methyl 3-amino-2-methylpropanoate

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

Procedure: A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester [from Example 1b] (2.03 g, 6.61 mmol) and 3-amino-2-methyl-propionic acid methyl ester (1.5 eq, 1.52 g, 9.91 mmol) in acetonitrile (25 mL) was heated at reflux for five days. It was cooled to room temperature and evaporated to an oil. The crude product was purified via column chromatography on silica (1:1 ethyl acetate/hexane) to give the product (0.75 g, 42%) as an orange oil. [M+H]+ 275. at reflux for five days evaporated to an oil The crude product was purified via column chromatography on silica (1:1 ethyl acetate/hexane)

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

Procedure: A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester [from Example 1b] (2.03 g, 6.61 mmol) and 3-amino-2-methyl-propionic acid methyl ester (1.5 eq, 1.52 g, 9.91 mmol) in acetonitrile (25 mL) was heated at reflux for five days. It was cooled to room temperature and evaporated to an oil. The crude product was purified via column chromatography on silica (1:1 ethyl acetate/hexane) to give the product (0.75 g, 42%) as an orange oil. [M+H]+ 275. at reflux for five days evaporated to an oil The crude product was purified via column chromatography on silica (1:1 ethyl acetate/hexane)

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

Procedure: 4-({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)benzoic acid (0.18 g) synthesized in the above-mentioned (2) was dissolved in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), 1-hydroxybenzotriazole.monohydrate (0.09 g) and methyl 3-amino-2-methylpropanoate (0.07 g) were added at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give methyl 3-({[4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}amino)-2-methylpropanoate (0.03 g) as a yellow oil. This was dissolved in ethanol (2.0 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (0.5 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.02 g, 9%) as a colorless solid. the mixture was extracted with diethyl ether The extract was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-6-methoxy-3-nitropyridine (3 g, 15.91 mmol) in tetrahydrofuran (20 mL) was added methyl-3-amino-2-methylpropanoate (2.05 g, 17.50 mmol) and potassium carbonate (4.40 g, 31.82 mmol). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated in vacuo and washed with water (20 mL), extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 100:1→80:1) to give methyl-3-((6-methoxy-3-nitropyridin-2-yl)amino)-2-methylpropanoate (4.2 g, 97%) as a yellow oil. The reaction mixture was concentrated in vacuo washed with water (20 mL) extracted with acetic ester (20 mL×3) The combined organic phase was dried by anhydrous sodium sulphate filtered The filtrate was concentrated purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 100:1→80:1)

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

Procedure: To a solution of 1,4-difluoro-2-nitrobenzene (14.3 g, 90 mmol) in tetrahydrofuran (250 mL) was added methyl 3-amino-2-methylpropanoate (10.5 g, 90 mmol) and potassium carbonate (24.8 g, 180 mmol). The reaction mixture was heated to reflux and stirred for 15 hours. Then the mixture was concentrated in vacuo, and the residue was dissolved in water (250 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers was separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford methyl 3-(4-fluoro-2-nitrophenylamino)-2-methylpropanoate as a red solid (14.0 g, 61%). The reaction mixture was heated to reflux Then the mixture was concentrated in vacuo the residue was dissolved in water (250 mL) extracted with ethyl acetate (100 mL*3) The combined organic layers was separated dried over anhydrous sodium sulfate concentrated to give a residue The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1)

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

Procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (9.4 g, 42.7 mmol) in tetrahydrofuran (100 mL) were added methyl 3-amino-2-methylpropanoate (5 g, 42.7 mmol) and potassium carbonate (11.8 g, 85.4 mmol). The reaction mixture was stirred with refluxing for 3 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 3-(5-bromo-2-nitrophenylamino)-2-methylpropanoate as a light yellow solid (8 g, 59%). with refluxing for 3 hours extracted with ethyl acetate (100 mL×3) The organic layers were separated dried over anhydrous sodium sulfate filtered concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1)