2-chloro-5-iodobenzoyl chloride

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-5-iodobenzoyl chloride (0.159 g, 0.528 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.019 g (22% yield) of pure product: MS (ES) m/z 570 (M+1). Upon cooling the mixture was poured onto a biotage prepak column the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient)

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to −7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (<0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1 N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area % by HPLC at 220 nm, 1.0 area % regioisomer at 200 nm, 98.5% “as-is” yield). temperature below 9° C was cooled to −7° C the internal temperature below +3° C The reaction mixture was warmed slightly the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask This quench was done in portions over 10 min with internal temperature remaining below 28° C The quenched biphasic mixture was stirred at 20° C. for 45 min the lower organic phase was washed with 1 N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash) The washed extract was concentrated on a rotary evaporator to afford

Conditions: temp:6.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to −7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (<0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1 N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area % by HPLC at 220 nm, 1.0 area % regioisomer at 200 nm, 98.5% “as-is” yield). temperature below 9° C was cooled to −7° C the internal temperature below +3° C The reaction mixture was warmed slightly the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask This quench was done in portions over 10 min with internal temperature remaining below 28° C The quenched biphasic mixture was stirred at 20° C. for 45 min the lower organic phase was washed with 1 N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash) The washed extract was concentrated on a rotary evaporator to afford

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

Procedure: A 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with 2-chloro-5-iodobenzoic acid (199.41 g, 0.706 mol), dichloromethane (1.2 L, KF=0.003 wt % water) and the suspension was set stirring at ambient temperature. Then N,N-dimethylformamide (0.6 mL, 1.1 mol %) was added followed by oxalyl chloride (63 mL, 0.722 mol, 1.02 equiv) which was added over 11 min. The reaction was allowed to stir at ambient overnight and became a solution. After 18.75 hours, additional oxalyl chloride (6 mL, 0.069 mol, 0.10 equiv) was added to consume unreacted starting material. After 2 hours, the reaction mixture was concentrated in vacuo to afford crude 2-chloro-5-iodobenzoyl chloride as a pale yellow foam which will be carried forward to the next step. was added over 11 min to stir at ambient overnight to consume unreacted After 2 hours the reaction mixture was concentrated in vacuo

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H). To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 0° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (20 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was dissolved in absolute ethanol (45 mL) refluxed with mechanical stirring (100 RPM) cooled to 0° C After stirring for another 16 h at 0˜5° C. the mixture was filtered the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL) dried under vacuum at 40° C. for 12 h

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser was added ethoxybenzene (6.4 g, 52.5 mmol) and dichloromethane (19.2 mL) and the mixture was cooled to −5° C. Aluminum (III) chloride (7.4 g, 55 mmol) was added over 1 h while maintaining the internal temperature below 0° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 50 mmol) in dichloromethane (21 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. Polymethylhydrosiloxane (PMHS) (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (50 mL) was added slowly dropwise over 1 hour with stirring. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (20 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was dissolved in absolute ethanol (45 mL) and refluxed with mechanical stirring (100 RPM) and cooled to 0° C. After stirring for another 16 h at 0˜5° C., the mixture was filtered and the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL), dried under vacuum at 40° C. for 12 h to give 14.2 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. This solid was recrystallized from ethanol (42.6 mL) to give 12.5 g of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a white solid. Yield, 67%, HPLC purity, HPLC-0002: 99.5%. 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H). To a 250 mL of 4-necked flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 0° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (20 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was dissolved in absolute ethanol (45 mL) refluxed with mechanical stirring (100 RPM) cooled to 0° C After stirring for another 16 h at 0˜5° C. the mixture was filtered the filter cake was washed with pre-cooled (0˜5° C.) ethanol (2×5 mL) dried under vacuum at 40° C. for 12 h

Conditions: temp:12.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 L 4-necked flask equipped with thermometer and mechanical stirrer (operating at 150 RPM) was charged with 2-chloro-5-iodobenzoic acid (14.1 g, 0.05 mol), DCM (70.5 mL) and oxalyl chloride (5.5 mL, 0.06 mol). After stirring for 10 min, the mixture was cooled to 10 to 15° C. and DMF (0.15 mL, 1.92 mmol) was added by syringe over 10 min in two bolus of 0.1 and 0.05 mL while keeping the reaction temperature below 20° C. After the addition was completed, the mixture was warmed to 25° C. and stirred for 16 h. The mixture was concentrated and the residue was dried under vacuum at 30° C. for 5 h to give 15.0 g of product as a white solid. Yield: 100%. LCMS-0013: 99% Purity. 1H NMR (CDCl3, 400 MHz): 8.33 (d, J=2.4 Hz, 1H), 7.81˜7.84 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H). A 1 L 4-necked flask equipped with thermometer and mechanical stirrer (operating at 150 RPM) the reaction temperature below 20° C After the addition the mixture was warmed to 25° C. stirred for 16 h The mixture was concentrated the residue was dried under vacuum at 30° C. for 5 h

Conditions: temp:-3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL of 4-neck flask equipped with an internal thermometer and a condenser were added anisole (5.7 g, 52.0 mmol) and dichloromethane (17 mL) and the mixture was cooled to −3° C. Aluminum (III) chloride (7.4 g, 55.0 mmol) was added to the above solution over 1 h while maintaining the internal temperature below 5° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 0.05 mol) in dichloromethane (15 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. PMHS (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (100 mL) was added slowly dropwise over 1 hour with stirring. Note: A severe exotherm would occur upon addition of the first portion of water. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (30 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was recrystallized from absolute ethanol (58 mL) to give 12.0 g of 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene as a white solid (yield, 67%, HPLC-0002: 98.7%). Note: The purity can be increased by doing a second recrystallization of 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene, HPLC purity could be up to 99.5% with 75˜80% yield. 1H NMR (CDCl3, 400 MHz): δ 7.50 (d, J=8.4 Hz, 2H), 7.10˜7.13 (m, 3H), 6.88 (d, J=8.4 Hz, 2H), 4.00 (s, 2H), 3.82 (s, 3H). MS ESI (m/z): 357 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 158.3, 141.5, 139.5, 136.6, 134.2, 131.2, 130.6, 129.9, 114.1, 91.71, 55.29, 38.09. A 250 mL of 4-neck flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 5° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (30 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was recrystallized from absolute ethanol (58 mL) to give

Conditions: temp:-3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL of 4-neck flask equipped with an internal thermometer and a condenser were added anisole (5.7 g, 52.0 mmol) and dichloromethane (17 mL) and the mixture was cooled to −3° C. Aluminum (III) chloride (7.4 g, 55.0 mmol) was added to the above solution over 1 h while maintaining the internal temperature below 5° C. After the addition was completed, the mixture was stirred for 30 min at 0˜5° C., and a solution of 2-chloro-5-iodobenzoyl chloride (15.0 g, 0.05 mol) in dichloromethane (15 mL) was added dropwise over 1 hour while maintaining the internal temperature below 5° C. The mixture was stirred for another 1 hour at 0˜5° C. and warmed to 10˜15° C. PMHS (15.0 g, 0.25 mol) was added dropwise while maintaining the internal temperature below 25° C. After stirring for 10 hours at 25° C., additional PMHS (9.0 g, 0.15 mol) was added to the above mixture. After stirring for another 16 hours at 30° C., the mixture was cooled to 5˜10° C. and ice water (100 mL) was added slowly dropwise over 1 hour with stirring. Note: A severe exotherm would occur upon addition of the first portion of water. The mixture was filtered and the filter cake was slurried with dichloromethane (100 mL) containing diatomite (30 g). The mixture was filtered and the filter cake was washed with dichloromethane (2×50 mL). The combined organic layers were washed with brine (100 mL). After removal of the volatiles, the residue was recrystallized from absolute ethanol (58 mL) to give 12.0 g of 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene as a white solid (yield, 67%, HPLC-0002: 98.7%). Note: The purity can be increased by doing a second recrystallization of 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene, HPLC purity could be up to 99.5% with 75˜80% yield. 1H NMR (CDCl3, 400 MHz): δ 7.50 (d, J=8.4 Hz, 2H), 7.10˜7.13 (m, 3H), 6.88 (d, J=8.4 Hz, 2H), 4.00 (s, 2H), 3.82 (s, 3H). MS ESI (m/z): 357 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 158.3, 141.5, 139.5, 136.6, 134.2, 131.2, 130.6, 129.9, 114.1, 91.71, 55.29, 38.09. A 250 mL of 4-neck flask equipped with an internal thermometer and a condenser while maintaining the internal temperature below 5° C After the addition while maintaining the internal temperature below 5° C The mixture was stirred for another 1 hour at 0˜5° C. warmed to 10˜15° C while maintaining the internal temperature below 25° C After stirring for 10 hours at 25° C. After stirring for another 16 hours at 30° C. the mixture was cooled to 5˜10° C. with stirring The mixture was filtered containing diatomite (30 g) The mixture was filtered the filter cake was washed with dichloromethane (2×50 mL) The combined organic layers were washed with brine (100 mL) After removal of the volatiles the residue was recrystallized from absolute ethanol (58 mL) to give

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

Procedure: 2-chloro-5-iodobenzoyl chloride (10.7 g, 35.5 mmol) was dissolved in methylene chloride (200 mL). The resulting mixture was cooled in an ice-water bath. To the mixture was added aluminum trichloride (10.4 g, 78.2 mmol), and then added dropwise a solution of anisole (4.2 g, 38.9 mmol) in methylene chloride (50 mL). After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 3 hr. The reaction mixture was poured into ice-water and quenched. To the reaction mixture was added 3 mol/L hydrochloric acid. The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL×2). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 12.0 g of a product in a yield of 91%. The resulting mixture was cooled in an ice-water bath After the completion of dropwise addition quenched To the reaction mixture was added 3 mol/L hydrochloric acid The resulting mixture was separated into an aqueous phase The aqueous phase was extracted with methylene chloride (150 mL×2) washed with a saturated sodium chloride solution dried over anhydrous sodium sulphate concentrated under a reduced pressure The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100)

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

Procedure: 2-chloro-5-iodobenzoyl chloride (10.7 g, 35.5 mmol) was dissolved in methylene chloride (200 mL). The resulting mixture was cooled in an ice-water bath. To the mixture was added aluminum trichloride (10.4 g, 78.2 mmol), and then added dropwise a solution of anisole (4.2 g, 38.9 mmol) in methylene chloride (50 mL). After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 3 hr. The reaction mixture was poured into ice-water and quenched. To the reaction mixture was added 3 mol/L hydrochloric acid. The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL×2). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100) to produce 12.0 g of a product in a yield of 91%. The resulting mixture was cooled in an ice-water bath After the completion of dropwise addition quenched To the reaction mixture was added 3 mol/L hydrochloric acid The resulting mixture was separated into an aqueous phase The aqueous phase was extracted with methylene chloride (150 mL×2) washed with a saturated sodium chloride solution dried over anhydrous sodium sulphate concentrated under a reduced pressure The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:100)

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

Procedure: 2-chloro-5-iodobenzoic acid (10.0 g, 35.5 mmol) was suspended in methylene chloride (200 mL). To the resulting mixture was added N,N-dimethylformamide (0.05 mL), and then added dropwise oxalyl chloride (11.3 g, 89.0 mmol) at 0° C. After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 4 hr. The resulting clear solution was evaporated by rotation to remove the solvent and produce 10.7 g of a product in a yield of 100%, which was directly used in the next reaction without purification. After the completion of dropwise addition The resulting clear solution was evaporated by rotation to remove the solvent