4-propylpyrrolidin-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:; See reaction.notes.procedure_details.

Procedure: In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (1 eq, 0.69 mmol, 170 mg), propionaldehyde (1.4 eq, 0.966 mmol, 56 mg, 71 μl), acetic acid (0.3 ml) and dioxane (4 ml) was heated at 65° C. during 40 h. After cooling to room temperature, the solvent was removed under vacuum and the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4) to give of 1-[(2-propyl)-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 94 (65 mg, 33%). the solvent was removed under vacuum the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4)

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

Procedure: In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (1 eq, 0.69 mmol, 170 mg), propionaldehyde (1.4 eq, 0.966 mmol, 56 mg, 71 μl), acetic acid (0.3 ml) and dioxane (4 ml) was heated at 65° C. during 40 h. After cooling to room temperature, the solvent was removed under vacuum and the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4) to give of 1-[(2-propyl)-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 94 (65 mg, 33%). the solvent was removed under vacuum the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4)

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

Procedure: In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (1 eq, 0.69 mmol, 170 mg), propionaldehyde (1.4 eq, 0.966 mmol, 56 mg, 71 μl), acetic acid (0.3 ml) and dioxane (4 ml) was heated at 65° C. during 40 h. After cooling to room temperature, the solvent was removed under vacuum and the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4) to give of 1-[(2-propyl)-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 94 (65 mg, 33%). the solvent was removed under vacuum the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 250 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a mixture of 4-propyl-pyrrolidin-2-one (0.5 g, 3.9 mmol) and ethyl glyoxylate (50% in toluene, 2.4 ml, 11 mmol) in acetone is heated up at 60° C. for 6 h and another portion of ethyl glyoxylate (0.4 ml) is added. After 17 h at 50° C., the reaction mixture is concentrated in vacuo to give the crude hydroxy-(2-oxo-4-propyl-pyrrolidin-1-yl)-acetic acid ethyl ester a19 (2.02 g). It is used in the next step without any further purification. the reaction mixture is concentrated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 250 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a mixture of 4-propyl-pyrrolidin-2-one (0.5 g, 3.9 mmol) and ethyl glyoxylate (50% in toluene, 2.4 ml, 11 mmol) in acetone is heated up at 60° C. for 6 h and another portion of ethyl glyoxylate (0.4 ml) is added. After 17 h at 50° C., the reaction mixture is concentrated in vacuo to give the crude hydroxy-(2-oxo-4-propyl-pyrrolidin-1-yl)-acetic acid ethyl ester a19 (2.02 g). It is used in the next step without any further purification. the reaction mixture is concentrated in vacuo

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

Procedure: 4-propylpyrrolidin-2-one x1 (0.23 g, 1.1 eq, 1.8 mmol) is dissolved in absolute DMF (10 ml). Then 60% NaH (0.072 g, 1.1 eq, 1.8 mmol) is added at 0° C. in a flow of argon. The reaction mixture is stirred for 10 min at 0° C., and then for 10 min at room temperature to complete the reaction. The mixture is cooled again to 0° C. and a solution of 6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine x212 (0.59 g, 1 eq) in absolute DMF (5 ml) additionally containing 0.1 g (0.2 eq, 0.32 mmol) of tetrabutylammonium bromide is added dropwise to the obtained suspension. The reaction mixture is stirred for 4 h at 5° C., then overnight at room temperature. The DMF is evaporated at 45° C. under 1 mmHg. The residue is partitioned in 10% aqueous NaH2PO4/ethyl acetate mixture. The aqueous layer is subjected to additional extraction with ethyl acetate. The combined extracts are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel to afford 0.52 g of 1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x213. for 10 min at room temperature to complete the reaction The mixture is cooled again to 0° C. is added dropwise to the obtained suspension The reaction mixture is stirred for 4 h at 5° C. overnight at room temperature The DMF is evaporated at 45° C. under 1 mmHg The residue is partitioned in 10% aqueous NaH2PO4/ethyl acetate mixture The aqueous layer is subjected to additional extraction with ethyl acetate The combined extracts are dried with anhydrous sodium sulfate evaporated The residue is purified by chromatography on silicagel

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-propylpyrrolidin-2-one x1 (0.22 g, 1.1 eq with respect to x199, 1.7 mmol) is dissolved in absolute THF (10 ml). A 1.06 M solution of Li—HMDS in THF (1.76 ml, 1.1 eq, 1.87 mmol) is added at −78° C. in a flow of argon. The reaction mixture is stirred for 15 min at −30° C. and cooled again to −78° C. A solution of 7-(chloromethyl)-3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine x202 in absolute THF (10 ml) is added dropwise at this temperature. The reaction mixture is allowed to heat up slowly to room temperature. In order to complete the reaction, the reaction mixture is refluxed the next morning for 1 h, and then partitioned between saturated aqueous NH4Cl and ethyl acetate. The organic layer is dried with anhydrous sodium sulfate and evaporated. The product is purified by HPLC (water/acetonitrile) to afford 0.14 g of 1-{[3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x205 (0.14 g). cooled again to −78° C to heat up slowly to room temperature the reaction the reaction mixture is refluxed the next morning for 1 h partitioned between saturated aqueous NH4Cl and ethyl acetate The organic layer is dried with anhydrous sodium sulfate evaporated The product is purified by HPLC (water/acetonitrile)

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

Procedure: A solution of 4-propylpyrrolidin-2-one x1 (0.50 g, 3.93 mmol, 1 eq) and 2-chloro-5-(chloromethyl)pyridine x37 (0.64 g, 3.93 mmol, 1 eq) in acetonitrile (3 ml) is heated at 50° C. NaH (60% dispersion in oil, 158 mg, 3.93 mmol, 1 eq) and acetonitrile (5 ml) are added and the solution is stirred for 8 h at 50° C. The mixture is then poured on ice/water and the aqueous phase is extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 99/1/0.1 (v/v/v)) to afford 790 mg of 1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228. The mixture is then poured on ice/water the aqueous phase is extracted with CH2Cl2 The combined organic phases are dried over MgSO4 filtered concentrated to dryness The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 99/1/0.1 (v/v/v))

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

Procedure: A solution of indole x4 (117 mg, 1 eq, 1 mmol), 4-propylpyrrolidin-2-one 1 (127 mg, 1 eq, 1 mmol), 2-furaldehyde x5 (0.33 ml, 4 eq, 4 mmol) and (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate x6 (25 mg, 0.1 eq, 0.1 mmol) in acetonitrile (3 ml) is heated 30 minutes in a microwave apparatus (Biotage, 150 W, 130° C.). After cooling to room temperature, the solvent is removed under reduced pressure, and the crude mixture is purified by preparative chromatography on silicagel (CH2Cl2) leading to 1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one 153 as a brown solid. the solvent is removed under reduced pressure the crude mixture is purified by preparative chromatography on silicagel (CH2Cl2)

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

Procedure: 4-propylpyrrolidin-2-one x1 (0.23 g, 1.1 eq, 1.8 mmol) is dissolved in absolute DMF (10 ml). Then 60% NaH (0.072 g, 1.1 eq, 1.8 mmol) is added at 0° C. in a flow of argon. The reaction mixture is stirred for 10 min at 0° C., and then for 10 min at room temperature to complete the reaction. The mixture is cooled again to 0° C. and a solution of 6-bromo-7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine x212 (0.59 g, 1 eq) in absolute DMF (5 ml) additionally containing 0.1 g (0.2 eq, 0.32 mmol) of tetrabutylammonium bromide is added dropwise to the obtained suspension. The reaction mixture is stirred for 4 h at 5° C., then overnight at room temperature. The DMF is evaporated at 45° C. under 1 mmHg. The residue is partitioned in 10% aqueous NaH2PO4/ethyl acetate mixture. The aqueous layer is subjected to additional extraction with ethyl acetate. The combined extracts are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel to afford 0.52 g of 1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x213. for 10 min at room temperature to complete the reaction The mixture is cooled again to 0° C. is added dropwise to the obtained suspension The reaction mixture is stirred for 4 h at 5° C. overnight at room temperature The DMF is evaporated at 45° C. under 1 mmHg The residue is partitioned in 10% aqueous NaH2PO4/ethyl acetate mixture The aqueous layer is subjected to additional extraction with ethyl acetate The combined extracts are dried with anhydrous sodium sulfate evaporated The residue is purified by chromatography on silicagel