5-ethoxypyrrolidin-2-one

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

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

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

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

Procedure: Adenosine 2',3',5'-triacetate (2.0 g) and 5-ethoxy-2-pyrrolidinone (1.2 g) were stirred in N,N-dimethylformamide (10 ml) at 130° C. overnight. The reaction mixture was distilled to remove the N,N-dimethylformamide and the residue was subjected to silica gel column chromatography using chloroformacetone (5:3) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give N6 -(5-oxo-2-pyrrolidinyl)adenosine 2',3',5'-triacetate as an oil (2.2 g). The reaction mixture was distilled to remove the N,N-dimethylformamide concentrated under reduced pressure

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

Procedure: A mixture of 4 g of 5-ethoxy-pyrrolidin-2-one, 30 cm3 of propanethiol and 2 g of Amberlite-15 resin is agitated for 2 hour 45 minutes at ambient temperature. The resin is filtered off, then the excess propanethiol is distillated. 2.8 g of the expected product is obtained, isolated from isopropyl ether. m.p. 40°-42° C. The resin is filtered off

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

Procedure: At 0° C., 12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of conc. sulphuric acid and 90 ml of glacial acetic acid were initially charged and admixed, a little at a time, with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once each with water and saturated sodium chloride solution, dried and concentrated. After some time, γ-2-hydroxyphenyl-y-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained after concentration was stirred with a 1:1 mixture of cyclohexane/ethyl acetate and gave, after filtration with suction, 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was concentrated. A further 3.35 g (total: 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam were obtained by recrystallization from dichloromethane/hexane. For work-up, the mixture was poured onto ice extracted three times with ethyl acetate the combined extracts were washed once each with water and saturated sodium chloride solution dried concentrated After some time, γ-2-hydroxyphenyl-y-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase The residue obtained after concentration was stirred with a 1:1 mixture of cyclohexane/ethyl acetate gave after filtration with suction, 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C The filtrate was concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C., 9.91 g of succinimide were initially charged in 415 ml of ethanol and admixed, a little at a time, with a total of 5.53 g of sodium borohydride. At this temperature, every 15 minutes 2 to 3 drops of 2N ethanolic hydrogen chloride were added dropwise over a period of 4½ hours. The mixture was subsequently acidified to pH 3 using more acid. The mixture was stirred at 0° C. for one hour and then neutralized with 1% strength ethanolic potassium hydroxide solution, stirred for a further 15 minutes and concentrated. The residue was taken up in water and extracted three times with dichloromethane. Drying over sodium sulphate and concentration gave 7.16 g (55% of theory) of γ-ethoxy-γ-butyrolactam. stirred for a further 15 minutes concentrated extracted three times with dichloromethane Drying over sodium sulphate and concentration

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

Procedure: 12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of concentrated sulphuric acid and 90 ml of glacial acetic acid were charged initially at 0° C. and admixed a little at a time with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-Up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, dried and evaporated. After some time, γ-2-hydroxyphenyl-γ-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained on evaporation was stirred with 1:1 mixture of cyclohexane/ethyl acetate and afforded on filtration with suction 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was evaporated. Recrystallization from dichloromethane/hexane gave a further 3.35 g (total 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam. For work-Up, the mixture was poured onto ice extracted three times with ethyl acetate the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution dried evaporated After some time, γ-2-hydroxyphenyl-γ-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase The residue obtained on evaporation

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

Procedure: At 0° C., 6.45 g of γ-ethoxy-γ-butyrolactam and 50 ml of concentrated sulphuric acid were charged initially, and 18.8 ml of benzene were added. After thawing, the mixture was stirred at room temperature for 4 days. For work-up, the mixture was poured onto ice, extracted three times with ethyl acetate and the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, dried and evaporated. 8.1 g (100% of theory) of γ-phenyl-γ-butyrolactam were obtained. For work-up, the mixture was poured onto ice extracted three times with ethyl acetate the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution dried evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C., 9.91 g of succinimide were charged initially in 415 ml of ethanol and a total of 5.53 g of sodium boranate was added a little at a time. At this temperature, every 15 minutes 2 to 3 drops of 2N ethanolic hydrogen chloride were added dropwise over 4½ hours. Subsequently, the mixture was acidified to pH 3 using more acid. After stirring for 1 hour at 0° C., the mixture was neutralized using 1% strength ethanolic potassium hydroxide solution and the mixture was stirred for a further 15 minutes and evaporated. The residue was taken up in water and extracted three times with dichloromethane. After drying over sodium sulphate and concentrating, 7.16 g (55% of theory) of γ-ethoxy-γ-butyrolactam were obtained. the mixture was stirred for a further 15 minutes evaporated extracted three times with dichloromethane After drying over sodium sulphate concentrating

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

Procedure: At 0° C., 6.45 g of γ-ethoxy-γ-butyrolactam and 50 ml of concentrated sulphuric acid were charged initially, and 18.8 ml of benzene were added. After thawing, the mixture was stirred at room temperature for 4 days. For work-up, the mixture was poured onto ice, extracted three times with ethyl acetate and the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, dried and evaporated. 8.1 g (100% of theory) of γ-phenyl-γ-butyrolactam were obtained. For work-up, the mixture was poured onto ice extracted three times with ethyl acetate the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution dried evaporated

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

Procedure: WO 93/09120 describes a process for the preparation of dimiracetam (2,5-dioxohexa-hydro-1H-pyrrolo[1,2-a]imidazole) 1 and related compounds. 5-Ethoxy-2-pyrrolidone is reacted with benzyl carbamate with a catalytic amount of p-toluenesulfonic acid to give 5-benzyloxycarbonylamino-2-pyrrolidone. This compound is then deprotonated at the pyrrolidine nitrogen with sodium hydride in acetonitrile, and reacted with ethyl bromoacetate to give ethyl 5-benzyloxycarbonylamino-2-oxo-1-pyrrolidine-acetate 2. Cyclization can then be performed after cleavage of the ethyl ester and/or the benzyloxycarbonyl protecting group in the presence of a variety of cyclizing agents.