1-aminopyrrolidin-2-one hydrochloride

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

Procedure: Stir a mixture of 2-(6-bromo-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g 4 Å unactivated sieves. Continue stirring an additional 13 h and add 10–15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. Add about 50 g 4 Å unactivated sieves Continue stirring an additional 13 h add 10–15 g silica filter the mixture through a 50 g silica plug Elute the silica plug with 3 L ethyl acetate concentrate in vacuo Collect the hydrazone precipitate by filtration and suction dry

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

Procedure: Stir a mixture of 2-(6-bromo-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g 4 Å unactivated sieves. Continue stirring an additional 13 h and add 10–15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. Add about 50 g 4 Å unactivated sieves Continue stirring an additional 13 h add 10–15 g silica filter the mixture through a 50 g silica plug Elute the silica plug with 3 L ethyl acetate concentrate in vacuo Collect the hydrazone precipitate by filtration and suction dry

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

Procedure: Place 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (200 g, 1.04 mol) then pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL), and extract with toluene (2×500 mL). Combine the organic layers, dry (sodium sulfate), filter and concentrate in vacuo to yield the subtitled compound as a dark oil (280 g, 98%). MS ES+ m/e 276 (M+1). 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×500 mL) Combine the organic layers, dry (sodium sulfate) filter concentrate in vacuo

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

Procedure: Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-(6-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (Preparation 1, Part A; 154 g, 0.66 mol), then pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×250 mL) Combine the organic layers, filter concentrate in vacuo

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

Procedure: Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-(6-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (Preparation 1, Part A; 154 g, 0.66 mol), then pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×250 mL) Combine the organic layers, filter concentrate in vacuo

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

Procedure: To a solution of 1-amino-pyrrolidine-2-one hydrochloride (3.8 g, 27.8 mmol) (WO 02/094833) add ethylbenzoylacetate (4.3 mL, 25 mmol) followed by pyridine (10 mL) at room temperature under nitrogen. Stir the mixture at room temperature for 20 hours and then, dilute with water (50 mL) and extract with toluene (2×50 mL). Dry the combined organic layers (MgSO4) and concentrate in vacuo to give a brown oil, 6.23 g, 82% yield, and treat with NaOEt (freshly prepared, 3.1 g, 45.4 mmol, 2 equiv) in toluene at 120° C. for 8 hours. Cool the mixture to room temperature and add water (100 mL) and concentrated HCl until a pH of 4 is reached. Extract the mixture with EtOAc (3×200 mL) and dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield. MS(ES+): m/z=257.1 (M+H)+ extract with toluene (2×50 mL) Dry the combined organic layers (MgSO4) concentrate in vacuo to give a brown oil, 6.23 g, 82% yield freshly prepared Cool the mixture to room temperature Extract the mixture with EtOAc (3×200 mL) dry (MgSO4) the combined organic layers concentrate in vacuo Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield

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

Procedure: To a solution of 1-amino-pyrrolidine-2-one hydrochloride (3.8 g, 27.8 mmol) (WO 02/094833) add ethylbenzoylacetate (4.3 mL, 25 mmol) followed by pyridine (10 mL) at room temperature under nitrogen. Stir the mixture at room temperature for 20 hours and then, dilute with water (50 mL) and extract with toluene (2×50 mL). Dry the combined organic layers (MgSO4) and concentrate in vacuo to give a brown oil, 6.23 g, 82% yield, and treat with NaOEt (freshly prepared, 3.1 g, 45.4 mmol, 2 equiv) in toluene at 120° C. for 8 hours. Cool the mixture to room temperature and add water (100 mL) and concentrated HCl until a pH of 4 is reached. Extract the mixture with EtOAc (3×200 mL) and dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield. MS(ES+): m/z=257.1 (M+H)+ extract with toluene (2×50 mL) Dry the combined organic layers (MgSO4) concentrate in vacuo to give a brown oil, 6.23 g, 82% yield freshly prepared Cool the mixture to room temperature Extract the mixture with EtOAc (3×200 mL) dry (MgSO4) the combined organic layers concentrate in vacuo Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield

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

Procedure: To a solution of 1-amino-pyrrolidine-2-one hydrochloride (3.8 g, 27.8 mmol) (WO 02/094833) add ethylbenzoylacetate (4.3 mL, 25 mmol) followed by pyridine (10 mL) at room temperature under nitrogen. Stir the mixture at room temperature for 20 hours and then, dilute with water (50 mL) and extract with toluene (2×50 mL). Dry the combined organic layers (MgSO4) and concentrate in vacuo to give a brown oil, 6.23 g, 82% yield, and treat with NaOEt (freshly prepared, 3.1 g, 45.4 mmol, 2 equiv) in toluene at 120° C. for 8 hours. Cool the mixture to room temperature and add water (100 mL) and concentrated HCl until a pH of 4 is reached. Extract the mixture with EtOAc (3×200 mL) and dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield. MS(ES+): m/z=257.1 (M+H)+ extract with toluene (2×50 mL) Dry the combined organic layers (MgSO4) concentrate in vacuo to give a brown oil, 6.23 g, 82% yield freshly prepared Cool the mixture to room temperature Extract the mixture with EtOAc (3×200 mL) dry (MgSO4) the combined organic layers concentrate in vacuo Purify the residue in a biotage system (eluent:CH2Cl2/MeOH 40:1) to obtain a yellow solid, 1.8 g, 36% yield

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

Procedure: Place 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 3-A; 200 g, 1.04 mol) and pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL) and extract with toluene (2×500 mL). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 280 g (98%) of the subtitled compound as a dark oil. MS ES+ m/e 276 (M+1). 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×500 mL) Combine the organic layers, dry (sodium sulfate) filter concentrate in vacuo

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

Procedure: Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×250 mL) Combine the organic layers, filter concentrate in vacuo

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

Procedure: Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×250 mL) Combine the organic layers, filter concentrate in vacuo

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

Procedure: Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet extract with toluene (2×250 mL) Combine the organic layers, filter concentrate in vacuo