1-叔丁氧羰基哌啶-4-亚基乙酸

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: 4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester. the reaction mixture was stirred for 12 hours at room temperature The reaction mixture was washed with water (50 mL) an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) evaporated in vacuo The residue was chromatographed on silica (2×20 cm)

反应条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a single-neck reaction flask (100 ml) were added 2-(1-(tert-butyloxycarbonyl)piperidin-4-ylidene)acetic acid (1 g) and anhydrous THF (20 ml). The mixture was stirred to dissolve and cooled to the temperature of −5° C. To the mixture were added isobutyl chloroformate (0.6 ml) and N-methylmorphine (0.5 ml). The resultant mixture was stirred for 20 min. 6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy) phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (2 g, 4.1 mmol) was dissolved in anhydrous pyridine (20 ml). The resulting solution was added into the reaction flask in an ice-water bath. After the reaction finished, the solvent was rotary-evaporated to dryness. To the residue were added chloroform and water. The solution was stood for separation. The chloroform layer was wash once with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and rotary-evaporated to dryness to give a crude product. The product was recrystallized with ethanol. to dissolve The resulting solution was added into the reaction flask in an ice-water bath the solvent was rotary-evaporated to dryness To the residue were added chloroform and water The solution was stood for separation The chloroform layer was wash once with saturated saline solution dried over anhydrous magnesium sulfate filtered rotary-evaporated to dryness

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

实验步骤: 4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester. the reaction mixture was stirred for 12 hours at room temperature The reaction mixture was washed with water (50 mL) an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) evaporated in vacuo The residue was chromatographed on silica (2×20 cm)

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

实验步骤: 4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester. the reaction mixture was stirred for 12 hours at room temperature The reaction mixture was washed with water (50 mL) an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) evaporated in vacuo The residue was chromatographed on silica (2×20 cm)

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

实验步骤: 4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester. the reaction mixture was stirred for 12 hours at room temperature The reaction mixture was washed with water (50 mL) an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) evaporated in vacuo The residue was chromatographed on silica (2×20 cm)

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

实验步骤: 1 g of 2-(1-(tert-butyloxycarbonyl)piperidine-4-ylidene)acetic acid was added to 20 mL of anhydrous THF in a one-neck flask (100 mL). The solution was stirred and cooled on salt-ice bath. Then, 0.6 mL of isobutyl chloroformate and 0.5 mL of N-methylmorpholine were added, and the reaction mixture was let stir for 20 min 1.046 g of N4-(3-ethynylphenyl)quinazoline-4,6-diamine dissolved in 10 mL of pyridine (dried over molecular sieves) and 0.4 mL of N-methylmorpholine were added to the reaction mixture on an ice bath with stirring. After reaction completion, the solvent was evaporated in vacuo and the remaining residue was partitioned with chloroform and water. The chloroform layer was washed once with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product. The crude product was recrystallized from isopropanol. MS (EI) 482 M+. cooled on salt-ice bath with stirring After reaction completion the solvent was evaporated in vacuo the remaining residue was partitioned with chloroform and water The chloroform layer was washed once with brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo

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

实验步骤: 1 g of 2-(1-(tert-butyloxycarbonyl)piperidine-4-ylidene)acetic acid was added to 20 mL of anhydrous THF in a one-neck flask (100 mL). The solution was stirred and cooled on salt-ice bath. Then, 0.6 mL of isobutyl chloroformate and 0.5 mL of N-methylmorpholine were added, and the reaction mixture was let stir for 20 min 1.046 g of N4-(3-ethynylphenyl)quinazoline-4,6-diamine dissolved in 10 mL of pyridine (dried over molecular sieves) and 0.4 mL of N-methylmorpholine were added to the reaction mixture on an ice bath with stirring. After reaction completion, the solvent was evaporated in vacuo and the remaining residue was partitioned with chloroform and water. The chloroform layer was washed once with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product. The crude product was recrystallized from isopropanol. MS (EI) 482 M+. cooled on salt-ice bath with stirring After reaction completion the solvent was evaporated in vacuo the remaining residue was partitioned with chloroform and water The chloroform layer was washed once with brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo

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: 1 g of 2-(1-(tert-butyloxycarbonyl)piperidine-4-ylidene)acetic acid was added to 20 mL of anhydrous THF in a one-neck flask (100 mL). The solution was stirred and cooled on salt-ice bath. Then, 0.6 mL of isobutyl chloroformate and 0.5 mL of N-methylmorpholine were added, and the reaction mixture was let stir for 20 min. 1.046 g of N4-(3-ethynylphenyl)quinazoline-4,6-diamine dissolved in 10 mL of pyridine (dried over molecular sieves) and 0.4 mL of N-methylmorpholine were added to the reaction mixture on an ice bath with stirring. After reaction completion, the solvent was evaporated in vacuo and the remaining residue was partitioned with chloroform and water. The chloroform layer was washed once with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product. The crude product was recrystallized from isopropanol. MS (EI) 482 M+. cooled on salt-ice bath the reaction mixture was let stir for 20 min with stirring After reaction completion the solvent was evaporated in vacuo the remaining residue was partitioned with chloroform and water The chloroform layer was washed once with brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo

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

实验步骤: An aqueous solution of 1 M sodium hydroxide (15 mL) was added to a solution of 3.02 g (11.8 mmol) of tert-butyl ester of 4-metoxycarbonylmethylenepiperidine-1-carboxylic acid in THF (15 mL) and stirred for 2 hours. Then an aqueous solution of 1 M sodium hydroxide (another 10 mL) was added thereto, and stirred for 18 hours. After the reaction was completed, the reaction mixture was neutralized by addition of 1 M hydrochloric acid and the solvent was removed under a reduced pressure. The residue was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure to obtain 2.78 g of tert-butyl ester of 4-carboxymethylenepiperidine-1-carboxylic acid. To a solution of 2.78 g of this 4-carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester in N,N-dimethylformamide (35 mL) was added 3.8 mL (34.6 mmol) of N-methylmolpholine, 2.34 g (17.3 mmol) of 1-hydroxybenzotriazole, 2.65 g (13.8 mmol) of 1-ethyl-3-(3′-dimethylaminopopyl)carbodiimide hydrochloride and 1.35 g (13.8 mmol) of N,O-dimethylhydroxylamine hydrochloride, and stirred for about 20 hours. After the reaction was completed, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine twice and dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. Its purification by silica gel column chromatography (developing solvent, hexane:ethyl acetate=3:2 to 1:1) gave 1.99 g (7.00 mmol) of 4-[(methoxymethylcarbamoyl)methylene]piperidine-1-carboxylic acid tert-butyl ester. Its physical property is shown below. followed by extraction with ethyl acetate The extract was washed with saturated brine twice dried over anhydrous magnesium sulfate the solvent was removed under a reduced pressure Its purification by silica gel column chromatography (developing solvent, hexane:ethyl acetate=3:2 to 1:1)

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

实验步骤: 1 g of 2-(1-(tert-butyloxycarbonyl)piperidine-4-ylidene)acetic acid was added to 20 mL of anhydrous THF in a one-neck flask (100 mL). The solution was stirred and cooled on salt-ice bath. Then, 0.6 mL of isobutyl chloroformate and 0.5 mL of N-methylmorpholine were added, and the reaction mixture was let stir for 20 min 1.046 g of N4-(3-ethynylphenyl)quinazoline-4,6-diamine dissolved in 10 mL of pyridine (dried over molecular sieves) and 0.4 mL of N-methylmorpholine were added to the reaction mixture on an ice bath with stirring. After reaction completion, the solvent was evaporated in vacuo and the remaining residue was partitioned with chloroform and water. The chloroform layer was washed once with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product. The crude product was recrystallized from isopropanol. MS (EI) 482 M+. cooled on salt-ice bath with stirring After reaction completion the solvent was evaporated in vacuo the remaining residue was partitioned with chloroform and water The chloroform layer was washed once with brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo