[(3S)-2-oxopyrrolidin-3-yl] methanesulfonate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Suspend the product of Example 1 (8 g., 79.2 mmol.) in dry methylene chloride (30 ml.) and cool to 0° C. Treat the suspension sequentially with dry triethylamine (16 ml., 118.8 mmol.) and methane sulfonyl chloride (6.74 ml., 87.12 mmol.). Stir at 5°-10° C. for 1.5 hours, and subject the mixture to flash chromatography using acetone (5-10%) in dichloromethane to yield the title compound as a white solid.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Suspend the product of Example 1 (8 g., 79.2 mmol.) in dry methylene chloride (30 ml.) and cool to 0° C. Treat the suspension sequentially with dry triethylamine (16 ml., 118.8 mmol.) and methane sulfonyl chloride (6.74 ml., 87.12 mmol.). Stir at 5°-10° C. for 1.5 hours, and subject the mixture to flash chromatography using acetone (5-10%) in dichloromethane to yield the title compound as a white solid.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Suspend the product of Example 1 (8 g., 79.2 mmol.) in dry methylene chloride (30 ml.) and cool to 0° C. Treat the suspension sequentially with dry triethylamine (16 ml., 118.8 mmol.) and methane sulfonyl chloride (6.74 ml., 87.12 mmol.). Stir at 5°-10° C. for 1.5 hours, and subject the mixture to flash chromatography using acetone (5-10%) in dichloromethane to yield the title compound as a white solid.

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 250 mL round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (2) (4.76 mmol, 852 mg) and 5-methoxyspiro[indene-2,4′-piperidin]-1(3H)-one (3) (4.32 mmol, 1.00 g) in DIEA (17.29 mmol, 3.02 mL) and acetonitrile (20 mL). The solution was then heated to 85° C. for 90 min. The reaction was concentrated in vacuo and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (1.05 g, 77% yield). Calculated MS=306.2. found MS (ESI) m/e 307.3 (M+H+); HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.253 min. The reaction was concentrated in vacuo and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 10 mL microwave vial containing methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (0.56 mmol, 100 mg) and (4-chloro-phenyl)-piperidin-4-yl-methanone (0.56 mmol, 125 mg) in DIEA (2.8 mmol, 0.5 mL) was heated to 85° C. for 105 min. The diisopropylethylamine was decanted off and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (53 mg, 31% yield). MS (ESI) m/e 307.3 (M+H+), calculated 306.2; HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.506 min. The diisopropylethylamine was decanted off flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 10 mL microwave vial was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (4.97 mmol, 890 mg) and (4-fluoro-phenyl)-piperidin-4-yl-methanone hydrochloride (4.97 mmol, 1.21 g) in DIEA (24.8 mmol, 5 mL) was heated to 85° C. for 105 min. The DIEA was decanted and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (112 mg, 7.8% yield). MS (ESI) m/e 291.2 (M+H+), calculated 290.33; HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.303 min. The DIEA was decanted flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate

反応条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 1 L round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (prepared according to procedure in Eur. Pat. Appl., 257602, 2 Mar. 1988) (18.75 mmol, 3.36 g) and (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone (18.75 mmol, 4.37 g) in DIEA (75 mmol, 13.1 mL) and acetonitrile (100 mL). The reaction mixture was heated at 85° C. for 4 hours. The reaction was evaporated under a vacuum and silica gel flash column chromatography was performed on the remaining residue eluting with ethyl acetate to 20% MeOH/ethyl acetate to provide the title compound as a white solid (4 g, 67.4% yield). Calculated for C18H24N2O3 MS=316.4036. found MS (ESI) m/e 317.1863 (M+H+); 1H NMR (400 MHz, MeOD) δ ppm 1.69-1.89 (m, 4H) 2.08-2.21 (m, 1H) 2.24-2.30 (m, 1H) 2.44-2.56 (m, 1H) 2.73-2.84 (m, 1H) 2.84-2.92 (m, 1H) 3.08-3.17 (m, 1H) 3.30-3.42 (m, 6H) 3.45-3.54 (m, 1H) 3.90 (s, 3H) 6.95-7.04 (m, 1H) 7.72-7.81 (m, 1H) 7.83-7.90 (m, 1H); analytical RP-HPLC retention time=4.67 min. The reaction was evaporated under a vacuum and silica gel flash column chromatography eluting with ethyl acetate to 20% MeOH/ethyl acetate