伊马替尼杂质61

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: A solution of ethyl methanesulfonate (4.14 mL, 40.2 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere. N-Butyllithium (20 ml, 50.0 mmol) was added slowly in 7 minutes after which stirring was continued for 15 minutes. Diethyl phosphorochloridate (4.36 mL, 30.2 mmol) was added, the reaction mixture was stirred for 2.5 h, the cooling bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was quenched with aqueous saturated ammonium chloride (150 ml) and the resulting mixture was extracted with EtOAc (2×100 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 9.20 g of a yellow oil. The oil was purified over silicagel (600 g) using a gradient of ethyl acetate (0-100%) in heptane to yield 1.75 g of the product (6.7 mol, 17%). the reaction mixture was stirred for 2.5 h the cooling bath was removed to reach room temperature The reaction mixture was quenched with aqueous saturated ammonium chloride (150 ml) the resulting mixture was extracted with EtOAc (2×100 ml) The combined extracts were dried over sodium sulfate concentrated under reduced pressure

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3,5-Dibromo-1H-1,2,4-triazole (2.5 g, 11.0 mmol, Eq: 1.00) was dissolved in dimethylformamide (31.8 ml) and sodium hydride (529 mg, 60% dispersion in mineral oil, 13.2 mmol, Eq: 1.2) was added slowly. Ethyl methanesulfonate (2.74 g, 2.27 ml, 22.0 mmol, Eq: 2) was added to the reaction and the mixture was heated in a microwave oven for 60 minutes at 100° C. The mixture was diluted with water and extracted 3× with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to give 3,5-dibromo-1-ethyl-1H-[1,2,4]triazole (2.54 g, 90.4%) as a white powder. MS: m/z=255.9 (M+H+) extracted 3× with ethyl acetate The organic layer was dried over magnesium sulfate filtered the solvent was evaporated

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

实验步骤: A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) was added. The solution was kept at -78° C. for 0.5 h and allowed to stay at -50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to the solution and the mixture warmed to room temperature. The mixture was concentrated (THF removed), diluted with water and extracted with methylene chloride (3×70 mL). The combined organic fractions were dried (MgSO4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound. to stay at -50° C. for 1 h The mixture was concentrated (THF removed) diluted with water extracted with methylene chloride (3×70 mL) The combined organic fractions were dried (MgSO4) concentrated purified by distillation

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

实验步骤: A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) was added. The solution was kept at -78° C. for 0.5 h and allowed to stay at -50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to the solution and the mixture warmed to room temperature. The mixture was concentrated (THF removed), diluted with water and extracted with methylene chloride (3×70 mL). The combined organic fractions were dried (MgSO4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound. to stay at -50° C. for 1 h The mixture was concentrated (THF removed) diluted with water extracted with methylene chloride (3×70 mL) The combined organic fractions were dried (MgSO4) concentrated purified by distillation

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

实验步骤: To a stirred mixture of the product of step (e) (272.5 mg, 0.852 mmol) and ethanol (2.6 ml) was added methanesulfonic acid (81.88 mg, 0.852 mmol). After stirring for a few minutes, ethyl methanesulfonate (211.6 mg, 1.70 mmol) was added. The reaction mixture was refluxed, with stirring, for 3 hours. Additional ethyl methanesulfonate (117 mg) was added and refluxing continued for 2 hours to complete the reaction. On cooling, the product crystallized to a thick mass. Ether was added and the product was isolated by filtration and then recrystallized from ethanol-ether to yield 407.3 mg of N-(4-(2-(3-chlorobenzylamino)ethyl)phenyl)carbamimidothioic acid ethyl ester dimethanesulfonate, m.p. 173°-5° C. The reaction mixture was refluxed with stirring, for 3 hours refluxing the reaction On cooling the product crystallized to a thick mass Ether was added the product was isolated by filtration recrystallized from ethanol-ether

反应条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(4-(2-((Phenylmethyl)(methyl)amino)ethyl)phenyl)-2-thiourea (step (f), 0.30 g) was suspended in 200 ethanol (2.5 ml), and the mixture was treated with methanesulfonic acid (0.065 ml) and then ethyl methanesulfonate (0.12 ml). After 3 hours at 100° C., TLC on C18 silica with 80% methanol/20% water with 0.8% ammonium acetate showed incomplete conversion to product. At this point additional ethyl methanesulfonate (0.20 g) was added and the mixture refluxed for one hour. After stirring overnight, the crude reaction product was treated with ethyl acetate (50 ml) and water (50 ml). The aqueous layer was treated with sodium carbonate (0.25 g) and extracted with diethyl ether (20 ml). The remaining aqueous layer was treated with sodium bicarbonate (1 g) and extracted with of diethyl ether (20 ml). The ether layers were identical by TLC and were combined, dried with sodium sulfate and evaporated to yield the free base which was then treated with maleic acid (0.24 g) in methanol (1 ml), then diluted with ethyl acetate (4 ml) followed by diethyl ether (25 ml), giving an oil. The solvents were decanted, and the resulting solids were dissolved in hot isopropanol (20 ml) and cooled to -20° C. The resulting solids were collected and air dried to provide N-(4-(2-((phenylmethyl)(methyl)amino)ethyl)phenyl) carbamimidothioic acid, ethyl ester, 0.34 g, m.p. 136°-137° C. the mixture refluxed for one hour the crude reaction product extracted with diethyl ether (20 ml) The remaining aqueous layer was treated with sodium bicarbonate (1 g) extracted with of diethyl ether (20 ml) dried with sodium sulfate evaporated to yield the free base which giving an oil The solvents were decanted the resulting solids were dissolved in hot isopropanol (20 ml) The resulting solids were collected air dried

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

实验步骤: A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78° C. with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 22.2 mmol) was added. The solution was kept at -78° C. for 0.5 h and allowed to stay at -50° C. for 1 h. Saturated ammonium chloride (75 mL) was added to the solution and the mixture warmed to room temperature. The mixture was concentrated (THF removed), diluted with water and extracted with methylene chloride (3×70 mL). The combined organic fractions were dried (MgSO4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound. to stay at -50° C. for 1 h The mixture was concentrated (THF removed) diluted with water extracted with methylene chloride (3×70 mL) The combined organic fractions were dried (MgSO4) concentrated purified by distillation

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

实验步骤: Into the cathode chamber of an electrolytic cell divided with an ion-exchange resin diaphragm was placed a solution of 10 mmols of methyl phenylacetate, 12 mmols of ethyl methanesulfonate and 1.0 g of tetraethylammonium tosylate in 30 ml of anhydrous dimethylformamide. And the anode chamber was provided with a solution of 1.0 g of tetraethylammonium tosylate in 10 ml of anhydrous dimethylformamide. Constant current electrolysis was performed at 0.2 A/cm2 with use of platinum for the cathode and carbon for the anode. After passing 1.5 F of electricity per mol of the methyl phenylacetate through the solution at 5 to 10 C, the cathode solution was added to a saturated aqueous solution of ammonium chloride and the mixture was extracted twice with ether. The ether was distilled off and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10:1), giving methyl α-ethylphenylacetate in a yield of 77% and α-ethylphenylacetic acid in a yield of 13%. The spectral data of the ester were as follows. the mixture was extracted twice with ether The ether was distilled off the residue was purified by silica gel column chromatography

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

实验步骤: To a solution of methanesulfonic acid, ethyl ester (11.00 mL, 0.1068 mol) in THF (200.0 mL, 2.466 mol) at −78° C. was added 2.500 M of n-butyllithium in hexane (50.00 mL) over 15 minutes and the mixture was stirred for 20 minutes. Phosphorochloridic acid, diethyl ester (10.0 mL, 0.0694 mol) was added to the mixture at −78° C. The mixture was stirred for 3.5 hours, allowing to warm to 0° C. The reaction was quenched with 5M ammonium chloride in water (100 mL) and the mixture was concentrated in vacuo to remove THF. The aqueous was extracted with EtOAc (2×150 mL) and the organics were combined and concentrated in vacuo. The product was purified by flash chromatography (0 to 100% EtOAc/Hexanes) to yield the product as an oil (9.07 g, 50%+10.4 g of a mixed fraction). The mixture was stirred for 3.5 hours The reaction was quenched with 5M ammonium chloride in water (100 mL) the mixture was concentrated in vacuo to remove THF The aqueous was extracted with EtOAc (2×150 mL) concentrated in vacuo The product was purified by flash chromatography (0 to 100% EtOAc/Hexanes)

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

实验步骤: A solution of ethyl methanesulfonate (4.14 mL, 40.2 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere. N-Butyllithium (20 ml, 50.0 mmol) was added slowly in 7 minutes after which stirring was continued for 15 minutes. Diethyl phosphorochloridate (4.36 mL, 30.2 mmol) was added, the reaction mixture was stirred for 2.5 h, the cooling bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was quenched with aqueous saturated ammonium chloride (150 ml) and the resulting mixture was extracted with EtOAc (2×100 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 9.20 g of a yellow oil. The oil was purified over silicagel (600 g) using a gradient of ethyl acetate (0-100%) in heptane to yield 1.75 g of the product (6.7 mol, 17%). the reaction mixture was stirred for 2.5 h the cooling bath was removed to reach room temperature The reaction mixture was quenched with aqueous saturated ammonium chloride (150 ml) the resulting mixture was extracted with EtOAc (2×100 ml) The combined extracts were dried over sodium sulfate concentrated under reduced pressure