反应详情

To 1.0 g (8.69 mmol) of (R)-(−)-5-(Hydroxymethyl)-2-pyrrolidinone and triethylamine (2.42 ml, 17.37 mmol) in 80 mL of methylene chloride at 0° C. was added 1.01 mL (13.03 mmol) of methanesulfonyl chloride. The resultant solution was stirred at 0° C. for 1 hour. The solvent was removed. Silica gel chromatography using (10:1 ethyl acetate/methanol) gave 1.54 g (92%) of methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester as an off-white solid that was used in the next step. Rf=0.21 (10:1 ethyl acetate/methanol). 1H NMR (400 MHz, CDCl3): δ 1.82–1.88 (m, 1H), 2.25–2.40 (m, 3H), 3.06 (s, 3H), 3.98–4.02 (m, 1H), 4.05–4.09 (dd, J=10.2, 7.1 Hz 1H), 4.22–4.25 (dd, J=9.1, 3.7 Hz 1H), 6.96 (bs, 1H). To 150 mg (0.40 mmol) of 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-H-quinolin-2-one, potassium carbonate (55 mg, 0.40 mmol), and and catalytic KI in 5 mL of DMF was added methanesulfonic acid 5-oxo-pyrrolidin-2-ylmethyl ester (92 mg, 0.47 mmol) The suspension was heated to 70° C. for 16 hours. The reaction was diluted with methylene chloride and washed three times with water, twice with brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (9:1 ethyl acetate/methanol) gave 30 mg (16%) of the title compound, a white foam. Rf=0.20 (9:1 ethyl acetate/methanol). MS (M+H)+=477.2; 1H NMR (400 MHz, CDCl3): δ 1.45–1.60 (m, 2H), 1.65–1.78 (m, 1H), 1.90–2.15 (m, 5H), 2.18–2.30 (m, 3H), 2.36–2.41 (dd, J=13.1, 6.7 Hz, 1H), 2.53–2.57 (t, J=7.4 Hz, 2H), 2.75–2.80 (m, 3H), 3.03–3.06 (m, 1H), 3.14 (s, 3H), 3.45–3.49 (m, 2H), 3.53 (s, 3H), 3.67–3.75 (m, 2H), 6.08 (bs, 1H), 6.50 (s, 1H), 6.66 (s, 1H), 7.24–7.36 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 21.2, 25.3, 25.5, 27.0, 29.7, 31.8, 45.3, 52.5, 55.5, 56.2, 61.5, 72.0, 109.9, 116.1, 127.3, 128.1, 129.4, 133.6, 140.4, 152.9, 170.0, 178.0. 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.

1. customThe solvent was removed