阿法替尼杂质39

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

实验步骤: Trithylamine (37.5 ml, 0.27 mol, 2.8 equiv) was dissolved in THF (100 ml), and dimethylamine hydrochloride (9.3 g, 0.114 mol, 1.2 equiv) was added. Methyl 4-bromocrotonate (20 g, 85% purity, 0.095 mol, 1.00 equiv) in 100 ml of THF was added drop-wise to the resulting solution at room temperature while stirring. The reaction mixture was allowed to react overnight at room temperature. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give yellow oil. The oil was dissolved in 50 ml of isopropanol, and hydrogen chloride was added until pH 2.0 was reached. The white solid was formed and filtered and dried to give 7.1 g product. MS (ESI) m/z: 563 (M+1). to react overnight at room temperature The reaction mixture was filtered the filtrate was evaporated under reduced pressure to give yellow oil The white solid was formed filtered dried

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

实验步骤: To a solution of (E)-methyl 4-bromobut-2-enoate (5.37 g, 30 mmol) in THF (60 mL) was added potassium carbonate (8.34 g, 60 mmol), followed by cyclobutanamine (2.13 g, 30 mmol, in 30 mL THF) under N2 atmosphere. The resulting reaction mixture was stirred at RT overnight. Excess potassium carbonate was removed by filtration and the filtrate was diluted with EA and water. The organic layer was separated and the aqueous later was extracted with EA. The combined organic phase was dried over Na2SO4. Solvent was removed in vacuum and the crude mixture was purified by flash chromatography (0-5% DCM/MeOH) to provide (E)-methyl 4-(cyclobutylamino)but-2-enoate (19) (1.7 g, 33%) as an oil. LC-MS (ESI): m/z (M+1), 170.2. The resulting reaction mixture Excess potassium carbonate was removed by filtration the filtrate was diluted with EA and water The organic layer was separated the aqueous later was extracted with EA The combined organic phase was dried over Na2SO4 Solvent was removed in vacuum the crude mixture was purified by flash chromatography (0-5% DCM/MeOH)

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

实验步骤: A suspension of activated zinc (40 g) in dry tetrahydrofuran (150 ml) was heated to reflux and a few crystals of iodine was added. A solution of 1-indanone (50 g) and methyl 4-bromo-crotonate (100 g) in 400 ml of dry tetrahydrofuran was added dropwise followed by reflux for 1 h. After cooling, ice was added and the pH adjusted to 1 with concentrated hydrochloric acid followed by extraction with dichloromethane. Concentration of the organic phase left a viscous oil which was dissolved in methanol (400 ml). Concentrated hydrochloric acid (100 ml) was added and the mixture stirred for 30 min. Removal of solvents in vacuo, addition of water, and extraction with ether gave, after drying over magnesium sulfate and removal of solvent in vacuo, an oil (34 g). The oil was dissolved in 300 ml of dry ether and added dropwise to a suspension of lithium aluminium hydride (21 g). After reflux for 2 h, the reaction mixture was hydrolyzed with water. Filtration and removal of solvent in vacuo gave a mixture of isomers from which 4-(1-indanyl)-but-3-en-1-ol (6 g) could be isolated by column chromatography (silica gel, eluent: dichloromethane/ether=9:1). The remaining mixture of isomers (9 g) was dissolved in 150 ml of methanol and hydrogenated at 3 atm of hydrogen pressure in a conventional Parr apparatus in the presence of 5% palladium on charcoal (6 g) for 12 h. Filtration and removal of solvent in vacuo gave 6 g of 4-(1 -indanyl)-1-butanol. was heated to reflux by reflux for 1 h After cooling ice was added followed by extraction with dichloromethane Concentration of the organic phase left a viscous oil which was dissolved in methanol (400 ml) Concentrated hydrochloric acid (100 ml) was added Removal of solvents in vacuo, addition of water, and extraction with ether gave after drying over magnesium sulfate and removal of solvent in vacuo The oil was dissolved in 300 ml of dry ether added dropwise to a suspension of lithium aluminium hydride (21 g) After reflux for 2 h Filtration and removal of solvent in vacuo gave The remaining mixture of isomers (9 g) Filtration and removal of solvent in vacuo

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

实验步骤: A suspension of activated zinc (80 g) in dry tetrahydrofuran (200 ml) was heated to reflux and a few crystals of iodine was added. A solution of 1-indanone (100 g) and methyl 4-bromo-crotonate (200 g) in 500 ml of dry tetrahydrofuran was added dropwise followed by reflux for 1 h. After cooling, ice and aq. ammonium chloride was added followed by extraction with dichloromethane. Removal of the solvent in vacuo gave a viscous oil which was purified on a silica gel column (eluent: dichloromethane/ether=1:1) giving methyl 4-(1 -hydroxyindan-1-yl)-crotonate (78 g). was heated to reflux by reflux for 1 h After cooling followed by extraction with dichloromethane Removal of the solvent in vacuo gave a viscous oil which was purified on a silica gel column (eluent: dichloromethane/ether=1:1)

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 phenethylamine (20 mL, 160 mmol) in anhydrous THF (250 mL) was added NaHCO3 (7 g) followed by methyl 4-bromocrotonate (10 mL, 84 mmol). After stirring for 4 h the reaction was concentrated to approximately half the volume and filtered through a pad of silica gel and eluted with 2% MeOH/CHCl3 to wash off the product. The crude product obtained after evaporation of the filtrate was purified by flash chromatography (silica gel, 2% MeOH/CHCl3) to give the title compound as a slightly yellow liquid (16.5 g, 81%). TLC Rf 0.53 (5% MeOH/CHCl3); 1H NMR (CDCl3) δ 1.2 (1H, s), 2.8 (4H, br s), 3.35 (2H, dd), 3.7 (3H, s), 5.95 (1H, dt), 7.0 (1H, dt), 7.25 (5H, br s) was concentrated to approximately half the volume filtered through a pad of silica gel eluted with 2% MeOH/CHCl3 to wash off the product The crude product obtained after evaporation of the filtrate was purified by flash chromatography (silica gel, 2% MeOH/CHCl3)

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

实验步骤: A mixture of 54 g of methyl 4-bromocrotonate and 30.2 g of calcium carbonate in 200 mL of methanol was refluxed for 5 days. The mixture was filtered and the solvent was removed from the filtrate. The residue was dissolved in ether and washed with water containing a trace of hydrochloric acid. The ether solution was dried over magnesium sulfate. The solvent was removed and the residue was distilled to give 30.6 g of methyl 4-methoxycrotonate. This material was stirred in 170 mL of 1N sodium hydroxide for 3 min. The solution was washed with ether and the aqueous layer was acidified with sulfuric acid. The mixture was extracted several times with ether. The combined extracts were washed with brine and dried over magnesium sulfate. The solvent was removed to give 4-methoxycrotonic acid as a crystalline solid. A 10 g portion of this acid was stirred in 50 mL of benzene at 0° C. and 8.3 mL of oxalyl chloride was added. The mixture was stirred at room temperature for 6 hr. The solvent was removed and the residue was distilled to give 4-methoxycrotonyl chloride as a colorless liquid. was refluxed for 5 days The mixture was filtered the solvent was removed from the filtrate The residue was dissolved in ether washed with water containing a trace of hydrochloric acid The ether solution was dried over magnesium sulfate The solvent was removed the residue was distilled

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

实验步骤: To a stirring solution of phenylmethyl 2-[(2-bromophenyl)methyl]imidazole-4-carboxylate in dimethyl foramide (0.1M) was added sodium hydride (1.2 eq) The reaction was allowed to stir for 10 mins. followed by addition of methyl 4-bromocrotonate continued stirring for 18 hr. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was extracted with 10% hydrochloric acid and the aqueous layer was neutralized with saturated sodium carbonate. The aqueous layer eas extracted with ethyl acetate and dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 406/408 (M+H)+ continued stirring for 18 hr extracted with ethyl acetate The organic layer was extracted with 10% hydrochloric acid The aqueous layer eas extracted with ethyl acetate dried with magnesium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography (50% EtOAc/Hexane)

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

实验步骤: N-(2-(2-Bromophenyl)ethyl)-N-(phenylmethyl)amine was dissolved in acetonitrile (0.2 M), followed by addition of methyl 4-bromocrotonate (1.2 eq) and triethylamine (1.5 eq), and the reaction was refluxed overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with 10% sodium carbonate, water, and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica; 50% EtOAc/Hex) afforded a colorless oil. EI-MS m/z 388/390 (M+H)+ the reaction was refluxed overnight washed with 10% sodium carbonate, water, and brine dried over magnesium sulfate filtered concentrated in vacuo Flash chromatography (silica; 50% EtOAc/Hex) afforded a colorless oil

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

实验步骤: N-(2-(2-Bromophenyl)ethyl)-N-(phenylmethyl)amine was dissolved in acetonitrile (0.2 M), followed by addition of methyl 4-bromocrotonate (1.2 eq) and triethylamine (1.5 eq), and the reaction was refluxed overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with 10% sodium carbonate, water, and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica; 50% EtOAc/Hex) afforded a colorless oil. EI-MS m/z 388/390 (M+H)+ the reaction was refluxed overnight washed with 10% sodium carbonate, water, and brine dried over magnesium sulfate filtered concentrated in vacuo Flash chromatography (silica; 50% EtOAc/Hex) afforded a colorless oil

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

实验步骤: Methyl-(2E)-4-bromobut-2-enoate (28.2 g, 0.158 mol) was added dropwise to 2-nitrophenol (20 g, 0.144 mol) and K2CO3 (29.8 g, 21.6 mol) in N,N-dimethylformamide (240 mL) at rt. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (2.0 L) and washed with water (1.0 L), sat. aq. Na2CO3 (1.0 L) and brine (1.0 L). The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford desired product (27.4 g, 80%) as a solid. washed with water (1.0 L), sat. aq. Na2CO3 (1.0 L) and brine (1.0 L) The organic phase was separated dried over anhydrous Na2SO4 filtered evaporated in vacuo

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

实验步骤: Methyl-(2E)-4-bromobut-2-enoate (28.2 g, 0.158 mol) was added dropwise to 2-nitrophenol (20 g, 0.144 mol) and K2CO3 (29.8 g, 21.6 mol) in N,N-dimethylformamide (240 mL) at rt. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (2.0 L) and washed with water (1.0 L), sat. aq. Na2CO3 (1.0 L) and brine (1.0 L). The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford desired product (27.4 g, 80%) as a solid. washed with water (1.0 L), sat. aq. Na2CO3 (1.0 L) and brine (1.0 L) The organic phase was separated dried over anhydrous Na2SO4 filtered evaporated in vacuo

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of Example 12A (128 g, 326 mmol) in acetonitrile (652 mL) was added (E)-methyl 4-bromobut-2-enoate (38.4 mL, 326 mmol) and potassium carbonate (90 g, 652 mmol), and the mixture was heated at 50° C. for 17 hours. A small amount of water was added, and the mixture was decanted into a separatory funnel. The solid left behind was washed three times with ethyl acetate, and the ethyl acetate washings were added to the separatory funnel followed by more water. The layers were separated and the organic layer was concentrated, then dissolved in dichloromethane and loaded onto a silica gel column packed in hexanes. The product was eluted with 15% ethyl acetate/hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38 (d, J=7.3 Hz, 5H), 7.31-7.12 (m, 15H), 6.83 (dt, J=5.6 Hz, 15.7 Hz, 1H), 6.07 (d, J=15.7 Hz, 1H), 3.67 (s, 3H), 3.42 (s, 2H), 3.05 (d, J=4.4 Hz, 2H), 2.58-2.49 (m, 2H), 2.11 (dd, J=6.2 Hz, 12.9 Hz, 2H). the mixture was decanted into a separatory funnel The solid left behind was washed three times with ethyl acetate the ethyl acetate washings were added to the separatory funnel The layers were separated the organic layer was concentrated dissolved in dichloromethane The product was eluted with 15% ethyl acetate/hexanes