1-methylpiperidine-2-carbaldehyde

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

Procedure: N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (300 mg, 0.48 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (530 μL, 0.53 mmol). After stirring for 30 minutes, a solution of l-methylpiperidine-2-carbaldehyde 6b (120 mg, 0.96 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methyl-2-piperidyl)prop-2-enamide 6 (14 mg, yield 4.9%) as a yellow solid. The reaction mixture was stirred for another 30 minutes stirred for 12 hours The reaction mixture was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

Procedure: Dimethyl sulfoxide (3.3 mL, 46 mmol) was dissolved in 15 mL of dichloromethane in a dry ice bath, followed by dropwise slowly addition of oxalyl chloride (2.6 mL, 31 mmol). After stirring for 45 minutes, a solution of (1-methyl-2-piperidyl)methanol 6a (1 g, 7.74 mmol) in 5 mL of dichloromethane was added dropwise to the solution. The reaction mixture was stirred for 45 minutes, then added with triethylamine (7.2 mL, 52 mmol), and stirred for 10 minutes, then warmed up to room temperature and stirred for 1 hour. The reaction mixture was washed with water (20 mL) and saturated brine (20 mL) successively. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure then the resulting residue was purified by alkaline alumina column chromatography with elution system A to obtain the title compound 1-methylpiperidine-2-carbaldehyde 6b (300 mg, yield 31.0%) as a brown oil, which was directly used in the next step without purification. The reaction mixture was stirred for 45 minutes stirred for 10 minutes stirred for 1 hour The reaction mixture was washed with water (20 mL) and saturated brine (20 mL) successively The combined organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by alkaline alumina column chromatography with elution system

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

Procedure: N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (300 mg, 0.48 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (530 μL, 0.53 mmol). After stirring for 30 minutes, a solution of 1-methylpiperidine-2-carbaldehyde 6b (120 mg, 0.96 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methyl-2-piperidyl)prop-2-enamide 6 (14 mg, yield 4.9%) as a yellow solid. The reaction mixture was stirred for another 30 minutes stirred for 12 hours The reaction mixture was concentrated under reduced pressure the resulting residue was purified by silica gel column chromatography with elution system

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

Procedure: Dimethyl sulfoxide (3.3 mL, 46 mmol) was dissolved in 15 mL of dichloromethane in a dry ice bath, followed by dropwise slowly addition of oxalyl chloride (2.6 mL, 31 mmol). After stirring for 45 minutes, a solution of (1-methyl-2-piperidyl)methanol 6a (1 g, 7.74 mmol) in 5 mL of dichloromethane was added dropwise to the solution. The reaction mixture was stirred for 45 minutes, then added with triethylamine (7.2 mL, 52 mmol), and stirred for 10 minutes, then warmed up to room temperature and stirred for 1 hour. The reaction mixture was washed with water (20 mL) and saturated brine (20 mL) successively. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure then the resulting residue was purified by alkaline alumina column chromatography with elution system A to obtain the title compound 1-methylpiperidine-2-carbaldehyde 6b (300 mg, yield 31.0%) as a brown oil, which was directly used in the next step without purification. The reaction mixture was stirred for 45 minutes stirred for 10 minutes stirred for 1 hour The reaction mixture was washed with water (20 mL) and saturated brine (20 mL) successively The combined organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure the resulting residue was purified by alkaline alumina column chromatography with elution system