3-methylpyrrolidin-2-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound, light yellow oil, MS: m/e=291.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and rac-3-methyl-pyrrolidin-2-one.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound, light yellow oil, MS: m/e=291.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and rac-3-methyl-pyrrolidin-2-one.

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an oven-dried 500 ml flask under argon was dissolved 3-methyl-2-pyrrolidinone (0.186 mol, 18.4 g) in 200 ml methylene chloride. To this solution was added Triethylamine (0.223 mol, 22.6 g), Dimethylaminopyridine (0.019 mol, 2.27 g), and t-Butyldimethylsilyl chloride (0.204 mol, 30.8 g). This mixture was stirred for 18 hrs at 20° C. after which time it was poured into 500 ml water, the organic layer separated, washed with water (2×100 ml), brine (100 ml), dried with MgSO4 and concentrated. Resulting crude oil was purified on 400 g silica (EtOAc/Hexanes) yielding 35.0 g (88%) of 1-[(1,1-dimethylethyl)(dimethyl)silyl]-3-methyl-2-pyrrolidinone a clear oil. LCMS (ESI+)=214 m/z (MH+). 1H NMR (400 MHz, CDCl3) δ 3.40-3.25 (m, 2H), 2.50-2.40 (m, 1H), 2.30-2.20 (m, 1H), 1.70-1.60 (m, 1H), 1.20-1.18 (d, 3H, J=7.06 Hz), 0.95 (s, 9H), 0.29-0.27 (d, 6H, J=6.70 Hz). the organic layer separated washed with water (2×100 ml), brine (100 ml) dried with MgSO4 concentrated Resulting crude oil was purified on 400 g silica (EtOAc/Hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: While 2 g of sodium hydride (60% oily) was being stirred in 50 ml of tetrahydrofuran, 5 g of 3-methyl-2-pyrrolidinone was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to not higher than 0° C., and 7.5 g of 4-methoxyphenyl isocyanate was added dropwise to the mixture, followed by stirring at the same temperature for 5 hours. Acetic acid was then added to the reaction mixture for neutralization, water was thereafter added to the mixture, and the solvent was distilled off in a vacuum. Water was added to the residue, and the precipitate was filtered off, giving 8.2 g of 3-methyl-1-(4-methoxyphenylcarbamoyl)-2-pyrrolidinone (yield 66%) having a melting point of 71° to 72° C. The reaction mixture was cooled to not higher than 0° C. by stirring at the same temperature for 5 hours was thereafter added to the mixture the solvent was distilled off in a vacuum Water was added to the residue the precipitate was filtered off

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: While 2 g of sodium hydride (60% oily) was being stirred in 50 ml of tetrahydrofuran, 5 g of 3-methyl-2-pyrrolidinone was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to not higher than 0° C., and 7.5 g of 4-methoxyphenyl isocyanate was added dropwise to the mixture, followed by stirring at the same temperature for 5 hours. Acetic acid was then added to the reaction mixture for neutralization, water was thereafter added to the mixture, and the solvent was distilled off in a vacuum. Water was added to the residue, and the precipitate was filtered off, giving 8.2 g of 3-methyl-1-(4-methoxyphenylcarbamoyl)-2-pyrrolidinone (yield 66%) having a melting point of 71° to 72° C. The reaction mixture was cooled to not higher than 0° C. by stirring at the same temperature for 5 hours was thereafter added to the mixture the solvent was distilled off in a vacuum Water was added to the residue the precipitate was filtered off

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a microwave vial equipped with magnetic stir bar, 6-bromo-2-[trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazole (3, 50 mg, 0.14 mmol) was added, Pd2(dba)3 (4.0 mg, 0.004 mmol), Xantphos (6.9 mg, 0.012 mmol) and CsCO3 (68 mg, 0.2 mmol), followed by 3-methylpyrrolidin-2-one (50 mg, 0.5 mmol). The reaction vial was then sealed with an aluminum cap, and placed under inert atmosphere by purging with N2. Dioxane (2 mL) was then introduced via a syringe. The reaction mixture was then subjected to sonication briefly to ensure mixing of the contents, and then heated in a commercial microwave oven at 150° C. for 60 min. The reaction mixture was cooled down to 23° C., and filtered to remove solids. The solvent was removed under vacuum, and from this, the residual mixture was purified by chromatography (SiO2, ethyl acetate (0-80%)/hexanes) to give the title compound as a pure product (28 mg, 55%). 1H NMR (300 MHz, CDCl3): δ=8.33 ppm (d, J=2.1 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.61 (dd, J=9.2, 2.1 Hz, 1H), 3.85 (m, 3H), 2.72 (m, 1H), 2.59 (m, 4H), 2.43 (m, 2H), 2.40 (m, 2H), 1.82 (m, 1H), 1.40-1.75 (m, 8H), 1.33 (d, J=7.1 Hz, 3H). MS (ESI, M+H+): 370.1. To a microwave vial equipped with magnetic stir bar cap by purging with N2 Dioxane (2 mL) was then introduced via a syringe The reaction mixture was then subjected to sonication briefly to ensure mixing of the contents The reaction mixture was cooled down to 23° C. filtered to remove solids The solvent was removed under vacuum from this, the residual mixture was purified by chromatography (SiO2, ethyl acetate (0-80%)/hexanes)

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a microwave vial equipped with magnetic stir bar, 6-bromo-2-[trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazole (3, 50 mg, 0.14 mmol) was added, Pd2(dba)3 (4.0 mg, 0.004 mmol), Xantphos (6.9 mg, 0.012 mmol) and CsCO3 (68 mg, 0.2 mmol), followed by 3-methylpyrrolidin-2-one (50 mg, 0.5 mmol). The reaction vial was then sealed with an aluminum cap, and placed under inert atmosphere by purging with N2. Dioxane (2 mL) was then introduced via a syringe. The reaction mixture was then subjected to sonication briefly to ensure mixing of the contents, and then heated in a commercial microwave oven at 150° C. for 60 min. The reaction mixture was cooled down to 23° C., and filtered to remove solids. The solvent was removed under vacuum, and from this, the residual mixture was purified by chromatography (SiO2, ethyl acetate (0-80%)/hexanes) to give the title compound as a pure product (28 mg, 55%). 1H NMR (300 MHz, CDCl3): δ=8.33 ppm (d, J=2.1 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.61 (dd, J=9.2, 2.1 Hz, 1H), 3.85 (m, 3H), 2.72 (m, 1H), 2.59 (m, 4H), 2.43 (m, 2H), 2.40 (m, 2H), 1.82 (m, 1H), 1.40-1.75 (m, 8H), 1.33 (d, J=7.1 Hz, 3H). MS (ESI, M+H+): 370.1. To a microwave vial equipped with magnetic stir bar cap by purging with N2 Dioxane (2 mL) was then introduced via a syringe The reaction mixture was then subjected to sonication briefly to ensure mixing of the contents The reaction mixture was cooled down to 23° C. filtered to remove solids The solvent was removed under vacuum from this, the residual mixture was purified by chromatography (SiO2, ethyl acetate (0-80%)/hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound, light yellow oil, MS: m/e=291.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and rac-3-methyl-pyrrolidin-2-one.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 150 mg, 0.522 mmol), (racemic) 3-methylpyrrolidin-2-one (75 mg, 0.719 mmol), K3PO4 (235 mg, 1.107 mmol) and CuI (10 mg, 0.053 mmol) in dioxane (1 ml) was heated to 120° C. for 135 min. The reaction mixture was cooled to room temperature, (1R,2R)-(−)-1,2-diaminocyclohexane (7 μL, 0.058 mmol) was added and the mixture was heated to 120° C. and stirred for 10 h. The reaction mixture was diluted with ethyl acetate and water, layers were separated and the aqueous layer was extracted with ethyl acetate. Organic layers were combined, washed with water and brine, dried using Na2SO4, filtered, evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as a brown solid. (UPLC-MS 3) tR 0.55 min; ESI-MS 306.1 [M+H]+. The reaction mixture was cooled to room temperature the mixture was heated to 120° C. were separated the aqueous layer was extracted with ethyl acetate washed with water and brine dried filtered evaporated The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM evaporated dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 12.7 grams (0.10 mole) of the ethyl imidate of 3-methyl-2-pyrrolidone in 30 milliliters of nitromethane was refluxed for four days with occasional distillation of ethanol by-product to bring the reflux temperature back to 100°C. Excess nitromethane (and ethanol present) then was evaporated under reduced pressure to give a dark oily residue. The residue was dissolved in ethyl acetate and passed through a Florisil column. Evaporation of the solvent from the filtrate left a crystalline residue, which when recrystallized from ether, gave 4.6 grams of 3-methyl-2-(nitromethylene)pyrrolidine, as a white solid, melting point: 47- 47.5°C. back to 100°C Excess nitromethane (and ethanol present) then was evaporated under reduced pressure to give a dark oily residue Evaporation of the solvent from the filtrate left a crystalline residue, which when recrystallized from ether