吉非替尼杂质44

反应条件: temp:0.00; pressure:0.00; stir:

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: N-(2-bromo-4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide: 2,2,2-trifluoroacetic anhydride (5.77 mL, 41.2 mmol) was added dropwise to a stirring mixture of sodium carbonate (6.19 g, 58.4 mmol) and 4-chloro-3-fluoroaniline (5.0 g, 34.3 mmol) in Et2O (50 mL) at −10° C. After 1 h, hexane (30 mL) was added and the reaction mixture filtered. The filtrate was washed with ice-water, 10% aq. NaHCO3 solution, and then brine. The organic phase was treated with activated charcoal, dried over sodium sulfate, filtered through a plug of Celite®, and concentrated to give N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide as a white solid. A solution of tert-Butyllithium (1.7M in pentane) (40.4 mL, 68.7 mmol) was added dropwise to N,N,N′,N′-tetramethylethylenediamine (10.37 mL, 68.7 mmol) in THF (60 mL) at −78° C. After 1 h, N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide in THF (40 mL) was added drop-wise to this yellow solution. After stirring for an additional hour, bromine (2.12 mL, 41.2 mmol) was slowly added and the complete mixture stirred for 1.5 h before quenching and neutralized with 1.0N HCl solution (final pH ˜6-7). The mixture was brought to rt, treated with brine (100 mL), and THF evaporated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with water, saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and dry-loaded onto silica gel. Purification by flash chromatography (120 g column; (hexane/EtOAc solvent system) gave Intermediate 7A (3.95 g, 36%) as a slowly solidifying tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.42 (1H, br. s.), 8.13 (1H, dd, J=9.09, 1.77 Hz), 7.43-7.49 (1H, m) ppm. the reaction mixture filtered The filtrate was washed with ice-water, 10% aq. NaHCO3 solution The organic phase was treated with activated charcoal dried over sodium sulfate filtered through a plug of Celite® concentrated

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: To a solution of 96 ml of 3-fluoroaniline in 1000 ml of dichloromethane, 147 g of N-chlorosuccinimide was added at 0° C. and stirred for 12 hours at room temperature. Water was added to the reaction solution which then was extracted with chloroform. The extract was washed with saturated brine, dried on anhydrous sodium sulfate and distilled. The residue was separated and purified on silica gel column chromatography (hexane/ethyl acetate=5/1) to provide 21 g of the title compound as a yellow solid. then was extracted with chloroform The extract was washed with saturated brine dried on anhydrous sodium sulfate distilled The residue was separated purified on silica gel column chromatography (hexane/ethyl acetate=5/1)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H2O was added NaHCO3 (21.6 g, 0.25 mmol). After cooling to 0° C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8 g of iodine was added and the reaction was stirred overnight. The reaction was extracted with DCM (4×250 mL), the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) and dried (Na2SO4). Purification by silica gel chromatography gave 47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H)+. The reaction was extracted with DCM (4×250 mL) the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) dried (Na2SO4) Purification by silica gel chromatography

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H2O was added NaHCO3 (21.6 g, 0.25 mmol). After cooling to 0° C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8 g of iodine was added and the reaction was stirred overnight. The reaction was extracted with DCM (4×250 mL), the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) and dried (Na2SO4). Purification by silica gel chromatography gave 47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H)+. The reaction was extracted with DCM (4×250 mL) the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) dried (Na2SO4) Purification by silica gel chromatography

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H2O was added NaHCO3 (21.6 g, 0.25 mmol). After cooling to 0° C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8 g of iodine was added and the reaction was stirred overnight. The reaction was extracted with DCM (4×250 mL), the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) and dried (Na2SO4). Purification by silica gel chromatography gave 47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H)+. The reaction was extracted with DCM (4×250 mL) the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) dried (Na2SO4) Purification by silica gel chromatography

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: TEA (2.28 g, 0.023 mol) was added at once to a solution of 3 g (0.0206 mol) 4-chloro-3-fluoroaniline in 50 ml of DCM and then ethyl 2-chloro-2-oxoacetate (2.81 g, 0.0206 mol) was added dropwise at 0° C. Reaction mixture was stirred at 0° C. for 1 h and then continued at room temperature (RT) for 6 h. The mixture was washed with 25% aqueous solution of K2CO3 (2×50 ml) and water (50 ml). The product was dried over Na2SO4 and evaporated. The residue was washed with ether and dried on the air to give ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (2′) (3.97 g, 78.6%) as a white powder; LC-MS (APCI+) m/z: calcd for C18H8CIFNO3: 245.03. found: 245 (M+H+). Reaction mixture continued at room temperature (RT) for 6 h The mixture was washed with 25% aqueous solution of K2CO3 (2×50 ml) and water (50 ml) The product was dried over Na2SO4 evaporated The residue was washed with ether dried on the air

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Chloro-3-fluoroaniline (2 g, 13.7 mmol) was dissolved in 60 mL of dichloromethane. Under ice bath, saturated sodium bicarbonate solution (60 mL) was added. The mixture was stirred at 0° C. and triphosgene (1.36 g, 4.58 mmol) was added. The mixture was stirred at 0° C. for 1 h and then extracted with dichloromethane and water. The organic layer was dried with sodium sulfate and filtered. The filtrate solution was concentrated and the residue was treated with 50 mL of hexanes. The hexane solution was concentrated to remove all solvents. The residue was taken up in 12 mL of hexanes and filtered. The solution was concentrated and dried to give 1-chloro-2-fluoro-4-isocyanatobenzene as an off white solid (1.69 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.82-6.90 (m, 1H) 6.93 (dd, J=9.22, 2.65 Hz, 1H) 7.31-7.41 (m, 1H). The mixture was stirred at 0° C. for 1 h extracted with dichloromethane and water The organic layer was dried with sodium sulfate filtered The filtrate solution was concentrated the residue was treated with 50 mL of hexanes The hexane solution was concentrated to remove all solvents filtered The solution was concentrated dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Chloro-3-fluoroaniline (2 g, 13.7 mmol) was dissolved in 60 mL of dichloromethane. Under ice bath, saturated sodium bicarbonate solution (60 mL) was added. The mixture was stirred at 0° C. and triphosgene (1.36 g, 4.58 mmol) was added. The mixture was stirred at 0° C. for 1 h and then extracted with dichloromethane and water. The organic layer was dried with sodium sulfate and filtered. The filtrate solution was concentrated and the residue was treated with 50 mL of hexanes. The hexane solution was concentrated to remove all solvents. The residue was taken up in 12 mL of hexanes and filtered. The solution was concentrated and dried to give 1-chloro-2-fluoro-4-isocyanatobenzene as an off white solid (1.69 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.82-6.90 (m, 1H) 6.93 (dd, J=9.22, 2.65 Hz, 1H) 7.31-7.41 (m, 1H). The mixture was stirred at 0° C. for 1 h extracted with dichloromethane and water The organic layer was dried with sodium sulfate filtered The filtrate solution was concentrated the residue was treated with 50 mL of hexanes The hexane solution was concentrated to remove all solvents filtered The solution was concentrated dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H2O was added NaHCO3 (21.6 g, 0.25 mmol). After cooling to 0° C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8 g of iodine was added and the reaction was stirred overnight. The reaction was extracted with DCM (4×250 mL), the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) and dried (Na2SO4). Purification by silica gel chromatography gave 47 g of Intermediate 5A.MS (ESI) m/z: 145.2 (M+H)+. The reaction was extracted with DCM (4×250 mL) the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) dried (Na2SO4) Purification by silica gel chromatography