阿法替尼杂质38

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate (13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole) were combined in a 250 mL round bottom flask with toluene (60 mL) and a magnetic stir-bar. The reaction was stirred at reflux with a Dean-Stark water trap. Reflux was stopped after 3 h. The product mixture was allowed to cool, and was then passed through a short pad of silica gel with methylene chloride, and concentrated in vacuo. Standing under high vacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanes overnight, then suction filtered to remove a solid impurity. The filtrate was concentrated, and put on high vacuum to afford an oil. The oil was chromatographed with hexanes, ethyl acetate (8:1), and put under high vacuum for 1 h to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1 Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 & J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5H), 10.21 (bs, 1H); MS(ES+): 319.99 (100) [MH+], 322.02 (30) [(M+2)H+]. Reflux to cool concentrated in vacuo Standing under high vacuum for 1 h afforded an oil suction filtered to remove a solid impurity The filtrate was concentrated to afford an oil The oil was chromatographed with hexanes, ethyl acetate (8:1) put under high vacuum for 1 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50 g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6 Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min). The resulting suspension was heated at reflux for 40 hours After cooling extracted with EtOAc (3×100 ml) The combined organics were washed with brine (2×100 ml) dried (MgSO4) filtered concentrated The crude product was dissolved in MeOH the product eluted with MeOH

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate (13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole) were combined in a 250 mL round bottom flask with toluene (60 mL) and a magnetic stir-bar. The reaction was stirred at reflux with a Dean-Stark water trap. Reflux was stopped after 3 h. The product mixture was allowed to cool, and was then passed through a short pad of silica gel with methylene chloride, and concentrated in vacuo. Standing under high vacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanes overnight, then suction filtered to remove a solid impurity. The filtrate was concentrated, and put on high vacuum to afford an oil. The oil was chromatographed with hexanes, ethyl acetate (8:1), and put under high vacuum for 1 h to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1 Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 & J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5 H), 10.21 (bs, 1H); MS (ES+): 319.99 (100) [MH+], 322.02 (30) [(M+2)H+]. Reflux to cool concentrated in vacuo Standing under high vacuum for 1 h afforded an oil suction filtered to remove a solid impurity The filtrate was concentrated to afford an oil The oil was chromatographed with hexanes, ethyl acetate (8:1) put under high vacuum for 1 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50 g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6 Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min). The resulting suspension was heated at reflux for 40 hours After cooling extracted with EtOAc (3×100 ml) The combined organics were washed with brine (2×100 ml) dried (MgSO4) filtered concentrated The crude product was dissolved in MeOH the product eluted with MeOH

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A room temperature solution of 2-fluoronicotinic acid (1 g) in DCM (20 mL) was sequentially treated with DMF (0.2 mL) and oxalyl chloride (0.62 mL, 1 eq). The resulting solution was stirred at RT for 1 hour and monitored by HPLC (analyte quenced with methanol) until the consumption of starting material was complete. The reaction mixture was cooled to 0° C. and sequentially treated with 2,3-difluoroaniline (1.4 g, 1.5 eq) and 2 mL of triethylamine. The reaction was warmed to RT and maintained for 3 additional hours, followed by washing the mixture with 2N HCl, saturated NaCl, and saturated NaHCO3 solution. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude 2-fluoro-N-(2,3-difluorophenyl)pyridine-3-carboxamide was dissolved in NMP (20 mL) and reacted with excess t-butylamine at 80° C. for 14 hours. After cooling to RT, the solution was poured into sat NaHCO3 solution. The resulting precipitate was collected by filtration and washed with water. The crude product, 2-(tert-butylamino)-N-(2,3-difluorophenyl)pyridine-3-carboxamide, was dried in vacuo and used directly in the next reaction without further purification. Using the same procedure, 2-(tert-butylamino)-N-(2,3-dichlorophenyl)pyridine-3-carboxamide and 2-(tert-butylamino)-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide can be produced from the reaction of 2-fluoronicotinic acid with 2,3-dichloroaniline and 3-chloro-2-fluoroaniline, respectively. monitored by HPLC (analyte quenced with methanol) until the consumption of starting material The reaction mixture was cooled to 0° C. The reaction was warmed to RT maintained for 3 additional hours by washing the mixture with 2N HCl, saturated NaCl, and saturated NaHCO3 solution The organic extracts were dried over MgSO4 filtered concentrated in vacuo The resulting crude 2-fluoro-N-(2,3-difluorophenyl)pyridine-3-carboxamide was dissolved in NMP (20 mL) reacted with excess t-butylamine at 80° C. for 14 hours After cooling to RT the solution was poured The resulting precipitate was collected by filtration washed with water The crude product, 2-(tert-butylamino)-N-(2,3-difluorophenyl)pyridine-3-carboxamide, was dried in vacuo used directly in the next reaction without further purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A room temperature solution of 2-fluoronicotinic acid (1 g) in DCM (20 mL) was sequentially treated with DMF (0.2 mL) and oxalyl chloride (0.62 mL, 1 eq). The resulting solution was stirred at RT for 1 hour and monitored by HPLC (analyte quenced with methanol) until the consumption of starting material was complete. The reaction mixture was cooled to 0° C. and sequentially treated with 2,3-difluoroaniline (1.4 g, 1.5 eq) and 2 mL of triethylamine. The reaction was warmed to RT and maintained for 3 additional hours, followed by washing the mixture with 2N HCl, saturated NaCl, and saturated NaHCO3 solution. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude 2-fluoro-N-(2,3-difluorophenyl)pyridine-3-carboxamide was dissolved in NMP (20 mL) and reacted with excess t-butylamine at 80° C. for 14 hours. After cooling to RT, the solution was poured into sat NaHCO3 solution. The resulting precipitate was collected by filtration and washed with water. The crude product, 2-(tert-butylamino)-N-(2,3-difluorophenyl)pyridine-3-carboxamide, was dried in vacuo and used directly in the next reaction without further purification. Using the same procedure, 2-(tert-butylamino)-N-(2,3-dichlorophenyl)pyridine-3-carboxamide and 2-(tert-butylamino)-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide can be produced from the reaction of 2-fluoronicotinic acid with 2,3-dichloroaniline and 3-chloro-2-fluoroaniline, respectively. monitored by HPLC (analyte quenced with methanol) until the consumption of starting material The reaction mixture was cooled to 0° C. The reaction was warmed to RT maintained for 3 additional hours by washing the mixture with 2N HCl, saturated NaCl, and saturated NaHCO3 solution The organic extracts were dried over MgSO4 filtered concentrated in vacuo The resulting crude 2-fluoro-N-(2,3-difluorophenyl)pyridine-3-carboxamide was dissolved in NMP (20 mL) reacted with excess t-butylamine at 80° C. for 14 hours After cooling to RT the solution was poured The resulting precipitate was collected by filtration washed with water The crude product, 2-(tert-butylamino)-N-(2,3-difluorophenyl)pyridine-3-carboxamide, was dried in vacuo used directly in the next reaction without further purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-aminopyrazine-2-carboxylic acid (2.0 g, 14.38 mmol) in anhydrous DMF (20 mL) was added 2,3-difluoroaniline (2.2 g, 17.04 mmol) and DIEA (7.6 mL, 43.63 mmol). The mixture was stirred at room temperature while PyBOP (7.5 g, 14.41 mmol) was added. The stirring was continued for another 14 hours until HPLC detected no starting material. The reaction solution was then poured into saturated sodium bicarbonate solution. The crude product was collected by vacuum filtration and washed with water. After drying on vacuum pump for 24 hours, the off-white product (2.9 g, 80%) was used directly in the next reaction without further purification. LC-MS m/e=250.8 (M+H); 1H-NMR (500 MHZ, DMSO-d6): 10.42 (s, 1H), 8.33 (d, 1H), 7.94 (d, 1H), 7.72 (m, 1H), 7.60 (br, 2H), 7.25 (m, 2H). Using the same procedure, 3-amino-N-(2,3-dichlorophenyl)pyrazine-2-carboxamide and 3-amino-N-(3-chloro-2-fluorophenyl)pyrazine-2-carboxamide can be produced by reacting 3-aminopyrazine-2-carboxylic acid with 2,3-dichloroaniline and 3-chloro-2-fluoroaniline, respectively. Analogously, this procedure can be used to produce 2-amino-N-(2,3-difluorophenyl)pyridine-3-carboxamide, 2-amino-N-(2,3-dichlorophenyl)pyridine-3-carboxamide, and 2-amino-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide by reacting 2-amino-pyridine-3-carboxylic acid with 2,3-difluoroaniline, 2,3-dichloroaniline, and 3-chloro-2-fluoroaniline, respectively.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-aminopyrazine-2-carboxylic acid (2.0 g, 14.38 mmol) in anhydrous DMF (20 mL) was added 2,3-difluoroaniline (2.2 g, 17.04 mmol) and DIEA (7.6 mL, 43.63 mmol). The mixture was stirred at room temperature while PyBOP (7.5 g, 14.41 mmol) was added. The stirring was continued for another 14 hours until HPLC detected no starting material. The reaction solution was then poured into saturated sodium bicarbonate solution. The crude product was collected by vacuum filtration and washed with water. After drying on vacuum pump for 24 hours, the off-white product (2.9 g, 80%) was used directly in the next reaction without further purification. LC-MS m/e=250.8 (M+H); 1H-NMR (500 MHZ, DMSO-d6): 10.42 (s, 1H), 8.33 (d, 1H), 7.94 (d, 1H), 7.72 (m, 1H), 7.60 (br, 2H), 7.25 (m, 2H). Using the same procedure, 3-amino-N-(2,3-dichlorophenyl)pyrazine-2-carboxamide and 3-amino-N-(3-chloro-2-fluorophenyl)pyrazine-2-carboxamide can be produced by reacting 3-aminopyrazine-2-carboxylic acid with 2,3-dichloroaniline and 3-chloro-2-fluoroaniline, respectively. Analogously, this procedure can be used to produce 2-amino-N-(2,3-difluorophenyl)pyridine-3-carboxamide, 2-amino-N-(2,3-dichlorophenyl)pyridine-3-carboxamide, and 2-amino-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide by reacting 2-amino-pyridine-3-carboxylic acid with 2,3-difluoroaniline, 2,3-dichloroaniline, and 3-chloro-2-fluoroaniline, respectively.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate (13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole) were combined in a 250 mL round bottom flask with toluene (60 mL) and a magnetic stir-bar. The reaction was stirred at reflux with a Dean-Stark water trap. Reflux was stopped after 3 h. The product mixture was allowed to cool, and was then passed through a short pad of silica gel with methylene chloride, and concentrated in vacuo. Standing under high vacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanes overnight, then suction filtered to remove a solid impurity. The filtrate was concentrated, and put on high vacuum to afford an oil. The oil was chromatographed with hexanes, ethyl acetate (8:1), and put under high vacuum for 1 h to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1 Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 & J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5H), 10.21 (bs, 1H); MS (ES+): 319.99 (100) [MH+], 322.02 (30) [(M+2)H+]. Reflux to cool concentrated in vacuo Standing under high vacuum for 1 h afforded an oil suction filtered to remove a solid impurity The filtrate was concentrated to afford an oil The oil was chromatographed with hexanes, ethyl acetate (8:1) put under high vacuum for 1 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate (13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole) were combined in a 250 mL round bottom flask with toluene (60 mL) and a magnetic stir-bar. The reaction was stirred at reflux with a Dean-Stark water trap. Reflux was stopped after 3 h. The product mixture was allowed to cool, and was then passed through a short pad of silica gel with methylene chloride, and concentrated in vacuo. Standing under high vacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanes overnight, then suction filtered to remove a solid impurity. The filtrate was concentrated, and put on high vacuum to afford an oil. The oil was chromatographed with hexanes, ethyl acetate (8:1), and put under high vacuum for 1 h to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1 Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 & J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5H), 10.21 (bs, 1H); MS (ES+): 319.99 (100) [MH+], 322.02 (30) [(M+2)H+]. Reflux to cool concentrated in vacuo Standing under high vacuum for 1 h afforded an oil suction filtered to remove a solid impurity The filtrate was concentrated to afford an oil The oil was chromatographed with hexanes, ethyl acetate (8:1) put under high vacuum for 1 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50 g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6 Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min). The resulting suspension was heated at reflux for 40 hours After cooling extracted with EtOAc (3×100 ml) The combined organics were washed with brine (2×100 ml) dried (MgSO4) filtered concentrated The crude product was dissolved in MeOH the product eluted with MeOH