate formed This solution was then heated to reflux with stirring to cool slowly overnight The following day, the mixture was filtered washed with MeOH (100 mL) to give 44 g of an off white solid The filtrate was concentrated to give an additional 20 g a mixture of product washed with 2N NaOH (400 mL) The DCM was separated the aqueous layer extracted 2 times with DCM (100 ml) The combined DCM extracts were dried over Na2SO4 concentrated under reduced pressure to afford a light yellow residue This process removed the acid from the mixture The first residue was dissolved in DCM (100 mL) this mixture was heated to reflux hexanes (500 mL) was added The mixture was again heated to reflux to stir at reflux without a condenser to crystallize to slowly cool to room temperature then filtered washed with hexanes The two solids were combined in a 1 L flask The filter cake was transferred into a 1 L flask dried under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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+). The mixture was evacuated purged with N2 three times cooled to 65° C then cooled to room temperature After stirring for 1 h by vigorous stirring for 30 min The mixture was then filtered over celite washed with DCM The two layers were separated the aqueous layer was extracted twice with DCM The DCM extracts were washed 2× brine dried over Na2SO4 filtered concentrated to afford a thick dark residue the solvent was removed under reduced pressure until a precipitate formed This solution was then heated to reflux with stirring to cool slowly overnight The following day, the mixture was filtered washed with MeOH (100 mL) to give 44 g of an off white solid The filtrate was concentrated to give an additional 20 g a mixture of product washed with 2N NaOH (400 mL) The DCM was separated the aqueous layer extracted 2 times with DCM (100 ml) The combined DCM extracts were dried over Na2SO4 concentrated under reduced pressure to afford a light yellow residue This process removed the acid from the mixture The first residue was dissolved in DCM (100 mL) this mixture was heated to reflux hexanes (500 mL) was added The mixture was again heated to reflux to stir at reflux without a condenser to crystallize to slowly cool to room temperature then filtered washed with hexanes The two solids were combined in a 1 L flask The filter cake was transferred into a 1 L flask dried under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (10.0 g, 22.01 mmol) in dimethyl sulfoxide (200 mL) was added copper(I) iodide (8.39 g, 44.0 mmol) and sodium isopropanesulfinate (5.73 g, 44.0 mmol). The mixture was evacuated, purged with N2 three times, and heated at 120° C. overnight. The mixture was cooled to room temperature, treated with iodomethane (4.13 mL, 66.0 mmol), and stirred for 1 h. The reaction mixture was diluted with methylene chloride (150 mL) and water (150 mL), stirred for 30 min, and filtered through Celite®. The filtrate was extracted with methylene chloride, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride) to give methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.55 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.91 (s, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.84 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+). The mixture was evacuated purged with N2 three times The mixture was cooled to room temperature stirred for 30 min filtered through Celite® The filtrate was extracted with methylene chloride the organic phase was washed with brine dried over Na2SO4 filtered concentrated The material was purified via column chromatography (ISCO, 0-30% ethyl acetate/methylene chloride)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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+). The mixture was evacuated purged with N2 three times cooled to 65° C then cooled to room temperature After stirring for 1 h by vigorous stirring for 30 min The mixture was then filtered over celite washed with DCM The two layers were separated the aqueous layer was extracted twice with DCM The DCM extracts were washed 2× brine dried over Na2SO4 filtered concentrated to afford a thick dark residue the solvent was removed under reduced pressure until a precipitate formed This solution was then heated to reflux with stirring to cool slowly overnight The following day, the mixture was filtered washed with MeOH (100 mL) to give 44 g of an off white solid The filtrate was concentrated to give an additional 20 g a mixture of product washed with 2N NaOH (400 mL) The DCM was separated the aqueous layer extracted 2 times with DCM (100 ml) The combined DCM extracts were dried over Na2SO4 concentrated under reduced pressure to afford a light yellow residue This process removed the acid from the mixture The first residue was dissolved in DCM (100 mL) this mixture was heated to reflux hexanes (500 mL) was added The mixture was again heated to reflux to stir at reflux without a condenser to crystallize to slowly cool to room temperature then filtered washed with hexanes The two solids were combined in a 1 L flask The filter cake was transferred into a 1 L flask dried under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of sodium isopropylsulfinate (3.3 g) and N-methyl-2-pyrrolidinone (20 mL), 2,3-dichloronitrobenzene (4 g) was added and stirred overnight at 70° C. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration and washed with diethyl ether to give 3-chloro-2-isopropylsulfonyl-1-nitrobenzene (3.0 g) as a white solid. was added the precipitated solid was collected by filtration washed with diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluorobenzaldehyde and by replacing methane sulfinic acid sodium salt with 2-propanesulfinic acid sodium salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluorobenzaldehyde and by replacing methane sulfinic acid sodium salt with 2-propanesulfinic acid sodium salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluorobenzaldehyde and by replacing methane sulfinic acid sodium salt with 2-propane sulfinic acid sodium salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluorobenzaldehyde and by replacing methane sulfinic acid sodium salt with 2-propane sulfinic acid sodium salt.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluorobenzaldehyde and by replacing methane sulfinic acid sodium salt with 2-propane sulfinic acid sodium salt.