methyl 2-(2-oxopyrrolidin-1-yl)acetate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml of N-methylpyrrolidone, was added 3.28 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. The mixture was heated to 50° C. and stirred for 40 minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture at 50° C. over a period of 30 minutes. After the stirrng at 50° C. for 20 minutes, the mixture was cooled to 15° C. and poured into 130 ml aqueous solution containing 13.5 g of ammonium chloride. After the stirrng at 50° C. for 20 minutes the mixture was cooled to 15° C.

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

Procedure: To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (1.0 g, 5.5 mmol) and methyl (2-oxopyrrolidin-1-yl)acetate (1.0 g, 7.0 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 4.2 mL, 11 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxo-4-(2-oxopyrrolidin-1-yl)butanenitrile as a brown oil (0.43 g, 1.4 mmol, 25% yield), MS (EI) for C16H18N2O4: 303 (MH+). the resulting mixture was heated at reflux for 18 hours This aqueous mixture was washed with dichloromethane (3×20 mL) The acidified mixture was extracted with ethyl acetate (3×30 mL) The combined extract was washed with aqueous sodium bicarbonate solution, brine dried over sodium sulfate filtered concentrated

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

Procedure: To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (1.0 g, 5.5 mmol) and methyl (2-oxopyrrolidin-1-yl)acetate (1.0 g, 7.0 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 4.2 mL, 11 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxo-4-(2-oxopyrrolidin-1-yl)butanenitrile as a brown oil (0.43 g, 1.4 mmol, 25% yield), MS (EI) for C16H18N2O4: 303 (MH+). the resulting mixture was heated at reflux for 18 hours This aqueous mixture was washed with dichloromethane (3×20 mL) The acidified mixture was extracted with ethyl acetate (3×30 mL) The combined extract was washed with aqueous sodium bicarbonate solution, brine dried over sodium sulfate filtered concentrated

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

Procedure: Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml of N-methylpyrrolidone, was added 3.28 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. The mixture was heated to 50° C. and stirred for 40 minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture at 50° C. over a period of 30 minutes. After the stirrng at 50° C. for 20 minutes, the mixture was cooled to 15° C. and poured into 130 ml aqueous solution containing 13.5 g of ammonium chloride. After the stirrng at 50° C. for 20 minutes the mixture was cooled to 15° C.

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

Procedure: Into a suspension of 1.26 g of sodium hydride (60% content) in 15 ml of N-methylpyrrolidone, was added 3.28 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. The mixture was heated to 50° C. and stirred for 40 minutes. Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture at 50° C. over a period of 30 minutes. After the stirrng at 50° C. for 20 minutes, the mixture was cooled to 15° C. and poured into 130 ml aqueous solution containing 13.5 g of ammonium chloride. After the stirrng at 50° C. for 20 minutes the mixture was cooled to 15° C.

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

Procedure: To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (1.0 g, 5.5 mmol) and methyl (2-oxopyrrolidin-1-yl)acetate (1.0 g, 7.0 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 4.2 mL, 11 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxo-4-(2-oxopyrrolidin-1-yl)butanenitrile as a brown oil (0.43 g, 1.4 mmol, 25% yield), MS (EI) for C16H18N2O4: 303 (MH+). the resulting mixture was heated at reflux for 18 hours This aqueous mixture was washed with dichloromethane (3×20 mL) The acidified mixture was extracted with ethyl acetate (3×30 mL) The combined extract was washed with aqueous sodium bicarbonate solution, brine dried over sodium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A 1.02M solution of diisobutylalminium hydride in toluene (16 ml) was added dropwise to a solution of methyl(2-oxopyrrolidin-1-yl)acetate (1.01 g) in toluene (10 ml) at −78° C., and the mixture was stirred for 1 hour. The reaction solution was quenched with methanol at −78° C., then diluted with a 1N aqueous solution of hydrochloric acid, and allowed to warm to room temperature with stirring. The reaction solution was filtered through celite and then the filtrate was dried up. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5→90:10) to yield 2-oxopyrrolidin-1-yl-acetaldehyde (120 mg) as a colorless oil. The reaction solution was quenched with methanol at −78° C. diluted with a 1N aqueous solution of hydrochloric acid with stirring The reaction solution was filtered through celite the filtrate was dried up The residue was purified by silica gel column chromatography (chloroform:methanol=95:5→90:10)

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

Procedure: A 1.02M solution of diisobutylalminium hydride in toluene (16 ml) was added dropwise to a solution of methyl(2-oxopyrrolidin-1-yl)acetate (1.01 g) in toluene (10 ml) at −78° C., and the mixture was stirred for 1 hour. The reaction solution was quenched with methanol at −78° C., then diluted with a 1N aqueous solution of hydrochloric acid, and allowed to warm to room temperature with stirring. The reaction solution was filtered through celite and then the filtrate was dried up. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5→90:10) to yield 2-oxopyrrolidin-1-yl-acetaldehyde (120 mg) as a colorless oil. The reaction solution was quenched with methanol at −78° C. diluted with a 1N aqueous solution of hydrochloric acid with stirring The reaction solution was filtered through celite the filtrate was dried up The residue was purified by silica gel column chromatography (chloroform:methanol=95:5→90:10)

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

Procedure: To a solution of methyl 2-(2-oxopyrrolidinyl)acetate (0.884 mL, 6.36 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.308 mL, 6.36 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ 8.17 (br s, 1H), 3.94 (s, 2H), 3.55 (t, 2H), 2.43 (t, 2H), 2.10 (quintet, 2H); ES-MS (m/z) 158 [M+H]+. The solution was heated to reflux temperature overnight The solvent was then removed under reduced pressure the product was isolated as a solid in a quantitative yield was used without further purification

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture consisting of 14.1 g (89.6 mmol) of methyl 2-oxo-1-pyrrolidineacetate and 11.4 g (81.4 mmol) of 7a-(aminomethyl)pyrrolizidine was heated and stirred for 6 hours at 80° C. under argon atmospher. After cooling, the reaction mixture was then solved with 1.0N-hydrochloric acid and extracted 3 times with dichloromethane. An aqueous layer was rendered alkaline by the addition of sodium hydroxide solution and extracted 3 times with dichloromethane followed by drying over anhydrous magnesium sulfate. After removal of the drying agent through filtration, the solvent was evaporated under reduced pressure to obtain a yellowish oil as a free base of the desired compound. The free base was converted to terephthalate by usual manner. Yield: 32.0 g (91.1%). was heated After cooling extracted 3 times with dichloromethane by the addition of sodium hydroxide solution extracted 3 times with dichloromethane by drying over anhydrous magnesium sulfate After removal of the drying agent through filtration the solvent was evaporated under reduced pressure