4-(2-methylpropanoylamino)butanoic acid

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)

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

Procedure: The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-isobutyrylaminobutyric acid (5.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is recrystallized in acetonitrile and then purified by chromatography on silica (0.063-0.2 mm; 130 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (98:2 by volume) mixture] collecting 25-cc fractions. Fractions 79 to 85 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized by stirring in isopropyl ether. 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-isobutyrylaminobutyrate (5.5 g), m.p. 208° C., is thereby obtained. The residue obtained is recrystallized in acetonitrile purified by chromatography on silica (0.063-0.2 mm; 130 g) collecting 25-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) The residue obtained is crystallized

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)

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

Procedure: The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-isobutyrylaminobutyric acid (5.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is recrystallized in acetonitrile and then purified by chromatography on silica (0.063-0.2 mm; 130 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (98:2 by volume) mixture] collecting 25-cc fractions. Fractions 79 to 85 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized by stirring in isopropyl ether. 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-isobutyrylaminobutyrate (5.5 g), m.p. 208° C., is thereby obtained. The residue obtained is recrystallized in acetonitrile purified by chromatography on silica (0.063-0.2 mm; 130 g) collecting 25-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) The residue obtained is crystallized

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)

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

Procedure: To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. the resulting mixture was stirred at room temperature for 2 hours The reaction mixture was filtered the filtrate concentrated under reduced pressure The residue was dissolved in 1N sodium hydroxide stirred for 30 minutes This solution was then poured into diethyl ether diluted with water the phases separated extracted with ethyl acetate dried over magnesium sulfate concentrated under reduced pressure to give an oil Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.)