methyl 2-[methyl(phenyl)sulfamoyl]acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium tert-butoxide (47.4 g, 493 mmol) was added in one portion to a 1 L flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (40.0 g, 164 mmol) and dissolved in dioxane (658 ml) at 0° C. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (52.7 g, 164 mmol) was added followed by palladium(II) acetate (1.846 g, 8.22 mmol) and tri-t-butylphosphonium tetrafluoroborate (7.16 g, 24.66 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction flask was cooled to 50° C., 1M NaOH (500 mL) was added and the solution was stirred for 1 h. Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) and extracted with dichloromethane (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/Hexanes gradient) to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (m, 1H); 8.17 (s, 1H); 7.81 (s, 2H); 7.47 (d, 1H); 7.32 (m, 5H); 7.21 (m, 1H); 4.75 (s, 2H); 3.24 (s, 3H). LRMS (APCI) calculated for C22H18ClN2O3S [M+H]+, 425.1; found 425.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction flask was cooled to 50° C. 1M NaOH (500 mL) was added the solution was stirred for 1 h Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) extracted with dichloromethane (3×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (EtOAc/Hexanes gradient)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium tert-butoxide (8.99 g, 94 mmol) was added in one portion to a 250 mL flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (7.59 g, 31.2 mmol) and dioxane (125 ml) at room temperature. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10.00 g, 31.2 mmol) was added followed by palladium(II) acetate (0.350 g, 1.560 mmol) and tri-t-butylphosphonium tetrafluoroborate (1.358 g, 4.68 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction mixture was cooled to room temperature, acidified with 1N HCl (100 mL), basified with saturated aqueous sodium hydrogen carbonate (400 mL) and extracted with dichloromethane (3×250 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow foam. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.46 (d, 1H); 8.42 (d, 1H); 8.03 (dd, 1H); 7.81 (d, 1H); 7.44 (d, 1H); 7.33 (d, 1H); 7.22 (m, 2H); 7.17 (m, 2H); 7.11 (m, 1H); 6.10 (s, 1H); 3.71 (s, 3H); 3.20 (s, 3H). LRMS (APCI) calculated for C24H20ClN2O5S [M+H]+, 483.1; found 483.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction mixture was cooled to room temperature extracted with dichloromethane (3×250 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient)

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

Procedure: Chlorine gas was passed through a suspension of 230 g of ice, CH2Cl2 (457 ml) and methyl thioglycolate (86 ml, 942 mmol), cooling with an ice/water bath to maintain an internal temperature below 30° C. After approximately six hours, the yellow/green color of the dissolved chlorine persisted for 30 minutes after gas flow was stopped and passing additional chlorine gas was no longer exothermic. The cooling bath was then removed and the biphasic mixture was allowed to stir at ambient temperature for 1 h before being sparged with nitrogen for 20 minutes. The layers were then separated and the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the intermediate methyl (chlorosulfonyl)acetate (160 g, 927 mmol) as a yellow oil. A portion of the intermediate methyl (chlorosulfonyl)acetate (100 g, 579 mmol) was added dropwise as a solution in CH2Cl2 (290 ml) to a stirring −15° C. solution of N-methylaniline (124 g, 1159 mmol) dissolved in CH2Cl2 (290 ml). The rate of addition was adjusted to maintain the internal temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over the course of 2 h and 1 M HCl (1000 mL) was added and the aqueous phase was extracted with dichloromethane (2×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was seed crystallized to afford a brown solid. Recrystallization from hot ethanol (320 mL) provided the title compound as an off-white solid. 1H NMR (600 MHz, DMSO-D6) δ 7.40 (m, 4H); 7.31 (m, 1H); 4.30 (s, 2H); 3.65 (s, 3H); 3.26 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 244.1; found 244.0. The rate of addition to maintain the internal temperature below 5° C After the addition was added the aqueous phase was extracted with dichloromethane (2×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure crystallized to afford a brown solid Recrystallization from hot ethanol (320 mL)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium tert-butoxide (47.4 g, 493 mmol) was added in one portion to a 1 L flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (40.0 g, 164 mmol) and dissolved in dioxane (658 ml) at 0° C. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (52.7 g, 164 mmol) was added followed by palladium(II) acetate (1.846 g, 8.22 mmol) and tri-t-butylphosphonium tetrafluoroborate (7.16 g, 24.66 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction flask was cooled to 50° C., 1M NaOH (500 mL) was added and the solution was stirred for 1 h. Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) and extracted with dichloromethane (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/Hexanes gradient) to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (m, 1H); 8.17 (s, 1H); 7.81 (s, 2H); 7.47 (d, 1H); 7.32 (m, 5H); 7.21 (m, 1H); 4.75 (s, 2H); 3.24 (s, 3H). LRMS (APCI) calculated for C22H18ClN2O3S [M+H]+, 425.1; found 425.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction flask was cooled to 50° C. 1M NaOH (500 mL) was added the solution was stirred for 1 h Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) extracted with dichloromethane (3×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (EtOAc/Hexanes gradient)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium tert-butoxide (8.99 g, 94 mmol) was added in one portion to a 250 mL flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (7.59 g, 31.2 mmol) and dioxane (125 ml) at room temperature. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10.00 g, 31.2 mmol) was added followed by palladium(II) acetate (0.350 g, 1.560 mmol) and tri-t-butylphosphonium tetrafluoroborate (1.358 g, 4.68 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction mixture was cooled to room temperature, acidified with 1N HCl (100 mL), basified with saturated aqueous sodium hydrogen carbonate (400 mL) and extracted with dichloromethane (3×250 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow foam. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.46 (d, 1H); 8.42 (d, 1H); 8.03 (dd, 1H); 7.81 (d, 1H); 7.44 (d, 1H); 7.33 (d, 1H); 7.22 (m, 2H); 7.17 (m, 2H); 7.11 (m, 1H); 6.10 (s, 1H); 3.71 (s, 3H); 3.20 (s, 3H). LRMS (APCI) calculated for C24H20ClN2O5S [M+H]+, 483.1; found 483.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction mixture was cooled to room temperature extracted with dichloromethane (3×250 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium tert-butoxide (8.99 g, 94 mmol) was added in one portion to a 250 mL flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (7.59 g, 31.2 mmol) and dioxane (125 ml) at room temperature. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10.00 g, 31.2 mmol) was added followed by palladium(II) acetate (0.350 g, 1.560 mmol) and tri-t-butylphosphonium tetrafluoroborate (1.358 g, 4.68 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction mixture was cooled to room temperature, acidified with 1N HCl (100 mL), basified with saturated aqueous sodium hydrogen carbonate (400 mL) and extracted with dichloromethane (3×250 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow foam. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.46 (d, 1H); 8.42 (d, 1H); 8.03 (dd, 1H); 7.81 (d, 1H); 7.44 (d, 1H); 7.33 (d, 1H); 7.22 (m, 2H); 7.17 (m, 2H); 7.11 (m, 1H); 6.10 (s, 1H); 3.71 (s, 3H); 3.20 (s, 3H). LRMS (APCI) calculated for C24H20ClN2O5S [M+H]+, 483.1; found 483.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction mixture was cooled to room temperature extracted with dichloromethane (3×250 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient)

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

Procedure: Chlorine gas was passed through a suspension of 230 g of ice, CH2Cl2 (457 ml) and methyl thioglycolate (86 ml, 942 mmol), cooling with an ice/water bath to maintain an internal temperature below 30° C. After approximately six hours, the yellow/green color of the dissolved chlorine persisted for 30 minutes after gas flow was stopped and passing additional chlorine gas was no longer exothermic. The cooling bath was then removed and the biphasic mixture was allowed to stir at ambient temperature for 1 h before being sparged with nitrogen for 20 minutes. The layers were then separated and the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the intermediate methyl (chlorosulfonyl)acetate (160 g, 927 mmol) as a yellow oil. A portion of the intermediate methyl (chlorosulfonyl)acetate (100 g, 579 mmol) was added dropwise as a solution in CH2Cl2 (290 ml) to a stirring −15° C. solution of N-methylaniline (124 g, 1159 mmol) dissolved in CH2Cl2 (290 ml). The rate of addition was adjusted to maintain the internal temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over the course of 2 h and 1 M HCl (1000 mL) was added and the aqueous phase was extracted with dichloromethane (2×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was seed crystallized to afford a brown solid. Recrystallization from hot ethanol (320 mL) provided the title compound as an off-white solid. 1H NMR (600 MHz, DMSO-D6) δ 7.40 (m, 4H); 7.31 (m, 1H); 4.30 (s, 2H); 3.65 (s, 3H); 3.26 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 244.1; found 244.0. The rate of addition to maintain the internal temperature below 5° C After the addition was added the aqueous phase was extracted with dichloromethane (2×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure crystallized to afford a brown solid Recrystallization from hot ethanol (320 mL)

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

Procedure: Chlorine gas was passed through a suspension of 230 g of ice, CH2Cl2 (457 ml) and methyl thioglycolate (86 ml, 942 mmol), cooling with an ice/water bath to maintain an internal temperature below 30° C. After approximately six hours, the yellow/green color of the dissolved chlorine persisted for 30 minutes after gas flow was stopped and passing additional chlorine gas was no longer exothermic. The cooling bath was then removed and the biphasic mixture was allowed to stir at ambient temperature for 1 h before being sparged with nitrogen for 20 minutes. The layers were then separated and the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the intermediate methyl (chlorosulfonyl)acetate (160 g, 927 mmol) as a yellow oil. A portion of the intermediate methyl (chlorosulfonyl)acetate (100 g, 579 mmol) was added dropwise as a solution in CH2Cl2 (290 ml) to a stirring −15° C. solution of N-methylaniline (124 g, 1159 mmol) dissolved in CH2Cl2 (290 ml). The rate of addition was adjusted to maintain the internal temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over the course of 2 h and 1 M HCl (1000 mL) was added and the aqueous phase was extracted with dichloromethane (2×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was seed crystallized to afford a brown solid. Recrystallization from hot ethanol (320 mL) provided the title compound as an off-white solid. 1H NMR (600 MHz, DMSO-D6) δ 7.40 (m, 4H); 7.31 (m, 1H); 4.30 (s, 2H); 3.65 (s, 3H); 3.26 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 244.1; found 244.0. The rate of addition to maintain the internal temperature below 5° C After the addition was added the aqueous phase was extracted with dichloromethane (2×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure crystallized to afford a brown solid Recrystallization from hot ethanol (320 mL)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a mixture of methyl {[methyl(phenyl)amino]sulfonyl}acetate (1021 mg, 4.20 mmol) and 1,6-dichloropyrido[4,3-c]-1,6-naphthyridine (350 mg, 1.400 mmol) in toluene (14.0 mL) at 0° C., LHMDS (4.20 mL, 4.20 mmol, 1 M in THF) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 5 h. The reaction mixture was then heated to 50° C. for 1 h. The reaction mixture was then stirred at room temperature for 72 h. To the reaction mixture, LHMDS (1.400 mL, 1.400 mmol, 1 M in THF) was added, and the reaction was stirred at room temperature overnight. This mixture was poured into aqueous ammonium chloride (saturated). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were filtered through a frit, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford 1-(1-chloropyrido[4,3-c]-1,6-naphthyridin-6-yl)-N-methyl-N-phenylmethanesulfonamide as a brown solid. LRMS (APCI) calc'd for (C19H16ClN4O2S) [M+H]+, 399.1; found 399.0. The reaction mixture was then heated to 50° C. for 1 h The reaction mixture was then stirred at room temperature for 72 h the reaction was stirred at room temperature overnight The aqueous layer was extracted with ethyl acetate The combined organic extracts were filtered through a frit dried over sodium sulfate concentrated under reduced pressure The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexanes

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium tert-butoxide (47.4 g, 493 mmol) was added in one portion to a 1 L flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (40.0 g, 164 mmol) and dissolved in dioxane (658 ml) at 0° C. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (52.7 g, 164 mmol) was added followed by palladium(II) acetate (1.846 g, 8.22 mmol) and tri-t-butylphosphonium tetrafluoroborate (7.16 g, 24.66 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction flask was cooled to 50° C., 1M NaOH (500 mL) was added and the solution was stirred for 1 h. Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) and extracted with dichloromethane (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/Hexanes gradient) to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (m, 1H); 8.17 (s, 1H); 7.81 (s, 2H); 7.47 (d, 1H); 7.32 (m, 5H); 7.21 (m, 1H); 4.75 (s, 2H); 3.24 (s, 3H). LRMS (APCI) calculated for C22H18ClN2O3S [M+H]+, 425.1. found 425.0. The resulting suspension was degassed by sparging with nitrogen for 30 min left Then, the reaction flask was cooled to 50° C. 1M NaOH (500 mL) was added the solution was stirred for 1 h Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) extracted with dichloromethane (3×500 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (EtOAc/Hexanes gradient)