(5-oxopyrrolidin-2-yl)methyl methanesulfonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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: An ice cold solution of 5-(hydroxymethyl)pyrrolidin-2-one (1.5 g, 13 mmol) prepared from 2-pyrrolidone-5-carboxylic acid (Valesinas et al., J. Org. Chem. 1992, 57, 2156-2160) in 20 mL of dichloromethane was treated with triethylamine (2.4 g, 23.5 mmol) and methylsulfonyl chloride (2.2 g, 19 mmol). The resulting solution was stirred at room temperature for 18 h. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated under reduced pressure. The crude, oily material was purified by chromatography (silica gel; 10% methanol in chloroform) to give 2.1 g of 5-(methanesulfonyloxymethyl)pyrrolidin-2-one as an oil which solidified upon addition of ether. The reaction mixture was filtered to remove triethylamine hydrochloride the filtrate was evaporated under reduced pressure The crude, oily material was purified by chromatography (silica gel; 10% methanol in chloroform)

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

Procedure: 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. The solvent was removed