反应详情

温度

60 °C

To of (S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone (1.0 g 8.69 mmol) and triethylamine (1.21 ml, 8.69 mmol) in 50 mL of methylene chloride was added 1.66 g (8.69 mmol) of p-toluenesulfonyl chloride. The resultant solution was stirred at room temperature for 3 days. The organic solution was washed 1× with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (95:5 ethyl acetate/methanol) gave 1.65 g (71%) of toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as a white powder that was used in the next step. Rf=0.29 (95:5 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.65–1.80 (m, 1H), 2.15–2.35 (m, 3H), 2.42 (s, 3H), 3.80–3.90 (m, 2H), 3.95–4.05 (m, 1H), 6.53 (bs, 1H), 7.30–7.35 (d, J=8.4 Hz, 2H), 7.74–7.76 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 21.7, 22.8, 29.3, 52.6, 72.0, 127.9, 130.1, 132.4, 145.4, 178.0. To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and catalytic KI in 4 mL of DMF was added toluene-4-sulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (107 mg, 0.40 mmol) The suspension was heated to 60° C. for 16 hours. The reaction was diluted with methylene chloride and washed 3× with water, 2× with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (85:15 ethyl acetate/methanol) gave 19 mg (10%) of the title compound, a white foam. Rf=0.10 (85:15 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.30–1.60 (m, 3H), 1.78–1.82 (dd, J=12.6, 3.0 Hz, 1H), 1.98–2.16 (m, 6H), 2.20–2.30 (m, 1H), 2.50–2.52 (dd, J=12.6, 11.0 Hz, 1H), 2.54–2.58 (t, J=7.4 Hz, 2H), 2.68 (bs, 1H), 2.76–2.80 (t, J=7.4 Hz, 2H), 3.14 (s, 3H), 3.25–3.29 (m, 1H), 3.30 (bs, 1H), 3.37–3.40 (d, J=13.9 Hz, 1H), 3.49 (s, 3H), 3.62–3.66 (d, J=13.9 Hz, 1H), 3.86–3.91 (m, 1H), 6.49 (s, 1H), 6.50–6.55 (bs, 1H), 6.60 (s, 1H), 7.20–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 20.1, 25.0, 25.5, 27.3, 29.6, 29.9, 31.8, 45.6, 50.8, 53.7, 55.5, 56.3, 61.1, 72.4, 109.9, 116.28, 127.1, 128.3, 128.9, 133.6, 140.6, 152.9, 170.0, 177.5. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=203–207° C.).

1. washwashed 3× with water, 2× with brine
2. dry with materialdried over MgSO4
3. filtrationfiltered
4. concentrationconcentrated