2-(2-oxopyrrolidin-1-yl)acetaldehyde

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2-Oxopyrrolidin-1-yl)acetaldehyde (2.00 g, 15.7 mmol) and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (2.00 g, 7.32 mmol) were combined in 1:1 dichloroethane/acetic acid (10 mL) and cooled under nitrogen to 0-5° C. Sodium trisacetoxyborohydride (3.10 g, 14.6 mmol) was added and the reaction was stirred for 15 min. Two additional portions of aldehyde (1.0 g, 7.8 mmol) plus sodium triacetoxyborohydride (1.65 g, 7.8 mmol) separated by 15 min. increments were made. The reaction mixture was evaporated in vacuo, dissolved in CH2Cl2, and treated with aqueous K2CO3 (5% w/v). After separating the layers, the aqueous phase was back-extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 0-3% MeOH in EtOAc to provide an oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); ES+ MS: 386 (M+H+). The reaction mixture was evaporated in vacuo dissolved in CH2Cl2 treated with aqueous K2CO3 (5% w/v) After separating the layers the aqueous phase was back-extracted twice with CH2Cl2 The combined organic phases were dried over MgSO4 filtered evaporated in vacuo purified on silica gel eluting with 0-3% MeOH in EtOAc to provide an oil

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2-Oxopyrrolidin-1-yl)acetaldehyde (2.00 g, 15.7 mmol) and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (2.00 g, 7.32 mmol) were combined in 1:1 dichloroethane/acetic acid (10 mL) and cooled under nitrogen to 0-5° C. Sodium trisacetoxyborohydride (3.10 g, 14.6 mmol) was added and the reaction was stirred for 15 min. Two additional portions of aldehyde (1.0 g, 7.8 mmol) plus sodium triacetoxyborohydride (1.65 g, 7.8 mmol) separated by 15 min. increments were made. The reaction mixture was evaporated in vacuo, dissolved in CH2Cl2, and treated with aqueous K2CO3 (5% w/v). After separating the layers, the aqueous phase was back-extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 0-3% MeOH in EtOAc to provide an oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); ES+ MS: 386 (M+H+). The reaction mixture was evaporated in vacuo dissolved in CH2Cl2 treated with aqueous K2CO3 (5% w/v) After separating the layers the aqueous phase was back-extracted twice with CH2Cl2 The combined organic phases were dried over MgSO4 filtered evaporated in vacuo purified on silica gel eluting with 0-3% MeOH in EtOAc to provide an oil

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

Procedure: A mixture of N-(2-Hydroxyethyl)-2-pyrrolidone (5.00 g, 38.8 mmol) and triacetoxyperiodinane (24.6 g, 58.0 mmol) in CH2Cl2 was stirred at ambient temperature for approximately 64 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with Et2O. After filtration of the solids, the mother liquor was evaporated in vacuo to provide the product as a crude oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m). The reaction mixture was evaporated in vacuo the residue was triturated with Et2O After filtration of the solids the mother liquor was evaporated in vacuo to provide the product as a crude oil

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

Procedure: A mixture of N-(2-Hydroxyethyl)-2-pyrrolidone (5.00 g, 38.8 mmol) and triacetoxyperiodinane (24.6 g, 58.0 mmol) in CH2Cl2 was stirred at ambient temperature for approximately 64 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with Et2O. After filtration of the solids, the mother liquor was evaporated in vacuo to provide the product as a crude oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m). The reaction mixture was evaporated in vacuo the residue was triturated with Et2O After filtration of the solids the mother liquor was evaporated in vacuo to provide the product as a crude oil

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

Procedure: (2-Oxopyrrolidin-1-yl)acetaldehyde and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate were treated in a manner similar to that described in Example 5, Step 1 to yield the product as an amber oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); HRMS calcd for C21H24FN3O3+H+: 386.1880. Found: 386.1880.

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

Procedure: (2-Oxopyrrolidin-1-yl)acetaldehyde and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate were treated in a manner similar to that described in Example 5, Step 1 to yield the product as an amber oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); HRMS calcd for C21H24FN3O3+H+: 386.1880. Found: 386.1880.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (0.87 mL, 10 mmol) was added dropwise to a solution of DMSO (0.71 mL, 10 mmol) in CH2Cl2 (7 mL) cooled to −78° C. After stirring 15 min at this temperature, 1-(2-hydroxyethyl)-2-pyrrolidinone (1 g, 7.7 mmol) was added dropwise. The mixture was stirred 30 min at −78° C. and Et3N (2.8 mL, 20 mmol) was added dropwise. After allowing the reaction to warm to rt, a solution of NaHCO3 was added and the mixture was extracted with CH2Cl2 (6×). The combined organic layers were dried and concentrated to give the product as an oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m). was added dropwise the reaction to warm to rt the mixture was extracted with CH2Cl2 (6×) The combined organic layers were dried concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (0.87 mL, 10 mmol) was added dropwise to a solution of DMSO (0.71 mL, 10 mmol) in CH2Cl2 (7 mL) cooled to −78° C. After stirring 15 min at this temperature, 1-(2-hydroxyethyl)-2-pyrrolidinone (1 g, 7.7 mmol) was added dropwise. The mixture was stirred 30 min at −78° C. and Et3N (2.8 mL, 20 mmol) was added dropwise. After allowing the reaction to warm to rt, a solution of NaHCO3 was added and the mixture was extracted with CH2Cl2 (6×). The combined organic layers were dried and concentrated to give the product as an oil: 1H NMR (CDCl3) δ 9.60 (1H, s), 4.16 (2H, s), 3.46 (2H, t, J=7 Hz), 2.45 (2H, t, J=8 Hz), 2.11 (2H, m). was added dropwise the reaction to warm to rt the mixture was extracted with CH2Cl2 (6×) The combined organic layers were dried concentrated

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)